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  • 301.
    Valham, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eriksson, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hägg, Erik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindberg, Eva
    Department of Respiratory Medicine and Allergology, Uppsala University, Uppsala, Sweden.
    Franklin, Karl
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Snoring and witnessed sleep apnea is related to diabetes mellitus in women2009In: Sleep Medicine, ISSN 1389-9457, E-ISSN 1878-5506, Vol. 10, no 1, p. 112-117Article in journal (Refereed)
    Abstract [en]

    Background

    Gender differences in the relationship of snoring and diabetes mellitus are mainly unknown. We aimed to analyze the relationship between snoring, witnessed sleep apnea and diabetes mellitus and to analyze possible gender related differences in an unselected population.

    Methods

    Questions on snoring and witnessed sleep apneas were included in the Northern Sweden component of the WHO, MONICA study. Invited were 10,756 men and women aged 25–79 years, randomly selected from the population register.

    Results

    There were 7905 (73%) subjects, 4047 women and 3858 men who responded to the questionnaire and attended a visit for a physical examination. Habitual snoring was related to diabetes mellitus in women, with an adjusted odds ratio (OR) = 1.58 (95% confidence interval (CI) 1.02–2.44, p = 0.041) independent of smoking, age, body mass index and waist circumference. Witnessed sleep apnea was also independently related to diabetes mellitus in women, with an adjusted OR = 3.29 (95% CI 1.20–8.32, p = 0.012). Neither snoring, nor witnessed sleep apneas were associated with diabetes mellitus among men, except for witnessed sleep apnea in men aged 25–54 years old. They had an adjusted OR = 3.84 (95% CI 1.36–10.9, p = 0.011) for diabetes mellitus.

    Conclusions

    Snoring and witnessed sleep apneas are related to diabetes mellitus in women. Witnessed sleep apnea is related to diabetes mellitus in men younger than 55 years old.

  • 302. Vanderveken, Olivier M
    et al.
    Devolder, Annick
    Umeå University, Faculty of Medicine, Department of Odontology, Ortodontics.
    Marklund, Marie
    Umeå University, Faculty of Medicine, Department of Odontology.
    Boudewyns, An N
    Braem, Marc J
    Okkerse, Walter
    Verbraecken, Johan A
    Franklin, Karl
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    De Backer, Wilfried A
    Van de Heyning, Paul H
    Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea2008In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 178, no 2, p. 197-202Article in journal (Refereed)
    Abstract [en]

    Rationale: The efficacy of immediate adaptation of mandibular advancement devices made of thermoplastic material as a treatment option for sleep-disordered breathing (SDB) has been demonstrated in clinical studies. To date, there have been no studies comparing the efficacy of such prefabricated devices with custom-made devices.

    Objectives: Our purpose was to compare the efficacy of both types of devices in patients with SDB.

    Methods: A randomized controlled cross-over trial, comprising 4 months of treatment with a thermoplastic and a custom-made device, with a 1-month washout interval.

    Measurements and Main Results: A total of 35 patients (29 males; age, 49 ± 9 yr; apnea–hypopnea index [AHI], 13 ± 11 events/h; body mass index, 28 ± 4 kg/m2) completed the protocol. AHI was only reduced with the custom-madedevice (P = 0.005). In addition, this device reduced snoring to a greater extent than the thermoplastic device. The success rate was higher with the custom-made device (60 vs. 31%; P = 0.02). One-third of the patients demonstrated compliance failure with the thermoplastic device, mainly because of insufficient overnight retention. Total failure rate with the thermoplastic device was 69%, whereas the majority (63%) of these were successfully treated with the custom-made device. At the end of the study, 82% of the patients preferred the custom-made device, and 9% had no preference (P < 0.0001).

    Conclusions: In this study, a custom-made device turned out to be more effective than a thermoplastic device in the treatment of SDB. Our results suggest that the thermoplastic device cannot be recommended as a therapeutic option nor can it be used as a screening tool to find good candidates for mandibular advancement therapy.

  • 303.
    Wadell, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lundgren, Rune
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Physical training with and without oxygen in patients with chronic obstructive pulmonary disease and exerciseinduced hypoxaemia2001In: Journal of Rehabilitation Medicine, ISSN 1650-1977, E-ISSN 1651-2081, Vol. 33, no 5, p. 200-205Article in journal (Refereed)
    Abstract [en]

    A randomized, controlled, single-blind study was performed on 20 patients with chronic obstructive pulmonary disease and exercise-induced hypoxaemia. Ten patients each were randomly assigned to one of two groups, one training with air and the other training with oxygen. There were no significant differences between the groups regarding values measured prior to the study. The patients trained 3 times per week for 30 minutes each time for a duration of 8 weeks. The training consisted of interval walking on a treadmill (intensity set according to Borg ratings) with either air or oxygen administered through a nasal cannula at a rate of 5 l/min. Training significantly improved the 6-minute walking distance by 20% and 14% in the air and oxygen group, respectively, when the patients were tested on air. In the same test the air group significantly decreased Borg ratings for perceived exertion. Borg ratings for dyspnoea and perceived exertion significantly decreased in the oxygen group when they were tested on oxygen. It was concluded that oxygen supplementation did not further improve the training effect, compared with training with air, in patients with chronic obstructive pulmonary disease and exercise-induced hypoxaemia.

  • 304.
    Wadell, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lundgren, Rune
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Sundelin, Gunnevi
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Group training in patients with COPD: long-term effects of decreased training frequency2005In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, Vol. 27, no 10, p. 571-581Article in journal (Refereed)
    Abstract [en]

    Purpose.To investigate effects of decreased training frequency in patients with COPD.

