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  • 1.
    Badi, Yusef Eamon
    et al.
    National Heart and Lung Institute, the Imperial College London, London, United Kingdom; NIHR Imperial Biomedical Research Centre, London, United Kingdom; Data Science Institute, Imperial College London, London, United Kingdom.
    Pavel, Ana B.
    Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, NY, New York, United States; Department of Biomedical Engineering, The University of Mississippi, Miss, Oxford, United States.
    Pavlidis, Stelios
    Data Science Institute, Imperial College London, London, United Kingdom.
    Riley, John H.
    GSK Respiratory Therapeutic Area Unit, Stevenage, United Kingdom.
    Bates, Stewart
    GSK Respiratory Therapeutic Area Unit, Stevenage, United Kingdom.
    Kermani, Nazanin Zounemat
    Data Science Institute, Imperial College London, London, United Kingdom.
    Knowles, Richard
    Knowles Consulting, Stevenage, United Kingdom.
    Kolmert, Johan
    Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden; Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Wheelock, Craig E.
    Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
    Worsley, Sally
    GSK Value Evidence and Outcomes, Brentford, United Kingdom.
    Uddin, Mohib
    Respiratory Global Medicines Development, AstraZeneca, Gothenburg, Sweden.
    Alving, Kjell
    Department of Women's and Children's Health: Paediatric Research, Uppsala University, Uppsala, Sweden.
    Bakke, Per S.
    Department of Clinical Science, University of Bergen, Bergen, Norway.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Caruso, Massimo
    Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
    Chanez, Pascal
    Aix-Marseille Universite, Assistance Publique des Hopitaux de Marseille, Clinic des Bronches, Allergies et Sommeil, Marseille, France.
    Fleming, Louise J.
    National Heart and Lung Institute, the Imperial College London, London, United Kingdom; NIHR Imperial Biomedical Research Centre, London, United Kingdom.
    Fowler, Stephen J.
    Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom; Manchester Academic Health Science Centre and NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
    Frey, Urs
    University Children's Hospital Basel, University of Basel, Basel, Switzerland.
    Howarth, Peter
    Clinical and Experimental Sciences and Human Development in Health, University of Southampton Faculty of Medicine, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Isle of Wight, Newport, United Kingdom.
    Horváth, Ildikó
    Department of Public Health, Semmelweis University, Budapest, Hungary.
    Krug, Norbert
    Fraunhofer ITEM, Hannover, Germany.
    Maitland-van der Zee, Anke H.
    Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, The Netherlands, Amsterdam, Netherlands.
    Montuschi, Paolo
    Pharmacology, Catholic University of the Sacred Heart, Agostino Gemelli University Hospital Foundation, Rome, Italy.
    Roberts, Graham
    Clinical and Experimental Sciences and Human Development in Health, University of Southampton Faculty of Medicine, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Isle of Wight, Newport, United Kingdom.
    Sanak, Marek
    Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.
    Shaw, Dominick E.
    University of Nottingham, NIHR Biomedical Research Centre, Nottingham, United Kingdom.
    Singer, Florian
    Division of Respiratory Medicine, Department of Paediatrics, Inselspital, University of Bern, Bern, Switzerland.
    Sterk, Peter J.
    Department of Respiratory Medicine, Amsterdam UMC, University of Amsterdam, The Netherlands, Amsterdam, Netherlands.
    Djukanovic, Ratko
    Clinical and Experimental Sciences and Human Development in Health, University of Southampton Faculty of Medicine, Southampton, United Kingdom; NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom; David Hide Asthma and Allergy Research Centre, St Mary's Hospital, Isle of Wight, Newport, United Kingdom.
    Dahlen, Sven-Eric
    Centre for Allergy Research, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden.
    Guo, Yi-Ke
    Data Science Institute, Imperial College London, London, United Kingdom.
    Chung, Kian Fan
    National Heart and Lung Institute, the Imperial College London, London, United Kingdom; NIHR Imperial Biomedical Research Centre, London, United Kingdom.
    Guttman-Yassky, Emma
    Laboratory of Inflammatory Skin Diseases, Department of Dermatology, Icahn School of Medicine at Mount Sinai, NY, New York, United States.
    Adcock, Ian M.
    National Heart and Lung Institute, the Imperial College London, London, United Kingdom; NIHR Imperial Biomedical Research Centre, London, United Kingdom.
    Mapping atopic dermatitis and anti–IL-22 response signatures to type 2–low severe neutrophilic asthma2022Ingår i: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 149, nr 1, s. 89-101Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.

    Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti–IL-22 (fezakinumab [FZ]) is enriched in severe asthma.

    Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.

    Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P <.05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P <.05) and particularly in neutrophilic and mixed granulocytic sputum (P <.05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways.

    Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.

  • 2. Baharom, Faezzah
    et al.
    Thomas, Saskia
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lepzien, Rico
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ahlm, Clas
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Infektionssjukdomar.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Smed-Sorensen, Anna
    Dendritic Cells and Monocytes with Distinct Inflammatory Responses Reside in Lung Mucosa of Healthy Humans2016Ingår i: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 196, nr 11, s. 4498-4509Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Every breath we take contains potentially harmful pathogens or allergens. Dendritic cells (DCs), monocytes, and macrophages are essential in maintaining a delicate balance of initiating immunity without causing collateral damage to the lungs because of an exaggerated inflammatory response. To document the diversity of lung mononuclear phagocytes at steady-state, we performed bronchoscopies on 20 healthy subjects, sampling the proximal and distal airways (bronchial wash and bronchoalveolar lavage, respectively), as well as mucosal tissue (endobronchial biopsies). In addition to a substantial population of alveolar macrophages, we identified subpopulations of monocytes, myeloid DCs (MDCs), and plasmacytoid DCs in the lung mucosa. Intermediate monocytes and MDCs were highly frequent in the airways compared with peripheral blood. Strikingly, the density of mononuclear phagocytes increased upon descending the airways. Monocytes from blood and airways produced 10-fold more proinflammatory cytokines than MDCs upon ex vivo stimulation. However, airway monocytes were less inflammatory than blood monocytes, suggesting a more tolerant nature. The findings of this study establish how to identify human lung mononuclear phagocytes and how they function in normal conditions, so that dysregulations in patients with respiratory diseases can be detected to elucidate their contribution to immunity or pathogenesis.

  • 3.
    Behndig, Annelie F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Duggan, Sean T
    Kelly, Frank J
    Mudway, Ian S
    Antioxidant responses to acute ozone challenge in the healthy human airway2009Ingår i: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 21, nr 11, s. 933-942Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the study was to characterize ozone-induced antioxidant responses in the human airway, including the resident leukocyte population, bronchial mucosa, and respiratory-tract lining fluids. Fifteen healthy subjects were exposed to 0.2 ppm ozone for 2 h, with bronchial wash, bronchoalveolar lavage, and biopsy sampling performed 6 h postexposure. Nasal lavage was also performed at multiple time points pre- and postexposure to evaluate responses during the actual exposure period. During the ozone challenge significant losses of nasal lining fluid urate and vitamin C were observed, which resolved 6 h postexposure. At this time point, increased numbers of neutrophils and enhanced concentrations of total glutathione, vitamin C, and urate were seen in bronchial airway lavages. In bronchoalveolar lavage, increased concentrations of total glutathione, vitamin C, urate, alpha-tocopherol, and extracellular superoxide dismutase occurred 6 h post ozone. In alveolar leukocytes significant losses of glutathione were observed, whereas ascorbate concentrations in endobronchial mucosal biopsies were elevated after ozone at this time. These data demonstrate that ozone elicits a broad spectrum of airway antioxidant responses, with initial losses of vitamin C and urate followed by a phase of augmentation of low-molecular-weight antioxidant concentrations at the air-lung interface. The temporal association between the increased RTLF glutathione following ozone and the loss of this thiol from macrophages implies a mobilization to the lung surface, despite the absence of a quantitative association. We propose this constitutes an acute protective adaptation to ozone.

  • 4.
    Behndig, Annelie F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Kelly, Frank J
    Mudway, Ian S
    Augmentation of respiratory tract lining fluid ascorbate concentrations through supplementation with vitamin C.2009Ingår i: Inhalation toxicology, ISSN 1091-7691, Vol. 21, nr 3, s. 250-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low molecular weight antioxidants within human respiratory tract lining fluids (RTLFs) have been proposed to confer protection against the damaging action of inhaled oxidant gases. There is therefore considerable interest in augmenting the concentrations of these moieties at the air-lung interface to protect against injury to the airway epithelium, the induction of inflammation, and declines in lung function. To determine whether RTLF ascorbate concentrations could be augmented through vitamin C supplementation, 24 healthy subjects with low plasma ascorbate (< 50 microM) were recruited into a double-blinded study. Subjects were divided into two groups, one receiving 60 mg/day of vitamin C for 14 days, the other placebo. On days 8 and 15 of this protocol, plasma, urine, and nasal lavage were obtained for ascorbate determination. After a 7-14-day non-intervention period, subjects previously on placebo received supplements containing 125 mg ascorbate, whilst the group previously on supplements received the placebo compound. This "switching" protocol was repeated three more times utilizing 250, 500, and 1000 mg/day ascorbate dosage regimens. Plasma ascorbate increased incrementally with vitamin C dose, as did its urinary excretion. Despite this, nasal lavage concentrations remained unaltered 24 h after the final supplement at all doses. Closer examination of this issue demonstrated that nasal lavage ascorbate concentrations increased acutely after ingestion of a high dose (1000 mg) supplement, peaking at 2-4 h (p < 0.05) before returning to baseline concentrations 24 h post-supplement. In the absence of a quantitative association between plasma and lavage ascorbate concentrations we contend that this response does not simply reflect ascorbate transudation from the plasma and interstitial space into the lavage medium. We therefore conclude that RTLF ascorbate can be augmented, albeit transiently, by oral vitamin C supplementation, with the transient nature of this response likely reflecting oxidative losses within the RTLF or its sequestration into airway cells.

  • 5.
    Behndig, Annelie F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Larsson, Nirina
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Brown, Joanna L
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Duggan, Sean T
    Dove, Rosamund E
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wilson, Susan J
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Kelly, Frank J
    Mudway, Ian S
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Proinflammatory doses of diesel exhaust in healthy subjects fail to elicit equivalent or augmented airway inflammation in subjects with asthma2011Ingår i: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 66, nr 1, s. 12-19Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure to diesel exhaust at concentrations consistent with roadside levels elicited an acute and active neutrophilic inflammation in the airways of healthy subjects. This response was absent in subjects with asthma, as was evidence supporting a worsening of allergic airway inflammation.

  • 6.
    Behndig, Annelie F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Linder, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Inflammatory Markers In Different COPD Subgroups Compared To Smokers And Healthy Controls2015Ingår i: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191, artikel-id A2884Artikel i tidskrift (Övrigt vetenskapligt)
  • 7.
    Behndig, Annelie F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Mirgorodskaya, Ekaterina
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Olin, Anna-Carin
    Surfactant Protein A in particles in exhaled air (PExA), bronchial lavage and bronchial wash - a methodological comparison2019Ingår i: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 20, nr 1, artikel-id 214Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: At present, there are few methods available for monitoring respiratory diseases affecting distal airways. Bronchoscopy is the golden standard for sampling the lower airways. The recently developed method for collecting non-volatile material from exhaled air – PExA (Particles in Exhaled air) is a promising new tool, but no direct comparison between the two methods has yet been performed. The aim of the present study was to compare sampling using PExA with bronchial wash (BW) representing the larger more proximal airways and broncho-alveolar lavage (BAL) representing the distal airways.

    Methods: 15 healthy non-smoking subjects (7 female/8 male), age 28 ± 4 years, with normal lung function were included in the study. PExA-sampling (2 × 250 ng particles) and bronchoscopy with BW (2 × 20 ml) and BAL (3 × 60 ml sterile saline) was performed. Albumin and Surfactant Protein A (SP-A) were analyzed with ELISA, and analyses of correlation were performed.

    Results: A significant association was found between BAL-fluid albumin and PExA-albumin (rs:0.65 p = 0.01). There was also an association between SP-A in PExA and BAL, when corrected for albumin concentration (rs:0.61, p = 0.015). When correlating concentrations of albumin and SP-A in bronchial wash and PExA respectively, no associations were found.

    Conclusions: This is the first direct comparison between the bronchoscopy-based BW/BAL-fluids and material collected using the PExA methodology. Both albumin and albumin-corrected SP-A concentrations were significantly associated between BAL and PExA, however, no such association was found in either marker between BW and PExA. These results indicate that the PExA method samples the distal airways. PExA is thus considered a new promising non-invasive assessment for monitoring of the distal airways.

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  • 8.
    Behndig, Annelie F
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, Ian S
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Kelly, Frank J
    Ascorbate and dehydroascorbate in nasal lining fluid following vitamin C supplementationManuskript (preprint) (Övrig (populärvetenskap, debatt, mm))
  • 9.
    Behndig, Annelie F.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Shanmuganathan, Karthika
    Whitmarsh, Laura
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Östersund Research Unit, Umeå University. .
    Brown, Joanna L.
    Frew, Anthony J.
    Kelly, Frank J.
    Mudway, Ian S.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wilson, Susan J.
    Effects of controlled diesel exhaust exposure on apoptosis and proliferation markers in bronchial epithelium: an in vivo bronchoscopy study on asthmatics, rhinitics and healthy subjects2015Ingår i: BMC Pulmonary Medicine, E-ISSN 1471-2466, Vol. 15, artikel-id 99Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Epidemiological evidence demonstrates that exposure to traffic-derived pollution worsens respiratory symptoms in asthmatics, but controlled human exposure studies have failed to provide a mechanism for this effect. Here we investigated whether diesel exhaust (DE) would induce apoptosis or proliferation in the bronchial epithelium in vivo and thus contribute to respiratory symptoms.

    Methods: Moderate (n = 16) and mild (n = 16) asthmatics, atopic non-asthmatic controls (rhinitics) (n = 13) and healthy controls (n = 21) were exposed to filtered air or DE (100 μg/m 3 ) for 2 h, on two separate occasions. Bronchial biopsies were taken 18 h post-exposure and immunohistochemically analysed for pro-apoptotic and anti-apoptotic proteins (Bad, Bak, p85 PARP, Fas, Bcl-2) and a marker of proliferation (Ki67). Positive staining was assessed within the epithelium using computerized image analysis.

    Results: No evidence of epithelial apoptosis or proliferation was observed in healthy, allergic or asthmatic airways following DE challenge.

    Conclusion: In the present study, we investigated whether DE exposure would affect markers of proliferation and apoptosis in the bronchial epithelium of asthmatics, rhinitics and healthy controls, providing a mechanistic basis for the reported increased airway sensitivity in asthmatics to air pollutants. In this first in vivo exposure investigation, we found no evidence of diesel exhaust-induced effects on these processes in the subject groups investigated.

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  • 10.
    Behndig, Annelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, IS
    Brown, JL
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Duggan, ST
    Wilson, SJ
    Boman, C
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik, Energiteknik och termisk processkemi.
    Cassee, FR
    Frew, AJ
    Kelly, FJ
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.2006Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 27, nr 2, s. 359-365Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.

  • 11.
    Behndig, Annelie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, IS
    Brown, JL
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Duggan, ST
    Wilson, SJ
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik, Energiteknik och termisk processkemi.
    Cassee, FR
    Frew, AJ
    Kelly, FJ
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Airway antioxidant and inflammatory responses to diesel exhaust exposure in healthy humans.2006Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 27, nr 2, s. 359-365Artikel i tidskrift (Refereegranskat)
    Abstract [sv]

    Pulmonary cells exposed to diesel exhaust (DE) particles in vitro respond in a hierarchical fashion with protective antioxidant responses predominating at low doses and inflammation and injury only occurring at higher concentrations. In the present study, the authors examined whether similar responses occurred in vivo, specifically whether antioxidants were upregulated following a low-dose DE challenge and investigated how these responses related to the development of airway inflammation at different levels of the respiratory tract where particle dose varies markedly. A total of 15 volunteers were exposed to DE (100 microg x m(-3) airborne particulate matter with a diameter of <10 microm for 2 h) and air in a double-blinded, randomised fashion. At 18 h post-exposure, bronchoscopy was performed with lavage and mucosal biopsies taken to assess airway redox and inflammatory status. Following DE exposure, the current authors observed an increase in bronchial mucosa neutrophil and mast cell numbers, as well as increased neutrophil numbers, interleukin-8 and myeloperoxidase concentrations in bronchial lavage. No inflammatory responses were seen in the alveolar compartment, but both reduced glutathione and urate concentrations were increased following diesel exposure. In conclusion, the lung inflammatory response to diesel exhaust is compartmentalised, related to differing antioxidant responses in the conducting airway and alveolar regions.

  • 12.
    Bosson, Jenny A
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Helleday, Ragnberth
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Kelly, Frank J.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, Ian S.
    Peripheral blood neutrophilia as a biomarker of ozone-induced pulmonary inflammation2013Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 8, nr 12, artikel-id e81816Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Ozone concentrations are predicted to increase over the next 50 years due to global warming and the increased release of precursor chemicals. It is therefore urgent that good, reliable biomarkers are available to quantify the toxicity of this pollutant gas at the population level. Such a biomarker would need to be easily performed, reproducible, economically viable, and reflective of ongoing pathological processes occurring within the lung.

    METHODOLOGY: We examined whether blood neutrophilia occurred following a controlled ozone challenge and addressed whether this could serve as a biomarker for ozone-induced airway inflammation. Three separate groups of healthy subjects were exposed to ozone (0.2 ppm, 2h) and filtered air (FA) on two separate occasions. Peripheral blood samples were collected and bronchoscopy with biopsy sampling and lavages was performed at 1.5h post exposures in group 1 (n=13), at 6h in group 2 (n=15) and at 18h in group 3 (n=15). Total and differential cell counts were assessed in blood, bronchial tissue and airway lavages.

    RESULTS: In peripheral blood, we observed fewer neutrophils 1.5h after ozone compared with the parallel air exposure (-1.1±1.0x10(9) cells/L, p<0.01), at 6h neutrophil numbers were increased compared to FA (+1.2±1.3x10(9) cells/L, p<0.01), and at 18h this response had fully attenuated. Ozone induced a peak in neutrophil numbers at 6h post exposure in all compartments examined, with a positive correlation between the response in blood and bronchial biopsies.

    CONCLUSIONS: These data demonstrate a systemic neutrophilia in healthy subjects following an acute ozone exposure, which mirrors the inflammatory response in the lung mucosa and lumen. This relationship suggests that blood neutrophilia could be used as a relatively simple functional biomarker for the effect of ozone on the lung.

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  • 13.
    Bosson, Jenny
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Barath, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie F
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Ädelroth, Ellinor
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Diesel exhaust exposure enhances the ozone-induced airway inflammation in healthy humans2008Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 31, nr 6, s. 1234-1240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Exposure to particulate matter and ozone cause adverse airway reactions. Individual pollutant effects are often addressed separately, despite coexisting in ambient air. The present investigation was performed to study the effects of sequential exposures to diesel exhaust (DE) and ozone on airway inflammation in human subjects. Healthy subjects underwent bronchoscopy with bronchoalveolar lavage (BAL) and bronchial wash (BW) sampling on two occasions. Once following a DE exposure (with 300 mug.m(-3) particles with a 50% cut-off aerodynamic diameter of 10 mum) with subsequent exposure to O(3) (0.2 ppm) 5 h later. The other bronchoscopy was performed after a filtered air exposure followed by an ozone exposure, using an identical protocol. Bronchoscopy was performed 24 h after the start of the initial exposure. Significant increases in neutrophil and macrophage numbers were found in BW after DE followed by ozone exposure versus air followed by ozone exposure. DE pre-exposure also raised eosinophil protein X levels in BAL compared with air. The present study indicates additive effects of diesel exhaust on the ozone-induced airway inflammation. Together with similar results from a recent study with sequential diesel exhaust and ozone exposures, the present data stress a need to consider the interaction and cumulative effects of different air pollutants.