    Methods.Forty-three COPD patients participated in a controlled study. The intervention group (30 patients) trained 3 times a week during 3 months and once a week during 6 months. Before, after 3 and 9 months all patients performed walking tests, cycle ergometer tests and responded questionnaires on health-related quality of life (HRQoL) (SGRQ, SF-36).

    Results.At 9 months compared to 3 months there were no changes in distance walked in the groups. Both groups decreased their VO2peak and the training group deteriorated in HRQoL. At 9 months compared to baseline the training group showed increased distance walked compared to the control group. In the disease-specific SGRQ the training group tended to improve their activity score while the control group tended to deteriorate in total score. In SF-36 the control group decreased their physical component score.

    Conclusion.Training once a week does not seem to be sufficient to maintain the level achieved after the 3-month period of training in COPD patients. However, training once a week during 6 months preceded by 3 months of high frequency training seems to prevent deterioration in physical capacity and HRQoL compared to baseline. Further studies are needed to investigate how to best sustain the benefits gained after physical training.

  • 305.
    Wadell, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Sundelin, Gunnevi
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Henriksson-Larsén, Karin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lundgren, Rune
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    High intensity physical training in water: an effective training modality for patients with COPD2004In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 98, no 5, p. 428-438Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine the effect of high intensity physical group training in water and on land for patients with COPD with regard to physical capacity and health related quality of life (HRQoL). A controlled, semi-randomised study was conducted where 30 patients were randomised to training either in water or on land. Thirteen patients constituted a control group. Forty-three outpatients, with moderate to severe COPD (27w/16m), from two local hospitals in northern Sweden, were included in the study. High intensity physical group training in water (water group) or on land (land group) was performed for 12weeks, three times per week, 45min per session. The control group received no intervention. Pre- and post-intervention, all patients performed incremental and endurance shuttle walking tests (ISWT and ESWT), cycle ergometer tests and responded questionnaires about HRQoL (St. Georges Respiratory Questionnaire--SGRQ and SF-36). The patients trained with a mean heart rate of 80-90% of peak heart rate. Both training groups increased the distance walked, i.e. land group in ISWT (25m) and water group in ESWT (179m). The water group increased the distance in ESWT significantly more that both the land and the control groups. Both training groups increased the time cycled (40-85s) and work load (10-20W) in the cycle ergometer test. The control group deteriorated in HRQoL according to total score in SGRQ while the training groups remained constant. The water group improved their activity score in SGRQ and their physical health score in SF-36 and those improvements were significant as compared to the land and the control groups. In conclusion, high intensity physical group training in water is of benefit for patients with COPD. It was in some areas found to be even more effective regarding improvements in physical capacity and experienced physical health compared to the same kind of training on land.

  • 306.
    Waern, Ida
    et al.
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Jonasson, Sofia
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Hjoberg, Josephine
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Åbrink, Magnus
    Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
    Pejler, Gunnar
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Wernersson, Sara
    Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Mouse mast cell protease 4 is the major chymase in murine airways and has a protective role in allergic airway inflammation.2009In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 183, no 10, p. 6369-6376Article in journal (Refereed)
    Abstract [en]

    It is widely established that mast cells (MCs) have a harmful role in asthma, for example by secreting various proinflammatory substances stored within their secretory granule. However, in this study, we show that one of the substances stored within MC granule, chymase, in fact has a protective role in allergic airway inflammation, indicating that MCs may possess both harmful and protective activities in connection with this type of disease. Wild-type (WT) mice and mice lacking mouse MC protease 4 (mMCP-4), a chymase that is functionally homologous to human chymase, were sensitized and challenged with OVA, followed by the assessment of airway physiology and inflammatory parameters. Our results show that the airway hyperresponsiveness was significantly higher in mMCP-4(-/-) as compared with WT mice. Moreover, the degree of lung tissue inflammation was markedly higher in mice lacking mMCP-4 than in WT controls. Histological analysis revealed that OVA sensitization/challenge resulted in a marked increased in the thickness of the smooth muscle cell (SMC) layer and, notably, that the degree of SMC layer thickening was more pronounced in mMCP-4(-/-) animals than in WT controls, thus indicating that chymase may have an effect on airway SMCs. In support of this, mMCP-4-positive MCs were located in the close vicinity of the SMC layer, mainly in the upper airways, and mMCP-4 was shown to be the major chymase expressed in these MCs. Taken together, our results indicate that chymase present in the upper airways protects against allergic airway responses, possibly by regulating SMCs.

  • 307. Wanhainen, Anders
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Pulmonary Medicine.
    Bergqvist, David
    Boman, Kurt
    Umeå University, Faculty of Medicine, Public Health and Clinical Medicine, Medicine.
    Björck, Martin
    Elevated tissue plasminogen activator in patients with screening-detected abdominal aortic aneurysm.2007In: J Vasc Surg, ISSN 0741-5214, Vol. 45, no 6, p. 1109-13Article in journal (Refereed)
  • 308.
    Warm, Katja
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    The epidemiology of allergic sensitization and the relation to asthma and rhinitis: the Obstructive Lung Disease in Northern Sweden (OLIN) studies thesis XIV2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Allergic sensitization is the most important risk factor for asthma and rhinitis among children, adolescents and young adults. Less is known about the incidence and remission of allergic sensitization, particularly in older adults. Furthermore, it is not clear if the earlier documented increase in prevalence of allergic sensitization continues. This thesis is focused on prevalence, incidence and remission of allergic sensitization to airborne allergens among adolescents and adults as well as on time trends in prevalence among adults. Furthermore, associated risk factors and the relation of allergic sensitization to asthma and rhinitis were assessed.

    Methods: In the study of children and adolescents, incidence, remission and prevalence of allergic sensitization were assessed in a cohort study of schoolchildren, aged 7-8 years (y) at baseline. In the studies of adults, incidence and remission of allergic sensitization were assessed in a randomly selected adult population sample in 1994 (n=664) aged 20-69 y, which was followed up in 2004 (n=555). Trends in prevalence of allergic sensitization were assessed by comparing two cross-sectional studies; the cohort from 1994 and another randomly selsected population sample examined in 2009 (n=737). The relation of allergic sensitization to asthma and rhinitis was determined in the adult cohort in 2009. Allergic sensitization was assessed by skin prick test (SPT) with ten common airborne allergens at ages 7-8, 11-12 and 19 y in the cohort of children and in the participants ≤ 60 y in the adult cohorts. Specific IgE to nine airborne allergens was analyzed in the adult cohorts in 2004 and 2009. Risk factors for allergic sensitization and variables defining respiratory disease and symptoms were assessed by questionnaires in the cohort of children and by structured interviews in the adult cohorts.

    Results: The 10-year cumulative incidence of allergic sensitization among the adults from 1994 to 2004 was 5%, while remission was 32%. In both adult cohorts, the prevalence of allergic sensitization was highest among young adults, aged 20-29 y, 55% and 61% and decreased significantly with increasing age. Among children and adolescents, both incidence and persistence of allergic sensitization were high, and the prevalence of allergic sensitization increased by age from 21% at age 7-8 y to 42% at age 19 y. Multisensitization at age 19 y was strongly associated with early onset of sensitization. The prevalence of sensitization to the major specific allergens birch, timothy, cat and dog as well as multisensitization (from 40% in 1994 to 56% in 2009, p=0.002) increased significantly from 1994 to 2009 among the adults. Sensitization to any allergen increased from 35% to 39%, however not significantly (p=0.13). A family history of allergic rhinitis was strongly and consistently associated with allergic sensitization in all ages. Male sex and urban living were significantly positively and birth order and furry animals at home in childhood were negatively associated with onset of sensitization before the age of 7-8 y, but not with onset of sensitization from 11-12y to 19 y. Young adult age and urban living were significant factors associated with allergic sensitization in adult age. Sensitization to any animal was significantly positively associated with current asthma (OR4.80 (95% CI 2.68-8.60)), whereas both sensitization to any pollen (OR 4.25 (2.55-7.06)) and any animal (OR 3.90 (95% CI 2.31-6.58)) were associated with current allergic rhinitis. The association between allergic sensitization and allergic rhinitis was strongest in young adult age and decreased with increasing age, while asthma was similarly associated with sensitization to any animal across all adult ages. Among asthmatics, the prevalence of allergic sensitization decreased with increasing age of asthma onset.

    Conclusion: Both incidence and persistence of allergic sensitization were high among children and adolescents explaining the increase in prevalence by increasing age. An inverse pattern with low incidence and high remission of allergic sensitization was seen among adults. The decrease in prevalence of allergic sensitization by increasing adult age might at least partly be explained by normal ageing and not only by an effect of year of birth (cohort effect). The significant increase in prevalence of sensitization to the specific allergens explained the significant increase in multisensitization over 15 years. A family history of allergy was the strongest and the only consistent risk factor for allergic sensitization in all ages. The prevalence of allergic sensitization decreased with increasing age of asthma onset among adult asthmatics.

  • 309.
    Warm, Katja
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Backman, Helena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Obstructive Lung Disease in Northern Sweden Studies, Norrbotten County Council, Luleå, Sweden.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Lundbäck, Bo
    Obstructive Lung Disease in Northern Sweden Studies, Norrbotten County Council, Luleå, Sweden.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Low incidence and high remission of allergic sensitization among adults2012In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 129, no 1, p. 136-142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prospective studies on the incidence and remission of allergic sensitization among adults are rare.

    OBJECTIVE: We sought to assess the incidence, remission, risk factors, and prevalence of allergic sensitization in relation to aging over a 10-year period.

    METHODS: In 1994, a sample of 664 adults (68% of invited) participated in clinical examinations, including a structured interview and skin prick tests (SPTs). The sample was randomly selected from a large questionnaire survey in Northern Sweden. In 2004, 555 subjects (93% of invited) were re-examined by using the same methods as in 1994. IgE levels were also measured in 2004.

    RESULTS: In 1994, the prevalence of any positive SPT response was significantly related to age, with the highest prevalence (55%) in subjects aged 20 to 29 years and the lowest prevalence (26%) in subjects aged 50 to 60 years. A similar age-related prevalence was found in 2004, and sensitization to pollen and pets was most common in both years. The results of the SPTs were verified by means of specific IgE measurement. The incidence of any positive SPT response was low. Only 9 subjects had any positive SPT response (ie, a cumulative incidence of 5% over 10 years). Remission was greater (ie, 32% over 10 years). The main risk factors for allergic sensitization were young age and a family history of allergy. Having had furred animals at home during childhood was negatively related to specific IgE levels.

    CONCLUSION: The low incidence and high remission in adulthood explain the decreasing prevalence of allergic sensitization by age. Thus the low prevalence of allergic sensitization among the elderly found in cross-sectional studies is an effect of normal aging and not primarily a birth cohort effect.