  • 14.
    Carlsen, Hanne Krage
    et al.
    Section of Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 16A, Gothenburg, Sweden.
    Haga, Susanna Lohman
    Section of Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 16A, Gothenburg, Sweden.
    Olsson, David
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Modig, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Meister, Kadri
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Forsberg, Bertil
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Olin, Anna-Carin
    Section of Occupational and Environmental Medicine, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 16A, Gothenburg, Sweden.
    Birch pollen, air pollution and their interactive effects on airway symptoms and peak expiratory flow in allergic asthma during pollen season: a panel study in Northern and Southern Sweden2022Ingår i: Environmental Health, E-ISSN 1476-069X, Vol. 21, nr 1, artikel-id 63Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Evidence of the role of interactions between air pollution and pollen exposure in subjects with allergic asthma is limited and need further exploration to promote adequate preventive measures. The objective of this study was to assess effects of exposure to ambient air pollution and birch pollen on exacerbation of respiratory symptoms in subjects with asthma and allergy to birch.

    Methods: Thirty-seven subjects from two Swedish cities (Gothenburg and Umeå) with large variation in exposure to both birch-pollen and air pollutants, participated in the study. All subjects had confirmed allergy to birch and self-reported physician-diagnosed asthma. The subjects recorded respiratory symptoms such as rhinitis or eye irritation, dry cough, dyspnoea, the use of any asthma or allergy medication and peak respiratory flow (PEF), daily for five consecutive weeks during two separate pollen seasons and a control season without pollen. Nitrogen oxides (NOx), ozone (O3), particulate matter (PM2.5), birch pollen counts, and meteorological data were obtained from an urban background monitoring stations in the study city centres. The data were analysed using linear mixed effects models.

    Results: During pollen seasons all symptoms and medication use were higher, and PEF was reduced in the subjects. In regression analysis, exposure to pollen at lags 0 to 2 days, and lags 0 to 6 days was associated with increased ORs of symptoms and decreased RRs for PEF. Pollen and air pollution interacted in some cases; during low pollen exposure, there were no associations between air pollution and symptoms, but during high pollen exposure, O3 concentrations were associated with increased OR of rhinitis or eye irritation, and PM2.5 concentrations were associated with increased ORs of rhinitis or eye irritation, dyspnea and increased use of allergy medication. Conclusions: Pollen and air pollutants interacted to increase the effect of air pollution on respiratory symptoms in allergic asthma. Implementing the results from this study, advisories for individuals with allergic asthma could be improved, minimizing the morbidities associated with the condition.

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  • 15. Carlsen, Hanne Krage
    et al.
    Koca, Hatice
    Lohman-Haga, Susanna
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Occupational and environmental medicine, School of Public Health and Community Medicine Sahlgrenska Academy, Sweden.
    Modig, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för hållbar hälsa.
    Olin, Anna-Carin
    In allergic individuals, FENO50 is associated with O3 and PM10 during pollen season2020Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 56Artikel i tidskrift (Övrigt vetenskapligt)
  • 16.
    Dove, Rosamund E.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. MRC-PHE Centre for Environment and Health, School of Biomedical Sciences, Kings College London, London, UK.
    Leong-Smith, Pheneatia
    Roos-Engstrand, Ester
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Shah, Mittal
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, Ian S.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Cigarette smoke-induced induction of antioxidant enzyme activities in airway leukocytes is absent in active smokers with COPD2015Ingår i: European Clinical Respiratory Journal, ISSN 2001-8525, Vol. 2, artikel-id 27837Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Oxidative injury to the airway has been proposed as an important underlying mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). As the extent of oxidant-mediated damage is dependent on the endogenous antioxidant defences within the airways, we examined whether COPD was associated with deficiencies in the antioxidant network within the respiratory tract lining fluids (RTLFs) and resident airway leukocytes. We hypothesised that COPD would be associated with both basal depression of antioxidant defences and impaired adaptive antioxidant responses to cigarette smoke.

    METHODS: Low molecular weight and enzymatic antioxidants together with metal-handling proteins were quantified in bronchoalveolar lavage fluid and airway leukocytes, derived from current (n=9) and ex-smoking COPD patients (n=15), as well as from smokers with normal lung function (n=16) and healthy never smokers (n=13).

    RESULTS: Current cigarette smoking was associated with an increase in ascorbate and glutathione within peripheral RTLFs in both smokers with normal lung function compared with healthy never smokers and in COPD smokers compared with COPD ex-smokers. In contrast, intra-cellular antioxidant enzyme activities (glutathione peroxidase, glutathione reductase, and catalase) were only up-regulated in smokers with normal lung function compared with healthy never smokers and not in actively smoking COPD patients relative to COPD ex-smokers.

    CONCLUSIONS: We found no evidence of impaired basal antioxidant defences, within either the RTLFs or airway leukocytes in stable ex-smoking COPD patients compared with healthy never smoking controls. Current cigarette smoking induced an up-regulation of low molecular weight antioxidants in the RTLFs of both control subjects with normal lung function and patients with COPD. Importantly, the present data demonstrated a cigarette smoke-induced increase in intra-cellular antioxidant enzyme activities only within the smokers with normal lung function, implying that patients with COPD who continue to smoke will experience enhanced oxidative stress, prompting disease progression.

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  • 17.
    Eriksson Ström, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Kebede Merid, Simon
    Department of Clinical Sciences and Education, Karolinska Institute, Stockholm, Sweden.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Ringh, Mikael V.
    Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden; Center for Molecular Medicine, 5Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
    Hagemann-Jensen, Michael
    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
    Ekström, Tomas J.
    Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Melén, Erik
    Department of Clinical Sciences and Education, Karolinska Institute, Stockholm, Sweden; Sachs Children’s Hospital, Stockholm, Sweden.
    Chronic obstructive pulmonary disease is associated with epigenome-wide differential methylation in BAL lung cells2022Ingår i: American Journal of Respiratory Cell and Molecular Biology, ISSN 1044-1549, E-ISSN 1535-4989, Vol. 66, nr 6, s. 638-647Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    DNA methylation patterns in chronic pulmonary obstructive disease (COPD) might offer new insights into disease pathogenesis. To assess methylation profiles in the main COPD target organ, we performed an epigenome-wide association study on BAL cells. Bronchoscopies were performed in 18 subjects with COPD and 15 control subjects (ex- and current smokers). DNA methylation was measured using the Illumina MethylationEPIC BeadChip Kit, covering more than 850,000 CpGs. Differentially methylated positions (DMPs) were examined for 1) enrichment in pathways and functional gene relationships using the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology, 2) accelerated aging using Horvath's epigenetic clock, 3) correlation with gene expression, and 4) colocalization with genetic variation. We found 1,155 Bonferroni-significant (P < 6.74 × 10-8) DMPs associated with COPD, many with large effect sizes. Functional analysis identified biologically plausible pathways and gene relationships, including enrichment for transcription factor activity. Strong correlation was found between DNA methylation and chronological age but not between COPD and accelerated aging. For 79 unique DMPs, DNA methylation correlated significantly with gene expression in BAL cells. Thirty-nine percent of DMPs were colocalized with COPD-associated SNPs. To the best of our knowledge, this is the first epigenome-wide association study of COPD on BAL cells, and our analyses revealed many differential methylation sites. Integration with mRNA data showed a strong functional readout for relevant genes, identifying sites where DNA methylation might directly affect expression. Almost half of DMPs were colocated with SNPs identified in previous genome-wide association studies of COPD, suggesting joint genetic and epigenetic pathways related to disease.

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  • 18.
    Eriksson Ström, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Linder, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Division of CBRN Defence and Security, Swedish Defence Research Agency, Stockholm, Sweden.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Airway regulatory T cells are decreased in COPD with a rapid decline in lung function2020Ingår i: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 21, nr 1, artikel-id 330Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1.

    Methods: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry.

    Results: The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function.

    Conclusions: COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1.

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  • 19.
    Eriksson Ström, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Linder, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking2018Ingår i: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 19, artikel-id 244Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Cytotoxic lymphocytes are increased in the airways of COPD patients. Whether this increase is driven primarily by the disease or by smoking is not clear, nor whether it correlates with the rate of decline in lung function.

    Methods: Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study according to pre-determined criteria; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry.

    Results: In BAL fluid, the proportions of NK, iNKT and NKT-like cells all increased with pack-years. Within the COPD group, NK cells – but not iNKT or NKT-like cells – were significantly elevated also in subjects that had quit smoking. In contrast, current smoking was associated with a marked increase in iNKT and NKT-like cells but not in NK cells. Rate of lung function decline did not significantly affect any of the results.

    Conclusions: In summary, increased proportions of NK cells in BAL fluid were associated with COPD; iNKT and NKT-like cells with current smoking but not with COPD. Interestingly, NK cell percentages did not normalize in COPD subjects that had quit smoking, indicating that these cells might play a role in the continued disease progression seen in COPD even after smoking cessation.

    Trial registration: Clinicaltrials.gov identifier NCT02729220.

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  • 20.
    Eriksson Ström, Jonas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Linder, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Rapid decline in lung function in COPD is associated with decreased CD25brightFoxP3 regulatory T cells in BAL2019Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift (Övrigt vetenskapligt)
  • 21.
    Friberg, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Bosson, J.A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Muala, Ala
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Barath, S.
    Department of Respiratory Medicine and Allergy, Lund University Hospital, Lund, Sweden.
    Dove, R.
    Wolfson Institute for Population Health, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
    Glencross, D.
    MRC Centre for Environment and Health, Imperial College London, London, United Kingdom; NIHR Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, United Kingdom.
    Kelly, F.J.
    MRC Centre for Environment and Health, Imperial College London, London, United Kingdom; NIHR Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, United Kingdom.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Mudway, I.S.
    MRC Centre for Environment and Health, Imperial College London, London, United Kingdom; NIHR Health Protection Research Unit in Environmental Exposures and Health, Imperial College London, London, United Kingdom.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response2023Ingår i: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 20, nr 1, artikel-id 47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Diesel exhaust (DE) induces neutrophilia and lymphocytosis in experimentally exposed humans. These responses occur in parallel to nuclear migration of NF-κB and c-Jun, activation of mitogen activated protein kinases and increased production of inflammatory mediators. There remains uncertainty regarding the impact of DE on endogenous antioxidant and xenobiotic defences, mediated by nuclear factor erythroid 2-related factor 2 (Nrf2) and the aryl hydrocarbon receptor (AhR) respectively, and the extent to which cellular antioxidant adaptations protect against the adverse effects of DE.