  • 310.
    Warm, Katja
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. The OLIN studies, Norrbotten County Council, Luleå and Department of Respiratory Medicine and Allergology, Sunderby Central Hospital of Norrbotten, Luleå.
    Lindberg, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. The OLIN studies, Norrbotten County Council, Luleå.
    Lundbäck, Bo
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. The OLIN studies, Norrbotten County Council, Luleå.
    Increase in sensitization to common airborne allergens among adults: two population-based studies 15 years apart2013In: Allergy, Asthma & Clinical Immunology, ISSN 1710-1484, E-ISSN 1710-1492, Vol. 9, no 1, p. 20-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Studies on time trends of allergic sensitization among adults are rare. The aim of the study was to compare the prevalence of allergic sensitization to common airborne allergens among adults 15 years apart and to identify risk factors for allergic sensitization.

    METHODS: Clinical examinations including skin prick test (SPT) and structured interviews were performed in two random population samples in 1994 and 2009. Furthermore, specific IgE was analyzed in 2009. SPT data were available for 483 subjects in 1994 and for 463 subjects in 2009 in ages 20--60 years. Specific IgE was analyzed in 692 subjects in ages 20--79 years.

    RESULTS: Sensitization to cat (16% to 26%, p < 0.001), dog (13% to 25%, p < 0.001), birch (13% to 18%, p = 0.031) and timothy (12% to 21%, p < 0.001), based on SPT, increased significantly from 1994 to 2009. Sensitization to any positive SPT increased from 35% to 39%, p = 0.13.The proportion of having >=3 positive SPT reactions increased from 40% to 56%, p = 0.002. The sensitization pattern yielded similar results based on specific IgE. Risk factors for allergic sensitization were having a family history of allergy (OR 3.1, 95% CI 2.0-4.8 for any positive SPT; OR 2.7, 95% CI 1.8-4.0 for any elevated IgE) and urban living (OR 1.7, 95% CI 1.0-2.7; OR 1.5, 95% CI 1.0-2.4).

    CONCLUSIONS: The prevalence of allergic sensitization to major airborne allergens as well as multi-sensitization increased significantly between the study years. Young age, a family history of allergy and urban living were significant risk factors for allergic sensitization.

  • 311. Wedzicha, Jadwiga A.
    et al.
    Decramer, Marc
    Ficker, Joachim H.
    Niewoehner, Dennis E.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Fowler Taylor, Angel
    D'Andrea, Peter
    Arrasate, Christie
    Chen, Hungta
    Banerji, Donald
    Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study2013In: Lancet Respiratory Medicine, ISSN 2213-2600, Vol. 1, no 3, p. 199-209Article in journal (Refereed)
    Abstract [en]

    Background: We evaluated the effect of dual, longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease (COPD).

    Methods: In this parallel-group study, 2224 patients (aged ≥40 years, Global Initiative for Chronic Obstructive Lung Disease stages III–IV, and one or more moderate COPD exacerbation in the past year) were randomly assigned (1:1:1; via interactive voice response or web system; stratified for smoking status) to once-daily QVA149 (fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg), glycopyrronium 50 μg, or tiotropium 18 μg for 64 weeks. Assignment to QVA149 and glycopyrronium was double-blind; tiotropium was open-label. Efficacy was assessed in all patients randomly assigned to treatment groups who received at least one dose of study drug; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group. The primary objective was to show superiority of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations (defined by worsening symptoms and categorised by treatment requirements) during treatment. This completed trial is registered at ClinicalTrials.gov, NCT01120691.

    Findings: Between April 27, 2010, and July 11, 2012, 741 patients were randomly assigned to receive QVA149, 741 to receive glycopyrronium, and 742 to receive tiotropium (729, 739, and 737 patients, respectively, analysed for efficacy). QVA149 significantly reduced the rate of moderate to severe exacerbations versus glycopyrronium by 12% (annualised rate of exacerbations 0·84 [95% CI 0·75–0·94] vs 0·95 [0·85–1·06]; rate ratio 0·88, 95% CI 0·77–0·99, p=0·038). Adverse events (including exacerbations) were reported for 678 (93%) of 729 patients on QVA149, 694 (94%) of 740 on glycopyrronium, and 686 (93%) of 737 on tiotropium. Incidence of serious adverse events was similar between groups (167 [23%] patients on QVA149, 179 [24%] on glycopyrronium, and 165 [22%] on tiotropium); COPD worsening was the most frequent serious adverse event (107 [15%] patients on QVA149, 116 [16%] on glycopyrronium, 87 [12%] on tiotropium).

    Interpretations: The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium, with concomitant improvements in lung function and health status. These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD.