    Methods: Using immunohistochemistry we investigated the nuclear localization of Nrf2 and AhR in the epithelium of endobronchial mucosal biopsies from healthy subjects six-hours post exposure to DE (PM10, 300 µg/m3) versus post-filtered air in a randomized double blind study, as a marker of activation. Cytoplasmic expression of cytochrome P450s, family 1, subfamily A, polypeptide 1 (CYP1A1) and subfamily B, Polypeptide 1 (CYP1B1) were examined to confirm AhR activation; with the expression of aldo–keto reductases (AKR1A1, AKR1C1 and AKR1C3), epoxide hydrolase and NAD(P)H dehydrogenase quinone 1 (NQO1) also quantified. Inflammatory and oxidative stress markers were examined to contextualize the responses observed.

    Results: DE exposure caused an influx of neutrophils to the bronchial airway surface (p = 0.013), as well as increased bronchial submucosal neutrophil (p < 0.001), lymphocyte (p = 0.007) and mast cell (p = 0.002) numbers. In addition, DE exposure enhanced the nuclear translocation of the AhR and increased the CYP1A1 expression in the bronchial epithelium (p = 0.001 and p = 0.028, respectively). Nuclear translocation of AhR was also increased in the submucosal leukocytes (p < 0.001). Epithelial nuclear AhR expression was negatively associated with bronchial submucosal CD3 numbers post DE (r = −0.706, p = 0.002). In contrast, DE did not increase nuclear translocation of Nrf2 and was associated with decreased NQO1 in bronchial epithelial cells (p = 0.02), without affecting CYP1B1, aldo–keto reductases, or epoxide hydrolase protein expression.

    Conclusion: These in vivo human data confirm earlier cell and animal-based observations of the induction of the AhR and CYP1A1 by diesel exhaust. The induction of phase I xenobiotic response occurred in the absence of the induction of antioxidant or phase II xenobiotic defences at the investigated time point 6 h post-exposures. This suggests DE-associated compounds, such as polycyclic aromatic hydrocarbons (PAHs), may induce acute inflammation and alter detoxification enzymes without concomitant protective cellular adaptations in human airways.

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  • 22.
    Frølich, Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Kumar, Abhinav
    Bicer, Elif Melis
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Mudway, Ian
    Age-related changes in the expression and oxidation of proteins in human respiratory tract lining fluids (RTLF)2019Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift (Övrigt vetenskapligt)
  • 23.
    Gouveia-Figueira, Sandra
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Nording, Malin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Fowler, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Relative and absolute reliability of measures of linoleic acid-derived oxylipins in human plasma2015Ingår i: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 121, nr Part B, s. 227-233Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Modern analytical techniques allow for the measurement of oxylipins derived from linoleic acid in biological samples. Most validatory work has concerned extraction techniques, repeated analysis of aliquots from the same biological sample, and the influence of external factors such as diet and heparin treatment upon their levels, whereas less is known about the relative and absolute reliability of measurements undertaken on different days. A cohort of nineteen healthy males were used, where samples were taken at the same time of day on two occasions, at least 7 days apart. Relative reliability was assessed using Lin's concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC). Absolute reliability was assessed by Bland-Altman analyses. Nine linoleic acid oxylipins were investigated. ICC and CCC values ranged from acceptable (0.56 [13-HODE]) to poor (near zero [9(10)- and 12(13)-EpOME]). Bland-Altman limits of agreement were in general quite wide, ranging from ±0.5 (12,13-DiHOME) to ±2 (9(10)-EpOME; log10 scale). It is concluded that relative reliability of linoleic acid-derived oxylipins varies between lipids with compounds such as the HODEs showing better relative reliability than compounds such as the EpOMEs. These differences should be kept in mind when designing and interpreting experiments correlating plasma levels of these lipids with factors such as age, body mass index, rating scales etc.

  • 24.
    Gouveia-Figueira, Sandra C.
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karimpour, Masoumeh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nording, Malin L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust2018Ingår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 1018, s. 62-69Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Experimental human exposure studies are an effective tool to study adverse health effects from acute inhalation of particulate matter and other constituents of air pollution. In this randomized and double-blinded crossover study, we investigated the systemic effect on bioactive lipid metabolite levels after controlled biodiesel exhaust exposure of healthy humans and compared it to filtered air at a separate exposure occasion. Eicosanoids and other oxylipins, as well as endocannabinoids and related lipids, were quantified in plasma from 14 healthy volunteers at baseline and at three subsequent time points (2, 6, and 24 h) after 1 h exposure sessions. Protocols based on liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) methods were developed to detect temporal changes in circulating levels after biodiesel exhaust exposure. The exhaust was generated by a diesel engine fed with an undiluted rapeseed methyl ester fuel. Among the 51 analyzed lipid metabolites, PGF(2 alpha), 9,10-DiHOME, 9-HODE, 5-HETE, 11-HETE, 12-HETE, and DEA displayed significant responsiveness to the biodiesel exhaust exposure as opposed to filtered air. Of these, 9-HODE and 5-HETE at 24 h survived the 10% false discovery rate cutoff (p < 0.003). Hence, the majority of the responsive lipid metabolites were monohydroxy fatty acids. We conclude that it is possible to detect alterations in circulating bioactive lipid metabolites in response to biodiesel exhaust exposure using LC-MS/MS, with emphasis on metabolites with inflammation related properties and implications on cardiovascular health and disease. These observations aid future investigations on air pollution effects, especially with regard to cardiovascular outcomes.

  • 25.
    Gouveia-Figueira, Sandra
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karimpour, Masoumeh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nording, Malin L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mass spectrometry profiling of oxylipins, endocannabinoids, and N-acylethanolamines in human lung lavage fluids reveals responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposure2017Ingår i: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 409, nr 11, s. 2967-2980Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The adverse effects of petrodiesel exhaust exposure on the cardiovascular and respiratory systems are well recognized. While biofuels such as rapeseed methyl ester (RME) biodiesel may have ecological advantages, the exhaust generated may cause adverse health effects. In the current study, we investigated the responses of bioactive lipid mediators in human airways after biodiesel exhaust exposure using lipidomic profiling methods. Lipid mediator levels in lung lavage were assessed following 1-h biodiesel exhaust (average particulate matter concentration, 159 mu g/m(3)) or filtered air exposure in 15 healthy individuals in a double-blinded, randomized, controlled, crossover study design. Bronchoscopy was performed 6 h post exposure and lung lavage fluids, i.e., bronchial wash (BW) and bronchoalveolar lavage (BAL), were sequentially collected. Mass spectrometry methods were used to detect a wide array of oxylipins (including eicosanoids), endocannabinoids, Nacylethanolamines, and related lipid metabolites in the collected BWand BAL samples. Six lipids in the human lung lavage samples were altered following biodiesel exhaust exposure, three from BAL samples and three from BW samples. Of these, elevated levels of PGE2, 12,13-DiHOME, and 13-HODE, all of which were found in BAL samples, reached Bonferroni-corrected significance. This is the first study in humans reporting responses of bioactive lipids following biodiesel exhaust exposure and the most pronounced responses were seen in the more peripheral and alveolar lung compartments, reflected by BAL collection. Since the responsiveness and diagnostic value of a subset of the studied lipid metabolites were established in lavage fluids, we conclude that our mass spectrometry profiling method is useful to assess effects of human exposure to vehicle exhaust.

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  • 26.
    Gouveia-Figueira, Sandra
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karimpour, Masoumeh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bosson, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pourazar, Jamshid
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nording, Malin L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Mass spectrometry profiling of oxylipins, endocannabinoids and N-acylethanolamines in human lung lavage fluids reveal responsiveness of prostaglandin E2 and associated lipid metabolites to biodiesel exhaust exposureManuskript (preprint) (Övrigt vetenskapligt)
  • 27.
    Gouveia-Figueira, Sandra
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karimpour, Masoumeh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Bosson, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Pourazar, Jamshid
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nording, Malin L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Effect of controlled exposure to biodiesel exhaust on human plasma bioactive lipid profilesManuskript (preprint) (Övrigt vetenskapligt)
  • 28. Gruber, Jan
    et al.
    Tang, Soon Yew
    Jenner, Andrew M
    Mudway, Ian
    Blomberg, Anders
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie
    Umeå universitet, Medicinsk fakultet, Folkhälsa och klinisk medicin, Lungmedicin.
    Kasiman, Katherine
    Lee, Chung-Yung J
    Seet, Raymond C S
    Zhang, Wenxia
    Chen, Christopher
    Kelly, Frank J
    Halliwell, Barry
    Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: avoiding artifacts and establishing real in vivo concentrations.2009Ingår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 11, nr 8, s. 1767-1776Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Urate is the terminal product of purine metabolism in primates, including humans. Urate is also an efficient scavenger of oxidizing species and is thought to be an important antioxidant in human body fluids. Allantoin, the major oxidation product of urate, has been suggested as a candidate biomarker of oxidative stress because it is not produced metabolically. Although urate is converted to allantoin under strongly alkaline pH, such conditions have been used in the past to facilitate extraction of allantoin. We evolved a method for the determination of allantoin concentrations in human plasma and serum by gas chromatography-mass spectrometry without such artifact. With this method, we show that alkaline conditions do indeed cause breakdown of urate, leading to significant overestimation of allantoin concentration in human samples. By using our alternative method, serum samples from 98 volunteers were analyzed, and allantoin levels were found to be significantly lower than was previously reported. The in vivo utility and sensitivity of our method was further evaluated in human nasal-lining fluids. We were able to demonstrate an ozone-induced increase in allantoin, in the absence of increases in either ascorbate or glutathione oxidation products.

  • 29.
    Gulyas, Miklos
    et al.
    Uppsala, Sweden.
    Mattsson, Johanna S. M.
    Uppsala, Sweden.
    Lindgren, Andrea
    Linkoping, Sweden.
    Sederholm, Christer
    Linkoping, Sweden.
    Ek, Lars
    Lund, Sweden.
    Lamberg, Kristina
    Uppsala, Sweden.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Holmberg, Erik
    Gothenburg, Sweden.
    Micke, Patrick
    Uppsala, Sweden.
    Bergman, Bengt
    Gothenburg, Sweden.
    COX-2 Expression Does Not Predict Outcome of Celecoxib in Addition to Standard Chemotherapy in Advanced Non-Small Cell Lung Cancer2015Ingår i: Journal of Thoracic Oncology, ISSN 1556-0864, E-ISSN 1556-1380, Vol. 10, nr 9, s. S541-S542Artikel i tidskrift (Övrigt vetenskapligt)
  • 30.
    Hansson, Alva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Uski, O.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Lindgren, Robert
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    García-López, Naxto
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Muala, Ala
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Reduced bronchoalveolar macrophage phagocytosis and cytotoxic effects after controlled short-term exposure to wood smoke in healthy humans2023Ingår i: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 20, nr 1, artikel-id 30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Exposure to wood smoke has been shown to contribute to adverse respiratory health effects including airway infections, but the underlying mechanisms are unclear. A preceding study failed to confirm any acute inflammation or cell influx in bronchial wash (BW) or bronchoalveolar lavage (BAL) 24 h after wood smoke exposure but showed unexpected reductions in leukocyte numbers. The present study was performed to investigate responses at an earlier phase, regarding potential development of acute inflammation, as well as indications of cytotoxicity.

    Methods: In a double-blind, randomised crossover study, 14 healthy participants were exposed for 2 h to filtered air and diluted wood smoke from incomplete wood log combustion in a common wood stove with a mean particulate matter concentration of 409 µg/m3. Bronchoscopy with BW and BAL was performed 6 h after exposure. Differential cell counts, assessment of DNA-damage and ex vivo analysis of phagocytic function of phagocytosing BAL cells were performed. Wood smoke particles were also collected for in vitro toxicological analyses using bronchial epithelial cells (BEAS-2B) and alveolar type II-like cells (A549).

    Results: Exposure to wood smoke increased BAL lactate dehydrogenase (LDH) (p = 0.04) and reduced the ex vivo alveolar macrophage phagocytic capacity (p = 0.03) and viability (p = 0.02) vs. filtered air. BAL eosinophil numbers were increased after wood smoke (p = 0.02), while other cell types were unaffected in BW and BAL. In vitro exposure to wood smoke particles confirmed increased DNA-damage, decreased metabolic activity and cell cycle disturbances.

    Conclusions: Exposure to wood smoke from incomplete combustion did not induce any acute airway inflammatory cell influx at 6 h, apart from eosinophils. However, there were indications of a cytotoxic reaction with increased LDH, reduced cell viability and impaired alveolar macrophage phagocytic capacity. These findings are in accordance with earlier bronchoscopy findings at 24 h and may provide evidence for the increased susceptibility to infections by biomass smoke exposure, reported in population-based studies.

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  • 31.
    Hansson, Alva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Uski, Oskari
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Thermochemical Energy Conversion Laboratory, Umeå University, Umeå, Sweden.
    Lindgren, Robert
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Thermochemical Energy Conversion Laboratory, Umeå University, Umeå, Sweden.
    Lopez, Naxto Garcia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Thermochemical Energy Conversion Laboratory, Umeå University, Umeå, Sweden.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Muala, Ala
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wood smoke effects on epithelial cell lines and human airway cells2019Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift (Övrigt vetenskapligt)
  • 32. Karlsson, Anna
    et al.
    Cirenajwis, Helena
    Ericson-Lindquist, Kajsa
    Brunnström, Hans
    Reuterswärd, Christel
    Jönsson, Mats
    Ortiz-Villalon, Cristian
    Hussein, Aziz
    Bergman, Bengt
    Vikström, Anders
    Monsef, Nastaran
    Branden, Eva
    Koyi, Hirsh
    de Petris, Luigi
    Micke, Patrick
    Patthey, Annika
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Planck, Maria
    Staaf, Johan
    A combined gene expression tool for parallel histological prediction and gene fusion detection in non-small cell lung cancer2019Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 9, artikel-id 5207Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accurate histological classification and identification of fusion genes represent two cornerstones of clinical diagnostics in non-small cell lung cancer (NSCLC). Here, we present a NanoString gene expression platform and a novel platform-independent, single sample predictor (SSP) of NSCLC histology for combined, simultaneous, histological classification and fusion gene detection in minimal formalin fixed paraffin embedded (FFPE) tissue. The SSP was developed in 68 NSCLC tumors of adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large-cell neuroendocrine carcinoma (LCNEC) histology, based on NanoString expression of 11 (CHGA, SYP, CD56, SFTPG, NAPSA, TTF-1, TP73L, KRT6A, KRT5, KRT40, KRT16) relevant genes for IHC-based NSCLC histology classification. The SSP was combined with a gene fusion detection module (analyzing ALK, RET, ROS1, MET, NRG1, and NTRK1) into a multicomponent NanoString assay. The histological SSP was validated in six cohorts varying in size (n = 11-199), tissue origin (early or advanced disease), histological composition (including undifferentiated cancer), and gene expression platform. Fusion gene detection revealed five EML4-ALK fusions, four KIF5B-RET fusions, two CD74-NRG1 fusion and three MET exon 14 skipping events among 131 tested cases. The histological SSP was successfully trained and tested in the development cohort (mean AUC = 0.96 in iterated test sets). The SSP proved successful in predicting histology of NSCLC tumors of well-defined subgroups and difficult undifferentiated morphology irrespective of gene expression data platform. Discrepancies between gene expression prediction and histologic diagnosis included cases with mixed histologies, true large cell carcinomas, or poorly differentiated adenocarcinomas with mucin expression. In summary, we present a proof-of-concept multicomponent assay for parallel histological classification and multiplexed fusion gene detection in archival tissue, including a novel platform-independent histological SSP classifier. The assay and SSP could serve as a promising complement in the routine evaluation of diagnostic lung cancer biopsies.

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  • 33. Kolmert, Johan
    et al.
    Gomez, Cristina
    Balgoma, David
    Sjodin, Marcus
    Bood, Johan
    Konradsen, Jon R.
    Ericsson, Magnus
    Thorngren, John-Olof
    James, Anna
    Mikus, Maria
    Sousa, Ana R.
    Riley, John H.
    Bates, Stewart
    Bakke, Per S.
    Pandis, Ioannis
    Caruso, Massimo
    Chanez, Pascal
    Fowler, Stephen J.
    Geiser, Thomas
    Howarth, Peter
    Horvath, Ildiko
    Krug, Norbert
    Montuschi, Paolo
    Sanak, Marek
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Shaw, Dominick E.
    Knowles, Richard G.
    Holweg, Cecile T. J.
    Wheelock, Asa M.
    Dahlen, Barbro
    Nordlund, Bjorn
    Alving, Kjell
    Hedlin, Gunilla
    Chung, Kian Fan
    Adcock, Ian M.
    Sterk, Peter J.
    Djukanovic, Ratko
    Dahlen, Sven-Erik
    Wheelock, Craig E.
    Urinary Leukotriene E-4 and Prostaglandin D-2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation A Clinical Observational Study2021Ingår i: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 203, nr 1, s. 37-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12-18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE(2) pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE(2) metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD(2) metabolite 2,3-dinor-11 beta-PGF(2 alpha). High concentrations of LTE4 and PGD(2) metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOARED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma.

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  • 34. Kumar, Abhinav
    et al.
    Bicer, Elif Melis
    Morgan, Anna Babin
    Pfeffer, Paul E.
    Monopoli, Marco
    Dawson, Kenneth A.
    Eriksson, Jonny
    Edwards, Katarina
    Lynham, Steven
    Arno, Matthew
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Somers, Graham
    Hassall, Dave
    Dailey, Lea Ann
    Forbes, Ben
    Mudway, Ian S.
    Enrichment of immunoregulatory proteins in the biomolecular corona of nanoparticles within human respiratory tract lining fluid2016Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 12, nr 4, s. 1033-1043Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    When inhaled nanoparticles deposit in the lungs, they transit through respiratory tract lining fluid (RTLF) acquiring a biomolecular corona reflecting the interaction of the RTLF with the nanomaterial surface. Label-free snapshot proteomics was used to generate semiquantitative profiles of corona proteins formed around silica (SiO2) and poly(vinyl) acetate (PVAc) nanoparticles in RTLF, the latter employed as an archetype drug delivery vehicle. The evolved PVAc corona was significantly enriched compared to that observed on SiO2 nanoparticles (698 vs. 429 proteins identified); however both coronas contained a substantial contribution from innate immunity proteins, including surfactant protein A, napsin A and complement (C1q and C3) proteins. Functional protein classification supports the hypothesis that corona formation in RTLF constitutes opsonisation, preparing particles for phagocytosis and clearance from the lungs. These data highlight how an understanding of the evolved corona is necessary for the design of inhaled nanomedicines with acceptable safety and tailored clearance profiles. From the Clinical Editor: Inhaled nanoparticles often acquire a layer of protein corona while they go through the respiratory tract. Here, the authors investigated the identity of these proteins. The proper identification would improve the understanding of the use of inhaled nanoparticles in future therapeutics. (C) 2016 Published by Elsevier Inc.

  • 35. Kumar, Abhinav
    et al.
    Bicer, Elif Melis
    Pfeffer, Paul
    Monopoli, Marco
    Dawson, Kenneth
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Dailey, Lea Ann
    Forbes, Ben
    Mudway, Ian
    Inhaled Nanoparticles Develop A Complex Protein Corona Of Biological Importance2015Ingår i: Journal of Aerosol Medicine, ISSN 1941-2711, E-ISSN 1941-2703, Vol. 28, nr 4, s. A3-A4Artikel i tidskrift (Övrigt vetenskapligt)
  • 36. Kumar, Abhinav
    et al.
    Bicer, Elif Melis
    Pfeffer, Paul
    Monopoli, Marco P.
    Dawson, Kenneth A.
    Eriksson, Jonny
    Edwards, Katarina
    Lynham, Steven
    Arno, Matthew
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Somers, Graham
    Hassall, Dave
    Dailey, Lea Ann
    Forbes, Ben
    Mudway, Ian
    Differences in the coronal proteome acquired by particles depositing in the lungs of asthmatic versus healthy humans2017Ingår i: Nanomedicine: Nanotechnology, Biology and Medicine, ISSN 1549-9634, E-ISSN 1549-9642, Vol. 13, nr 8, s. 2517-2521Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Most inhaled nanomedicines in development are for the treatment of lung disease, yet little is known about their interaction with the respiratory tract lining fluids (RTLFs). Here we combined the use of nano-silica, as a protein concentrator, with label-free snapshot proteomics (LC-MS/MS; key findings confirmed by ELISA) to generate a quantitative profile of the RTLF proteome and provided insight into the evolved corona; information that may be used in future to improve drug targeting to the lungs by inhaled medicines. The asthmatic coronal proteome displayed a reduced contribution of surfactant proteins (SP-A and B) and a higher contribution of alpha 1-antitrypsin. Pathway analysis suggested that asthmatic RTLFs may also be deficient in proteins related to metal handling (e.g. lactoferrin). This study demonstrates how the composition of the corona acquired by inhaled nanoparticles is modified in asthma and suggests depressed mucosal immunity even in mild airway disease.