  • 312. Wedzicha, Jadwiga A
    et al.
    Decramer, Marc
    Ficker, Joachim H
    Niewoehner, Dennis E
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Fowler Taylor, Angel
    D'Andrea, Peter
    Arrasate, Christie
    Chen, Hungta
    Banerji, Donald
    QVA149 versus glycopyrronium for COPD Reply2013In: Lancet Respiratory Medicine, ISSN 2213-2600, Vol. 1, no 5, p. E23-E23Article in journal (Refereed)
  • 313. Wigenstam, Elisabeth
    et al.
    Elfsmark, Linda
    Ågren, Lina
    Akfur, Christine
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Swedish Defence Research Agency, CBRN Defence and Security, Umeå, Sweden.
    Jonasson, Sofia
    Anti-inflammatory and anti-fibrotic treatment in a rodent model of acute lung injury induced by sulfur dioxide2018In: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 56, no 12, p. 1185-1194Article in journal (Refereed)
    Abstract [en]

    Context: Inhalation of sulfur dioxide (SO2) affects the lungs and exposure to high concentrations can be lethal. The early pulmonary response after inhaled SO2 involves tissue injury, acute neutrophilic lung inflammation and airway hyperresponsiveness (AHR). In rats, long-term pulmonary fibrosis is evident 14 days post-exposure as indicated by analysis of collagen deposition in lung tissue. Early treatment with a single dose of dexamethasone (DEX,10 mg/kg) significantly attenuates the acute inflammatory response in airways. However, this single DEX-treatment is not sufficient for complete protection against SO2-induced injuries.

    Methods: Female Sprague–Dawley rats exposed to SO2 (2200 ppm, nose-only exposure, 10 min) were given treatments (1, 5 and 23 h after SO2-exposure) with the anti-fibrotic and anti-inflammatory substance Pirfenidone (PFD, 200 mg/kg) or DEX (10 mg/kg) to evaluate whether the inflammatory response, AHR and lung fibrosis could be counteracted.

    Results: Both treatment approaches significantly reduced the total leukocyte response in bronchoalveolar lavage fluid and suppressed pulmonary edema. In contrast to DEX-treatment, PFD-treatment reduced the methacholine-induced AHR to almost control levels and partially suppressed the acute mucosal damage whereas multiple DEX-treatment was the only treatment that reduced collagen formation in lung tissue.

    Conclusions: To enable an accurate extrapolation of animal derived data to humans, a detailed understanding of the underlying mechanisms of the injury, and potential treatment options, is needed. The findings of the present study suggest that treatments with the capability to reduce both AHR, the inflammatory response, and fibrosis are needed to achieve a comprehensive mitigation of the acute lung injury caused by SO2.

  • 314.
    Wigenstam, Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Jonasson, Sofia
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Koch, Bo
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Corticosteroid treatment inhibits airway hyperreactivity and lung injury in a murine model of chemical-induced airway inflammationManuscript (preprint) (Other academic)
    Abstract [en]

    Context: Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 hr after lung exposure to the alkylating mustard melphalan, protect mice from acute and sub-acute inflammatory responses, as well as from lung fibrosis.

    Objective: In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 hrs following exposure to melphalan.

    Methods: Female C57BL/6 mice were via intratracheal instillation exposed to the nitrogen mustard analogue melphalan and treated i.p. with dexamethasone 1, 2 or 6 hours after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of neutrophils and lymphocytes in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs.

    Results: Melphalan exposure exerted a significant effect on both central and peripheral respiratory function. Dexamethasone given one hour post exposure protected the lung against the damaging effects of melphalan. Collagen deposition 14 days after exposure was decreased with dexamethasone treatment.

    Conclusion: Early dexamethasone treatment (within one hour after exposure) is important in order to reduce the airway reactivity and inflammation caused by toxic alkylating mustards such as melphalan.

  • 315.
    Wigenstam, Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Jonasson, Sofia
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Koch, Bo
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Corticosteroid treatment inhibits airway hyperresponsiveness and lung injury in a murine model of chemical-induced airway inflammation2012In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 301, no 1-3, p. 66-71Article in journal (Refereed)
    Abstract [en]

    Context: Exposure to toxic alkylating mustard agents causes both acute and long-term effects to the lungs as indicated by increased number of inflammatory cells in airways, lung edema and lung tissue fibrosis. We have previously demonstrated that treatment with the corticosteroid dexamethasone 1 h after lung exposure to the nitrogen mustard analog melphalan protects mice from acute and sub-acute inflammatory responses, as well as from lung tissue fibrosis. Objective: In order to address the importance of early anti-inflammatory treatment, we investigated the therapeutic effect of dexamethasone administered 1, 2 or 6 h following exposure to melphalan. Methods: C57BL/6 mice were exposed to melphalan and treated with dexamethasone 1,2 or 6 h after exposure. Twenty hours or 14 days post exposure mice were subjected to analysis of respiratory mechanics where the effects of incremental doses of methacholine on central and peripheral lung components were measured. We also determined the amount of inflammatory cells in the bronchoalveolar lavage fluid and measured the amount of collagen content in the lungs. Results: Melphalan exposure increased airway hyperresponsiveness in both central and peripheral airways and induced an airway inflammation dominated by infiltration of macrophages and neutrophils. Dexamethasone given 1 h after exposure to melphalan provided better protection against airway inflammation than administration 2 or 6 h after exposure. Collagen deposition 14 days after exposure was decreased due to dexamethasone treatment. Conclusion: Early treatment with dexamethasone is important in order to reduce the airway hyperresponsiveness and inflammation caused by toxic alkylating mustards such as melphalan. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

  • 316. Wigenstam, Elisabeth
    et al.
    Koch, Bo
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Jonasson, Sofia
    N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury2015In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 328, p. 40-47Article in journal (Refereed)
    Abstract [en]

    Chlorine (Cl-2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1 h after Cl-2-exposure could improve protection against acute lung injury in Cl-2-exposed mice. BALB/c mice were exposed to 300 ppm Cl-2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24 h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated.