  • 37.
    Larsson, Nirina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Brown, Joanna
    Stenfors, Nikolai
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wilson, Susan
    Mudway, Ian S
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie F
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Airway inflammatory responses to diesel exhaust in allergic rhinitics2013Ingår i: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 25, nr 3, s. 160-167Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Proximity to traffic, particularly to diesel-powered vehicles, has been associated with inducing and enhancing allergies. To investigate the basis for this association, we performed controlled exposures of allergic rhinitics to diesel exhaust (DE) at a dose known to be pro-inflammatory in healthy individuals.

    Objective: We hypothesized that diesel-exhaust exposure would augment lower airway inflammation in allergic rhinitics.

    Materials and methods: Fourteen allergic rhinitics were exposed in a double-blinded, randomized trial to DE (100 mu g/m(3) PM10) and filtered air for 2 h on separate occasions. Bronchoscopy with endobronchial mucosal biopsies and airway lavage was performed 18 h post-exposure, and inflammatory markers were assessed.

    Results: No evidence of neutrophilic airway inflammation was observed post-diesel, however, a small increase in myeloperoxidase was found in bronchoalveolar lavage (p = 0.032). We found no increases in allergic inflammatory cells. Reduced mast cell immunoreactivity for tryptase was observed in the epithelium (p = 0.013) parallel to a small decrease in bronchial wash stem cell factor (p = 0.033). Discussion and conclusion: DE, at a dose previously shown to cause neutrophilic inflammation in healthy individuals, induced no neutrophilic inflammation in the lower airways of allergic rhinitics, consistent with previous reports in asthmatics. Although there was no increase in allergic inflammatory cell numbers, the reduction in tryptase in the epithelium may indicate mast cell degranulation. However, this occurred in the absence of allergic symptoms. These data do not provide a simplistic explanation of the sensitivity in rhinitics to traffic-related air pollution. The role of mast cells requires further investigation.

  • 38.
    Larsson, Nirina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Lundström, Susanna
    Pinto, Rui
    Rankin, Greg
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Karimpour, Masoumeh
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wheelock, Craig
    Nording, Malin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Lipid mediator profiles differ between lung compartments in asthmatic and healthy humans2014Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 43, nr 2, s. 453-463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Oxylipins are oxidised fatty acids that can exert lipid mediator functions in inflammation, and several oxylipins derived from arachidonic acid are linked to asthma. This study quantified oxylipin profiles in different regions of the lung to obtain a broad-scale characterisation of the allergic asthmatic inflammation in relation to healthy individuals. Bronchoalveolar lavage fluid (BALF), bronchial wash fluid and endobronchial mucosal biopsies were collected from 16 healthy and 16 mildly allergic asthmatic individuals. Inflammatory cell counts, immunohistochemical staining and oxylipin profiling were performed. Univariate and multivariate statistics were employed to evaluate compartment-dependent and diagnosis-dependent oxylipin profiles in relation to other measured parameters. Multivariate modelling showed significantly different bronchial wash fluid and BALF oxylipin profiles in both groups ((RY)-Y-2[cum]=0.822 and Q(2)[cum]=0.759). Total oxylipin concentrations and five individual oxylipins, primarily from the lipoxygenase (LOX) pathway of arachidonic and linoleic acid, were elevated in bronchial wash fluid from asthmatics compared to that from healthy controls, supported by immunohistochemical staining of 15-LOX-1 in the bronchial epithelium. No difference between the groups was found among BALF oxylipins. In conclusion, bronchial wash fluid and BALF contain distinct oxylipin profiles, which may have ramifications for the study of respiratory diseases. Specific protocols for sampling proximal and distal airways separately should be employed for lipid mediator studies.

  • 39.
    Larsson, Nirina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Rankin, Greg
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bicer, Melis
    Roos-Engstrand, Ester
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, Ian
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Vitamin C transporters in the airways of healthy and asthmatic humansManuskript (preprint) (Övrigt vetenskapligt)
  • 40.
    Larsson, Nirina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Rankin, Gregory D.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bicer, Elif M.
    Roos-Engstrand, Ester
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Mudway, Ian S.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Identification of vitamin C transporters in the human airways: a cross-sectional in vivo study2015Ingår i: BMJ Open, E-ISSN 2044-6055, Vol. 5, nr 4, artikel-id e006979Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objectives: Vitamin C is an important low-molecular weight antioxidant at the air-lung interface. Despite its critical role as a sacrificial antioxidant, little is known about its transport into the respiratory tract lining fluid (RTLF), or the underlying airway epithelial cells. While several vitamin C transporters have been identified, such as sodium-ascorbate cotransporters (SVCT1/2) and glucose transporters (GLUTs), the latter transporting dehydroascorbate, knowledge of their protein distribution within the human lung is limited, in the case of GLUTs or unknown for SVCTs.

    Setting and participants: Protein expression of vitamin C transporters (SVCT1/2 and GLUT1-4) was examined by immunohistochemistry in endobronchial biopsies, and by FACS in airway leucocytes from lavage fluid, obtained from 32 volunteers; 16 healthy and 16 mild asthmatic subjects. In addition, antioxidant concentrations were determined in RTLF. The study was performed at one Swedish centre.

    Primary and secondary outcome measures: The primary outcome measure was to establish the location of vitamin C transporters in the human airways. As secondary outcome measures, RTLF vitamin C concentration was measured and related to transporter expression, as well as bronchial epithelial inflammatory and goblet cells numbers.

    Results: Positive staining was identified for SVCT1 and 2 in the vascular endothelium. SVCT2 and GLUT2 were present in the apical bronchial epithelium, where SVCT2 staining was predominately localised to goblet cells and inversely related to RTLF vitamin C concentrations.

    Conclusions: This experimental study is the first to demonstrate protein expression of GLUT2 and SVCT2 in the human bronchial epithelium. A negative correlation between SVCT2-positive goblet cells and bronchial RTLF vitamin C concentrations suggests a possible role for goblet cells in regulating the extracellular vitamin C pool.

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  • 41. Liljedahl, Helena
    et al.
    Karlsson, Anna
    Oskarsdottir, Gudrun N.
    Salomonsson, Annette
    Brunnström, Hans
    Erlingsdottir, Gigja
    Jönsson, Mats
    Isaksson, Sofi
    Arbajian, Elsa
    Ortiz-Villalón, Cristian
    Hussein, Aziz
    Bergman, Bengt
    Vikström, Anders
    Monsef, Nastaran
    Branden, Eva
    Koyi, Hirsh
    de Petris, Luigi
    Patthey, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Planck, Maria
    Staaf, Johan
    A gene expression-based single sample predictor of lung adenocarcinoma molecular subtype and prognosis2021Ingår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 148, nr 1, s. 238-251Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Disease recurrence in surgically treated lung adenocarcinoma (AC) remains high. New approaches for risk stratification beyond tumor stage are needed. Gene expression-based AC subtypes such as the Cancer Genome Atlas Network (TCGA) terminal-respiratory unit (TRU), proximal-inflammatory (PI) and proximal-proliferative (PP) subtypes have been associated with prognosis, but show methodological limitations for robust clinical use. We aimed to derive a platform independent single sample predictor (SSP) for molecular subtype assignment and risk stratification that could function in a clinical setting. Two-class (TRU/nonTRU=SSP2) and three-class (TRU/PP/PI=SSP3) SSPs using the AIMS algorithm were trained in 1655 ACs (n = 9659 genes) from public repositories vs TCGA centroid subtypes. Validation and survival analysis were performed in 977 patients using overall survival (OS) and distant metastasis-free survival (DMFS) as endpoints. In the validation cohort, SSP2 and SSP3 showed accuracies of 0.85 and 0.81, respectively. SSPs captured relevant biology previously associated with the TCGA subtypes and were associated with prognosis. In survival analysis, OS and DMFS for cases discordantly classified between TCGA and SSP2 favored the SSP2 classification. In resected Stage I patients, SSP2 identified TRU-cases with better OS (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.18-0.49) and DMFS (TRU HR = 0.52; 95% CI = 0.33-0.83) independent of age, Stage IA/IB and gender. SSP2 was transformed into a NanoString nCounter assay and tested in 44 Stage I patients using RNA from formalin-fixed tissue, providing prognostic stratification (relapse-free interval, HR = 3.2; 95% CI = 1.2-8.8). In conclusion, gene expression-based SSPs can provide molecular subtype and independent prognostic information in early-stage lung ACs. SSPs may overcome critical limitations in the applicability of gene signatures in lung cancer.

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  • 42.
    Lindberg, Anne
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Linder, Robert
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Backman, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Eriksson Ström, Jonas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Frølich, Andreas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Nilsson, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rönmark, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Johansson Strandkvist, Viktor
    Behndig, Annelie F
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process2017Ingår i: European Clinical Respiratory Journal, ISSN 2001-8525, Vol. 4, artikel-id 1415095Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Chronic obstructive pulmonary disease (COPD) is a largely underdiagnosed disease including several phenotypes. In this report, the design of a study intending to evaluate the pathophysiological mechanism in COPD in relation to the specific phenotypes non-rapid and rapid decline in lung function is described together with the recruitment process of the study population derived from a population based study.

    Method: The OLIN COPD study includes a population-based COPD cohort and referents without COPD identified in 2002–04 (n = 1986), and thereafter followed annually since 2005. Lung function decline was estimated from baseline in 2002–2004 to 2010 (first recruitment phase) or to 2012/2013 (second recruitment phase). Individuals who met the predefined criteria for the following four groups were identified; group A) COPD grade 2–3 with rapid decline in FEV1 and group B) COPD grade 2–3 without rapid decline in FEV1 (≥60 and ≤30 ml/year, respectively), group C) ever-smokers, and group D) non-smokers with normal lung function. Groups A–C included ever-smokers with >10 pack years. The intention was to recruit 15 subjects in each of the groups A-D.

    Results: From the database groups A–D were identified; group A n = 37, group B n = 29, group C n = 41, and group D n = 55. Fifteen subjects were recruited from groups C and D, while this goal was not reached in the groups A (n = 12) and B (n = 10). The most common reasons for excluding individuals identified as A or B were comorbidities contraindicating bronchoscopy, or inflammatory diseases/immune suppressive medication expected to affect the outcome.

    Conclusion: The study is expected to generate important results regarding pathophysiological mechanisms associated with rate of decline in lung function among subjects with COPD and the in-detail described recruitment process, including reasons for non-participation, is a strength when interpreting the results in forthcoming studies.

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  • 43.
    Linder, Robert
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Proteolytic imbalance is related to FEV1 decline in COPDManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background

    It is generally accepted that metalloproteinases contribute to lung tissue destruction. This study intends to examine how proteolytic imbalance impacts COPD in relation to phenotypes of non-rapid and rapid decline in lung function, by clinically assessing subjects recruited from a population-based cohort.

    Methods

    Subjects were recruited from the longitudinal OLIN COPD study providing spirometry data over time. In total 52 subjects were included: 12 with COPD and a rapid decline in FEV1 (≥60 mL/year), 10 with COPD and a non-rapid decline in FEV1 (≤30 mL/year), 15 current and ex-smokers with normal lung function, and 15 non-smokers with normal lung function. Proteolytic markers MMP-9, MMP-12 and TIMP-1 were assessed in serum and airway lavages.

    Results

    MMP-12 in BW and BAL was higher in COPD compared to both ever- smokers (BW: p = 0.001, BAL: p = 0.001) and non-smokers with normal lung function (BW: p = 0.001, BAL: p = 0.001). BAL-MMP-12 in COPD displayed a positive association to annual decline in FEV1

    (r = 0.61, p = 0.005). The lowest concentration of S-TIMP-1 (477 (295- 717) ng/mL) was found in COPD with a rapid decline in lung function, with a negative association between annual decline in FEV1 and s-TIMP- 1 (r = -0.42, p = 0.05).

    Conclusion

    Airway protease activity measured as MMP-12 concentration in BAL was increased in COPD, compared to both smokers with normal lung function and healthy. Individuals with the highest levels of airway MMP- 12 experienced the greatest decline in FEV1. Furthermore, a negative association was found between TIMP-1 in serum and FEV1 decline. Increased airway proteolytic activity may play an important role in the progress of COPD.

  • 44.
    Linder, Robert
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rönmark, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Serum metalloproteinase-9 is related to COPD severity and symptoms - cross-sectional data from a population based cohort-study2015Ingår i: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 16, artikel-id 28Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Chronic obstructive pulmonary disease, COPD, is an increasing cause of morbidity and mortality worldwide, and an imbalance between proteases and antiproteases has been implicated to play a role in COPD pathogenesis. Matrix metalloproteinases (MMP) are important proteases that along with their inhibitors, tissue inhibitors of metalloproteinases (TIMP), affect homeostasis of elastin and collagen, of importance for the structural integrity of human airways. Small observational studies indicate that these biomarkers are involved in the pathogenesis of COPD. The aim of this study was to investigate serum levels of MMP-9 and TIMP-1 in a large Swedish population- based cohort, and their association with disease severity and important clinical symptoms of COPD such as productive cough.

    Methods: Spirometry was performed and peripheral blood samples were collected in a populations-based cohort (median age 67 years) comprising subjects with COPD (n = 594) and without COPD (n = 948), in total 1542 individuals. Serum MMP-9 and TIMP-1 concentrations were measured with enzyme linked immunosorbant assay (ELISA) and related to lung function data and symptoms.

    Results: Median serum MMP-9 values were significantly higher in COPD compared with non-COPD 535 vs. 505 ng/ml (P = 0.017), without any significant differences in serum TIMP-1-levels or MMP-9/TIMP-1-ratio. In univariate analysis, productive cough and decreasing FEV1% predicted correlated significantly with increased MMP-9 among subjects with COPD (P = 0.004 and P = 0.001 respectively), and FEV1% predicted remained significantly associated to MMP-9 in a multivariate model adjusting for age, sex, pack years and productive cough (P = 0.033).

    Conclusion: Productive cough and decreasing FEV1 were each associated with MMP-9 in COPD, and decreasing FEV1 remained significantly associated with MMP-9 also after adjustment for common confounders in this population-based COPD cohort. The increased serum MMP-9 concentrations in COPD indicate an enhanced proteolytic activity that is related to disease severity, and further longitudinal studies are important for the understanding of MMP-9 in relation to the disease process and the pathogenesis of different COPD phenotypes.

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  • 45.
    Linder, Robert
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rönmark, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin. The OLIN unit.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lindberg, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Proteolytic biomarkers are related to prognosis in COPD: report from a population-based cohort2018Ingår i: Respiratory Research, ISSN 1465-9921, E-ISSN 1465-993X, Vol. 19, artikel-id 64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The imbalance between proteases and anti-proteases is considered to contribute to the development of COPD. Our aim was to evaluate the protease MMP-9, the antiprotease TIMP-1 and the MMP-9/TIMP-1-ratio as biomarkers in relation to prognosis. Prognosis was assessed as lung function decline and mortality. This was done among subjects with COPD in a population-based cohort.

    METHODS: In 2005, clinical examinations including spirometry and peripheral blood sampling, were made in a longitudinal population-based cohort. In total, 1542 individuals participated, whereof 594 with COPD. In 2010, 1031 subjects participated in clinical examinations, and 952 subjects underwent spirometry in both 2005 and 2010. Serum MMP-9 and TIMP-1 concentrations were measured with enzyme linked immunosorbent assay (ELISA). Mortality data were collected from the Swedish national mortality register from the date of examination in 2005 until 31st December 2010.

    RESULTS: The correlation between biomarkers and lung function decline was similar in non-COPD and COPD, but only significant for MMP-9 and MMP-9/TIMP-1-ratio in non-COPD. Mortality was higher in COPD than non-COPD (16% vs. 10%, p = 0.008). MMP-9 concentrations and MMP-9/TIMP-1 ratios in 2005 were higher among those who died during follow up, as well as among those alive but not participating in 2010, when compared to those participating in the 2010-examination. In non-COPD, male sex, age, burden of smoking, heart disease and MMP-9/TIMP-1 ratio were associated with increased risk for death, while increased TIMP-1 was protective. Among those with COPD, age, current smoking, increased MMP-9 and MMP-9/TIMP-1 ratio were associated with an increased risk for death.

    CONCLUSIONS: The expected association between these biomarkers and lung function decline in COPD was not confirmed in this population-based study, probably due to a healthy survivor effect. Still, it is suggested that increased proteolytic imbalance may be of greater prognostic importance in COPD than in non-COPD.

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  • 46.
    Midttun, Øivind
    et al.
    Bevital AS, Laboratory Building, Bergen, Norway.
    Ulvik, Arve
    Bevital AS, Laboratory Building, Bergen, Norway.
    Meyer, Klaus
    Bevital AS, Laboratory Building, Bergen, Norway.
    Zahed, Hana
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Giles, Graham G.
    Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia; Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia.
    Manjer, Jonas
    Department of Surgery, Skane University Hospital, Malmö, Sweden; Lund University, Malmö, Sweden.
    Sandsveden, Malte
    Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
    Langhammer, Arnulf
    Department of Public Health and Nursing, Hunt Research Centre, Norwegian University of Science and Technology, Levanger, Norway; Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway.
    Sørgjerd, Elin Pettersen
    Department of Public Health and Nursing, Hunt Research Centre, Norwegian University of Science and Technology, Levanger, Norway; Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Levanger, Norway.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Johansson, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Freedman, Neal D.
    Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, Bethesda, United States.
    Huang, Wen-Yi
    Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, Bethesda, United States.
    Chen, Chu
    Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, United States.
    Prentice, Ross
    Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, United States.
    Stevens, Victoria L.
    American Cancer Society, Atlanta, United States.
    Wang, Ying
    American Cancer Society, Atlanta, United States.
    Le Marchand, Loïc
    University of Hawai'i Cancer Center, University of Hawai'i at Mānoa, Honolulu, United States.
    Weinstein, Stephanie J.
    Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, MD, Bethesda, United States.
    Cai, Qiuyin
    Vanderbilt University Medical Center, Nashville, United States.
    Arslan, Alan A.
    Department of Obstetrics and Gynecology, NYU Langone Health, New York, NY, USA; Department of Population Health, NYU Langone Health, New York, NY, USA; Perlmutter Comprehensive Cancer Center, NYU Langone Health, New York, NY, USA.
    Chen, Yu
    Department of Population Health, NYU Langone Health, New York, NY, USA; Perlmutter Comprehensive Cancer Center, NYU Langone Health, New York, NY, USA.
    Shu, Xiao-Ou
    Department of Population Health, NYU Langone Health, New York, NY, USA.
    Zheng, Wei
    Department of Population Health, NYU Langone Health, New York, NY, USA.
    Yuan, Jian-Min
    University of Pittsburgh and UPMC Hillman Cancer Center, Pittsburgh, United States.
    Koh, Woon-Puay
    Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
    Visvanathan, Kala
    Johns Hopkins Institute for Clinical and Translational Research, Baltimore, United States.
    Sesso, Howard D.
    Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Harvard T.H. Chan School of Public Health, Boston, United States.
    Zhang, Xuehong
    Brigham and Women's Hospital, Harvard Medical School, Boston, United States; Harvard T.H. Chan School of Public Health, Boston, United States.
    Gaziano, J. Michael
    Brigham and Women's Hospital, Boston, United States; VA Boston Healthcare System, MA, Boston, United States.
    Fanidi, Anouar
    Université Claude Bernard Lyon 1, Lyon, France.
    Robbins, Hilary A.
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Brennan, Paul
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Johansson, Mattias
    Genomic Epidemiology Branch, International Agency for Research on Cancer, Lyon, France.
    Ueland, Per M.
    Bevital AS, Laboratory Building, Bergen, Norway.
    A cross-sectional study of inflammatory markers as determinants of circulating kynurenines in the Lung Cancer Cohort Consortium2023Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 13, nr 1, artikel-id 1011Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Circulating concentrations of metabolites (collectively called kynurenines) in the kynurenine pathway of tryptophan metabolism increase during inflammation, particularly in response to interferon-gamma (IFN-γ). Neopterin and the kynurenine/tryptophan ratio (KTR) are IFN-γ induced inflammatory markers, and together with C-reactive protein (CRP) and kynurenines they are associated with various diseases, but comprehensive data on the strength of associations of inflammatory markers with circulating concentrations of kynurenines are lacking. We measured circulating concentrations of neopterin, CRP, tryptophan and seven kynurenines in 5314 controls from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). The associations of neopterin, KTR and CRP with kynurenines were investigated using regression models. In mixed models, one standard deviation (SD) higher KTR was associated with a 0.46 SD higher quinolinic acid (QA), and 0.31 SD higher 3-hydroxykynurenine (HK). One SD higher neopterin was associated with 0.48, 0.44, 0.36 and 0.28 SD higher KTR, QA, kynurenine and HK, respectively. KTR and neopterin respectively explained 24.1% and 16.7% of the variation in QA, and 11.4% and 7.5% of HK. CRP was only weakly associated with kynurenines in regression models. In summary, QA was the metabolite that was most strongly associated with the inflammatory markers. In general, the inflammatory markers were most strongly related to metabolites located along the tryptophan-NAD axis, which may support suggestions of increased production of NAD from tryptophan during inflammation.