  • 317.
    Wigenstam, Elisabeth
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Rocksén, David
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Ekstrand-Hammarström, Barbro
    Swedish Defence Research Agency, Division of CBRN Defence and Security, Umeå, Sweden.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Treatment with dexamethasone or liposome-encapsuled vitamin E provides beneficial effects after chemical-induced lung injury.2009In: Inhalation Toxicology, ISSN 0895-8378, E-ISSN 1091-7691, Vol. 21, no 11, p. 958-964Article in journal (Refereed)
    Abstract [en]

    The pathogenesis of lung injury by exposure to highly toxic sulfur and nitrogen mustards involves alkylating damage of the respiratory epithelium followed by an acute inflammatory response and lung edema. The acute phase is followed by long-term respiratory complications characterized by bronchitis, lung fibrosis, and airway hyperreactivity. In this study, we utilized a mouse model for airway inflammation induced by inhalation exposure to the alkylating nitrogen mustard melphalan, in order to investigate possible beneficial treatment effects by the corticosteroid dexamethasone. In addition, we investigated therapeutic efficacy of liposome-encapsuled vitamin E, an antioxidant formulation previously shown to be efficient in counteracting inflammatory conditions. Influx of inflammatory cells to airways, edema formation, and expression of different cytokines were analyzed 6 and 18 hours after exposure to melphalan. In order to evaluate long-term lung effects, we also investigated collagen deposition and accumulation of lymphocytes at 2 and 4 weeks after exposure. A single intraperitoneal injection of dexamethasone (10 mg/kg body weight) 1 hour after melphalan exposure significantly reduced interleukin (IL)-1 and IL-6 in bronchoalveolar lavage fluid (BALF) and diminished the acute airway inflammation. Our results also indicate that early single-dose treatment with dexamethasone protects against long-term effects observed 2-4 weeks after melphalan exposure, as indicated by reduced lymphocytic response in airways and decreased collagen deposition. Furthermore, our results indicate that also vitamin E (50 mg/kg) reduces acute inflammatory cell influx, and suppresses collagen formation in lung tissue, indicating that this drug could be used in combination with corticosteroids for protection against chemical-induced lung injury.

  • 318. Wilson, Susan J.
    et al.
    Ward, Jonathan A.
    Sousa, Ana R.
    Corfield, Julie
    Bansal, Aruna T.
    De Meulder, Bertrand
    Lefaudeux, Diane
    Auffray, Charles
    Loza, Matthew J.
    Baribaud, Frederic
    Fitch, Neil
    Sterk, Peter J.
    Chung, Kian Fan
    Gibeon, David
    Sun, Kai
    Guo, Yi-Ke
    Adcock, Ian
    Djukanovic, Ratko
    Dahlen, Barbro
    Chanez, Pascal
    Shaw, Dominick
    Krug, Norbert
    Hohlfeld, Jens
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Howarth, Peter H.
    Severe asthma exists despite suppressed tissue inflammation: findings of the U-BIOPRED study2016In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 48, no 5, p. 1307-1319Article in journal (Refereed)
    Abstract [en]

    The U-BIOPRED study is a multicentre European study aimed at a better understanding of severe asthma. It included three steroid-treated adult asthma groups (severe nonsmokers (SAn group), severe current/ex-smokers (SAs/ex group) and those with mild-moderate disease (MMA group)) and healthy controls (HC group). The aim of this cross-sectional, bronchoscopy substudy was to compare bronchial immunopathology between these groups.In 158 participants, bronchial biopsies and bronchial epithelial brushings were collected for immunopathologic and transcriptomic analysis. Immunohistochemical analysis of glycol methacrylate resin-embedded biopsies showed there were more mast cells in submucosa of the HC group (33.6 mm(-2)) compared with both severe asthma groups (SAn: 17.4 mm(-2), p<0.001; SAs/ex: 22.2 mm(-2), p=0.01) and with the MMA group (21.2 mm(-2), p=0.01). The number of CD4(+) lymphocytes was decreased in the SAs/ex group (4.7 mm(-2)) compared with the SAn (11.6 mm(-2), p=0.002), MMA (10.1 mm(-2), p=0.008) and HC (10.6 mm(-2), p<0.001) groups. No other differences were observed.Affymetrix microarray analysis identified seven probe sets in the bronchial brushing samples that had a positive relationship with submucosal eosinophils. These mapped to COX-2 (cyclo-oxygenase-2), ADAM-7 (disintegrin and metalloproteinase domain-containing protein 7), SLCO1A2 (solute carrier organic anion transporter family member 1A2), TMEFF2 (transmembrane protein with epidermal growth factor like and two follistatin like domains 2) and TRPM-1 (transient receptor potential cation channel subfamily M member 1); the remaining two are unnamed.We conclude that in nonsmoking and smoking patients on currently recommended therapy, severe asthma exists despite suppressed tissue inflammation within the proximal airway wall.

  • 319. Wilson, Susan Jane
    et al.
    Faruqi, Ali
    Ward, Jonathan
    Norman, Jenny
    Sousa, Ana
    Corfield, Julie
    Sterk, Peter
    Chung, Fan
    Djukanovic, Ratko
    Dahlen, Barbro
    Chanez, Pascal
    Shaw, Dominick
    Krug, Norbert
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Howarth, Peter
    Holweg, Cecile
    Periostin expression in the U-BIOPRED severe asthma bronchoscopy cohort2018In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 52Article in journal (Other academic)
    Abstract [en]

    Periostin (POSTN) is secreted basolaterally by bronchial epithelial cells in asthma and is expressed in the extracellular matrix where it is thought to play a role in fibrosis and is associated with airway eosinophilia.