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  • 47.
    Muala, Ala
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Nyström, Robin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Pettersson, Esbjörn
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Bergvall, Christoffer
    Westerholm, Roger
    Jalava, Pasi I.
    Happo, Mikko S.
    Uski, Oskari
    Hirvonen, Maija-Riitta
    Kelly, Frank J.
    Mudway, Ian S.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Acute exposure to wood smoke from incomplete combustion - indications of cytotoxicity2015Ingår i: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 12, artikel-id 33Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Smoke from combustion of biomass fuels is a major risk factor for respiratory disease, but the underlying mechanisms are poorly understood. The aim of this study was to determine whether exposure to wood smoke from incomplete combustion would elicit airway inflammation in humans. Methods: Fourteen healthy subjects underwent controlled exposures on two separate occasions to filtered air and wood smoke from incomplete combustion with PM1 concentration at 314 mu g/m(3) for 3 h in a chamber. Bronchoscopy with bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial mucosal biopsies was performed after 24 h. Differential cell counts and soluble components were analyzed, with biopsies stained for inflammatory markers using immunohistochemistry. In parallel experiments, the toxicity of the particulate matter (PM) generated during the chamber exposures was investigated in vitro using the RAW264.7 macrophage cell line. Results: Significant reductions in macrophage, neutrophil and lymphocyte numbers were observed in BW (p < 0.01, < 0.05, < 0.05, respectively) following the wood smoke exposure, with a reduction in lymphocytes numbers in BAL fluid (< 0.01. This unexpected cellular response was accompanied by decreased levels of sICAM-1, MPO and MMP-9 (p < 0.05, < 0.05 and < 0.01). In contrast, significant increases in submucosal and epithelial CD3+ cells, epithelial CD8+ cells and submucosal mast cells (p < 0.01, < 0.05, < 0.05 and < 0.05, respectively), were observed after wood smoke exposure. The in vitro data demonstrated that wood smoke particles generated under these incomplete combustion conditions induced cell death and DNA damage, with only minor inflammatory responses. Conclusions: Short-term exposure to sooty PAH rich wood smoke did not induce an acute neutrophilic inflammation, a classic hallmark of air pollution exposure in humans. While minor proinflammatory lymphocytic and mast cells effects were observed in the bronchial biopsies, significant reductions in BW and BAL cells and soluble components were noted. This unexpected observation, combined with the in vitro data, suggests that wood smoke particles from incomplete combustion could be potentially cytotoxic. Additional research is required to establish the mechanism of this dramatic reduction in airway leukocytes and to clarify how this acute response contributes to the adverse health effects attributed to wood smoke exposure.

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  • 48.
    Muala, Ala
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Unosson, Jon
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bosson, Jenny
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Nyström, Robin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Pettersson, Esbjörn
    Bergvall, Christoffer
    Westerholm, Roger
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Kelly, Frank
    Mudway, Ian
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bronchial mucosal inflammation in healthy subjects after exposure to wood smoke from incomplete combustionManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Indoor smoke from combustion of solid biomass fuel is a major risk factor for respiratory disease worldwide. The mechanisms by which wood smoke exhibits its effects on human health are not well understood. The aim of this study was to determine whether exposure to wood smoke produced from incomplete combustion would elicit an airway inflammatory response.

    Methods Fourteen healthy subjects underwent controlled chamber exposure on two occasions to filtered air and to sooty wood smoke (PM1 ~ 314 μg/m3), generated by a common Nordic wood stove firing birch logs. The study was performed with a double-blind randomized cross-over design and the subjects alternated between exercise (VE=20 L/min/m2) and rest at 15-minute intervals for 3 hours. Bronchoscopies were performed 24 hours after each exposure where bronchial wash (BW), bronchoalveolar lavage (BAL) and endobronchial biopsies were taken. Differential cell counts and soluble components were analyzed in BW and BAL. Bronchial mucosal biopsies were analyzed using immunohistochemistry. Blood tests for inflammatory markers were sampled pre-exposure as well as at 24 and 44-hour time points post-exposure. Spirometry and Fraction of exhaled nitric oxide (FENO) were performed before, immediately after and 24 hours after each exposure.

    Results There was a significant increase in submucosal and epithelial CD3+ lymphocytes (p<0.01 and <0.05 respectively), together with CD8+ cells in the epithelium (p<0.05) after exposure to wood smoke compared to filtered air. Mast cells were also significantly increased in the submucosa (p<0.01) after wood smoke exposure.

    There were significant reductions in macrophages, neutrophils and lymphocytes in BW after exposure to wood smoke compared to filtered air, accompanied by decreased levels of soluble Intercellular Adhesion Molecule-1 (sICAM-1), myeloperoxidase (MPO) and matrix metalloproteinase-9 (MMP-9). No significant effects on cell numbers or acute inflammatory markers were demonstrated in BAL fluid or peripheral blood. Lung function and FENO were not affected by exposure to wood smoke.

    Conclusions Wood smoke exposure caused a significant increase in bronchial epithelial and submucosal CD3+ lymphocytes together with an increase in mucosal mast cells. Further examination revealed a significant increase in CD8+ lymphocytes within the epithelium. Unexpectedly there were no indications of any neutrophilic airway response or recruitment of alveolar macrophages. BW cell numbers, MPO and MMP-9 levels were also significantly reduced after wood smoke exposure. Further research is needed to determine the precise role of these events in relationship to the adverse health effects attributed to wood smoke exposure.

  • 49.
    Muala, Ala
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bion, Anne
    Renault Technocentre, Guyancourt, France.
    Österlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Swedish Defence Research Agency, FOI, Umeå, Sweden.
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Mudway, Ian S.
    MRC-PHE Centre for Environment and Health, School of Biomedical Sciences, King’s College London, London, UK.
    Langrish, Jeremy P.
    BHF/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK .
    Couderc, Stephane
    Renault Technocentre, Guyancourt, France.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Assessment of the capacity of vehicle cabin air inlet filters to reduce diesel exhaust-induced symptoms in human volunteers2014Ingår i: Environmental Health, E-ISSN 1476-069X, Vol. 13, nr 1, artikel-id 16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Exposure to particulate matter (PM) air pollution especially derived from traffic is associated with increases in cardiorespiratory morbidity and mortality. In this study, we evaluated the ability of novel vehicle cabin air inlet filters to reduce diesel exhaust (DE)-induced symptoms and markers of inflammation in human subjects.

    METHODS: Thirty healthy subjects participated in a randomized double-blind controlled crossover study where they were exposed to filtered air, unfiltered DE and DE filtered through two selected particle filters, one with and one without active charcoal. Exposures lasted for one hour. Symptoms were assessed before and during exposures and lung function was measured before and after each exposure, with inflammation assessed in peripheral blood five hours after exposures. In parallel, PM were collected from unfiltered and filtered DE and assessed for their capacity to drive damaging oxidation reactions in a cell-free model, or promote inflammation in A549 cells.

    RESULTS: The standard particle filter employed in this study reduced PM10 mass concentrations within the exposure chamber by 46%, further reduced to 74% by the inclusion of an active charcoal component. In addition use of the active charcoal filter was associated by a 75% and 50% reduction in NO2 and hydrocarbon concentrations, respectively. As expected, subjects reported more subjective symptoms after exposure to unfiltered DE compared to filtered air, which was significantly reduced by the filter with an active charcoal component. There were no significant changes in lung function after exposures. Similarly diesel exhaust did not elicit significant increases in any of the inflammatory markers examined in the peripheral blood samples 5 hour post-exposure. Whilst the filters reduced chamber particle concentrations, the oxidative activity of the particles themselves, did not change following filtration with either filter. In contrast, diesel exhaust PM passed through the active charcoal combination filter appeared less inflammatory to A549 cells.

    CONCLUSIONS: A cabin air inlet particle filter including an active charcoal component was highly effective in reducing both DE particulate and gaseous components, with reduced exhaust-induced symptoms in healthy volunteers. These data demonstrate the effectiveness of cabin filters to protect subjects travelling in vehicles from diesel exhaust emissions.

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  • 50.
    Muala, Ala
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Österdahl, Rebecka
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sehlstedt, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Rankin, Gregory
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Pourazar, Jamshid
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bosson, Jenny A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Boman, Christoffer
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Thermochemical Energy Conversion Laboratory, Umeå University, Umeå, Sweden.
    Lindgren, Robert
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Thermochemical Energy Conversion Laboratory, Umeå University, Umeå, Sweden.
    Lopez, Natxo Garcia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik. Thermochemical Energy Conversion Laboratory, Umeå University, Umeå, Sweden.
    Behndig, Annelie F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Öhberg, Fredrik
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Small airways effects of exposure to wood smoke2019Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift (Övrigt vetenskapligt)
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