    In this study we have assessed the protein expression of POSTN in bronchial biopsies by immunohistochemistry, in serum by the Elecsys Periostin Immunoassay and measured gene expression by Affymetrix arrays in bronchial biopsies, bronchial brushings and in sputum in the U-BIOPRED severe asthma study in the bronchoscopy sub-cohort, which included 4 groups; severe non-smoker asthmatics (SAns), current / ex-smoker severe asthmatics (SAs), mild-moderate asthmatics (MMA) and non-asthmatic healthy controls (HC).

    Subepithelial protein expression in the bronchial biopsies was higher (p=0.02) in SAns, 9.2% (IQR 5.8-12.6)(n=44) compared to SAs 6.2% (3-9.2)(n=16), and in MMA 11% (7.5-12.6)(n=32) compared to SAs (p=0.002) or HC 7.1% (5.5-10.3)(p=0.01)(n=39). There was no difference between SAns and MMA. Gene expression was higher in biopsies from SAns (n=30), -0.044 (IQR -0.425-0.508), compared to both the SAs (n=9), -0.274 (-0.590-0.200), (p=0.02) and HC (n=21), -0.377 (-0.583-0.125), (p=0.008), but similar in MMA. There was no difference between the groups in POSTN serum levels or in gene expression in bronchial brushings or sputum.

    In asthmatics, the biopsy protein expression correlated with the biopsy gene expression, and both correlated with eosinophils numbers in the biopsies and blood, exhaled NO, and thickness of the lamina reticularis.

    These results highlight the potential relevance of tissue POSTN to asthma pathophysiology however, this does not appear to be reflected by serum POSTN measures.

  • 320.
    Zakereh, Khavare
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Exposure to petrodiesel or biodiesel exhaust results in comparable ex vivo thrombus formation2016Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 321. Zou, Ding
    et al.
    Wennman, Heini
    Ekblom, Örjan
    Grote, Ludger
    Arvidsson, Daniel
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Torén, Kjell
    Bergström, Göran
    Börjesson, Mats
    Hedner, Jan
    Insomnia and cardiorespiratory fitness in a middle-aged population: the SCAPIS pilot study2019In: Sleep and Breathing, ISSN 1520-9512, E-ISSN 1522-1709, Vol. 23, no 1, p. 319-326Article in journal (Refereed)
    Abstract [en]

    BackgroundThe relationship between insomnia and cardiorespiratory fitness (CRF), a well-established risk factor for cardiovascular disease, has not been extensively studied. We aimed to assess the independent association between insomnia and CRF in a population-based cohort of subjects aged 50 to 64years.MethodsSubjects participating in the Swedish CArdioPulmonary bioImaging Study (SCAPIS) pilot cohort (n=603, men 47.9%) underwent a submaximal cycle ergometer test for estimation of maximal oxygen consumption (VO(2)max). Data on physical activity and sedentary time were collected via waist-worn accelerometers. An insomnia severity index score 10 was used to define insomnia.ResultsInsomnia was identified in 31.8% of the population. The VO(2)max was significantly lower in insomnia subjects compared with the non-insomnia group (31.26.3 vs. 32.4 +/- 6.5ml*kg(-1)*min(-1), p=0.028). There was no difference in objectively assessed physical activity or time spent sedentary between the groups. In a multivariate generalized linear model adjusting for confounders, an independent association between insomnia status and lower VO(2)max was found in men, but not in women (=-1.15 [95% CI -2.23--0.06] and -0.09 [-1.09-0.92], p=0.038 and 0.866, respectively).Conclusionsp id=ParWe found a modest, but significant, association between insomnia and lower CRF in middle-aged men, but not in women. Our results suggest that insomnia may link to cardiovascular disease via reduced CRF. Insomnia may require a specific focus in the context of health campaigns addressing CRF.

  • 322.
    Ädelroth, Ellinor
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Lungmedicin.
    Hedlund, Ulf
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Lungmedicin.
    Helleday, Ragnberth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Lungmedicin.
    Ledin, M-C
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Levin, Jan-Olof
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pourazar, Jamshid
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Lungmedicin.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine. Lungmedicin.
    Järvholm, Bengt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Yrkes- och miljömedicin.
    Airway inflammation in iron ore miners exposed to dust and diesel exhaust.2006In: Eur Respir J, ISSN 0903-1936, Vol. 27, no 4, p. 714-719Article in journal (Refereed)
  • 323.
    Österlund, Camilla
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Activation of lung epithelial cells by group 2 mite allergens2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Throughout many parts of the world house dust mites (HDM) are considered as a major source of indoor aeroallergens and they are powerful inducers of allergic diseases. Proteolytic HDM allergens are recognised as being able to directly activate respiratory epithelial cells and thereby actively participate in innate immune responses. Although several major HDM allergens lack proteolytic activity, their possible ability to similarly interact with epithelial cells is not known.

    The overall aim of this thesis was therefore to elucidate if and how major non-proteolytic group 2 allergens from different mite species interact with respiratory epithelial cells. The effects of the structurally related Der p 2, Der f 2 and Eur m 2 from different HDM species as well as the storage mite allergen Lep d 2 were studied in vitro using human respiratory epithelial cells. Also the non-proteolytic, but structurally dissimilar, Fel d 1 from cat, Can f 2 from dog, Bet v 1 from birch and Phl p 5a from timothy were studied.

    In this thesis evidence that major group 2 mite allergens activate bronchial epithelial cells is presented. Following allergen exposure the secreted amount of the inflammatory mediators G-CSF, GM-CSF, IL-6, IL-8, MCP-1, MIP-3α and sICAM-1 was increased. Surface expression of ICAM-1 was also increased following allergen exposure. Moreover, Fel d 1 and Can f 2 induced secretion of the same mediators from bronchial epithelial cells, representing two additional protein structures being able to directly induce cell activation. In experiments using specific inhibitors and siRNA transfection, it was shown that the mite allergens engage TLR4 and activation through MyD88, MAPK and NF-κB signal transduction pathways.

    In conclusion, the novel findings in this thesis provide knowledge on how major aeroallergens, in addition to their ability to provoke specific adaptive immune responses, may aggravate a respiratory airway disease by adjuvant-like activation of inflammatory responses in bronchial epithelial cells. This differs from previously reported allergen-induction of epithelial cells by the clear independency of proteolytic activation.

  • 324.
    Österlund, Camilla
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Activation of bronchial epithelial cells by the house mite allergens Der p 2 and Der f 2 is mediated through TLR4 signalling while activation by the cat allergen Fel d 1 is mediated through TLR2Article in journal (Refereed)
  • 325.
    Österlund, Camilla
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Grönlund, H
    Polovic, N
    Sundström, S
    Gafvelin, G
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    The non-proteolytic house dust mite allergen Der p 2 induce NF-kappaB and MAPK dependent activation of bronchial epithelial cells2009In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 39, no 8, p. 1199-1208Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: House dust mites (HDM) are well-known as a source of indoor aeroallergens and for causing allergic airway diseases. Some proteolytic HDM allergens are known to activate respiratory epithelial cells to produce pro-inflammatory mediators, while there is limited knowledge regarding such activity among non-proteolytic HDM allergens.

    OBJECTIVE: To investigate whether Der p 2, a major non-proteolytic allergen of Dermatophagoides pteronyssinus, activates respiratory epithelial cells to produce mediators involved in asthma pathogenesis and to elucidate the mechanism of such activation.

    METHODS: The human bronchial epithelial cell line BEAS-2B, normal human bronchial epithelial (NHBE) cells and the alveolar epithelial cell line A549 were exposed to recombinant Der p 2. Following exposure, we analysed a panel of soluble mediators and cell adhesion receptors involved in asthma pathogenesis by promoting recruitment, survival and binding of inflammatory cells. The involvement of nuclear factor (NF)-kappaB and mitogen-activated protein kinases (MAPKs) was studied using specific inhibitors.

    RESULTS: Der p 2 activated bronchial BEAS-2B and NHBE cells, but not alveolar A549 cells. In BEAS-2B cells Der p 2 induced dose-dependent up-regulation in both mRNA level and protein secretion of granulocyte-macrophage colony-stimulating factor, IL-6, IL-8, monocyte-chemotactic protein-1 and macrophage inflammatory protein-3alpha. Secretion as well as surface expression of intercellular adhesion molecule (ICAM)-1 was also up-regulated, which was associated with increased adhesion of monocytes to the epithelial cells. The release of cytokines and chemokines was regulated by NF-kappaB and MAPK activation in different ways, while expression of ICAM-1 was solely dependent on NF-kappaB activation.

    CONCLUSION: These results show that Der p 2 activates respiratory epithelial cells, indicating that this non-proteolytic allergen, in addition to its immunogenic properties, can aggravate respiratory airway disease by adjuvant-like activation of the lung epithelium.

  • 326.
    Österlund, Camilla
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Grönlund, Hans
    Gafvelin, Guro
    Bucht, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Non-proteolytic aeroallergens from mites, cat and dog exert adjuvant-like activation of bronchial epithelial cells2011In: International Archives of Allergy and Immunology, ISSN 1018-2438, E-ISSN 1423-0097, Vol. 155, no 2, p. 111-118Article in journal (Refereed)
    Abstract [en]

    Background: Exposure to seasonal or indoor allergens may cause sensitisation and development of allergic airway diseases. We have previously demonstrated that the non-proteolytic major house dust mite (HDM) allergen Der p 2 stimulates pro-inflammatory responses in bronchial epithelial cells. We aimed to determine if other clinically relevant non-proteolytic aeroallergens originating from HDMs, storage mites, cat, dog, birch and timothy also activate respiratory epithelial cells.

    Methods: Cultures of human bronchial epithelial cell line BEAS-2B, normal human bronchial epithelial cells and alveolar epithelial cell line A549 were exposed to recombinant (r)Der p 2, natural (n)Der f 2, rEur m 2, rLep d 2, rFel d 1, nFel d 1, rCan f 2, rBet v 1 or rPhl p 5a. A panel of secreted mediators and expression of cell adhesion receptors involved in recruitment, survival and adhesion of inflammatory cells in asthmatic airways was assessed.

    Results: The mite allergens rDer p 2, nDer f 2, rEur m 2 and rLep d 2 as well as the cat and dog allergens rFel d 1, nFel d 1 and rCan f 2 induced granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6, IL-8, monocyte-chemotactic protein-1 and macrophage inflammatory protein-3α secretion from bronchial epithelial cells as well as surface expression of intracellular adhesion molecule-1. The pollen allergens rBet v 1 and rPhl p 5a from birch and timothy did not activate the cells. None of the studied allergens affected the alveolar epithelial cells.

    Conclusion: These results show that both mite and structurally unrelated cat and dog allergens can activate respiratory epithelial cells by adjuvant-like protease-independent mechanisms.

4567 301 - 326 of 326
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