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Sehlstedt, Maria
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Friberg, M., Behndig, A. F., Bosson, J., Muala, A., Barath, S., Dove, R., . . . Pourazar, J. (2023). Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response. Particle and Fibre Toxicology, 20(1), Article ID 47.
Öppna denna publikation i ny flik eller fönster >>Human exposure to diesel exhaust induces CYP1A1 expression and AhR activation without a coordinated antioxidant response
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2023 (Engelska)Ingår i: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 20, nr 1, artikel-id 47Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BioMed Central (BMC), 2023
Nyckelord
Aryl hydrocarbon receptor, Diesel exhaust, Immunohistochemistry, Oxidative stress, Xenobiotic metabolism
Nationell ämneskategori
Farmakologi och toxikologi
Identifikatorer
urn:nbn:se:umu:diva-218128 (URN)10.1186/s12989-023-00559-1 (DOI)38062420 (PubMedID)2-s2.0-85178874563 (Scopus ID)
Forskningsfinansiär
Västerbottens läns landstingHjärt-LungfondenUmeå universitet
Tillgänglig från: 2023-12-15 Skapad: 2023-12-15 Senast uppdaterad: 2023-12-15Bibliografiskt granskad
Hansson, A., Rankin, G., Uski, O., Sehlstedt, M., Pourazar, J., Lindgren, R., . . . Muala, A. (2023). Reduced bronchoalveolar macrophage phagocytosis and cytotoxic effects after controlled short-term exposure to wood smoke in healthy humans. Particle and Fibre Toxicology, 20(1), Article ID 30.
Öppna denna publikation i ny flik eller fönster >>Reduced bronchoalveolar macrophage phagocytosis and cytotoxic effects after controlled short-term exposure to wood smoke in healthy humans
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2023 (Engelska)Ingår i: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 20, nr 1, artikel-id 30Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
BioMed Central (BMC), 2023
Nyckelord
Air pollution, Biomass combustion, Bronchoscopy, Controlled human exposure, Cytotoxicity, In vitro, Macrophages, Phagocytosis, Wood smoke
Nationell ämneskategori
Lungmedicin och allergi Dermatologi och venereologi
Identifikatorer
urn:nbn:se:umu:diva-212714 (URN)10.1186/s12989-023-00541-x (DOI)37517998 (PubMedID)2-s2.0-85165871931 (Scopus ID)
Forskningsfinansiär
Hjärt-LungfondenVästerbottens läns landstingEnergimyndighetenUmeå universitet
Tillgänglig från: 2023-08-15 Skapad: 2023-08-15 Senast uppdaterad: 2023-08-15Bibliografiskt granskad
Pourazar, J., Sehlstedt, M., Rankin, G., Uski, O., Boman, C., Lopez, N., . . . Muala, A. (2019). Exposure to wood smoke induced activation of lymphocyte subtypes in peripheral blood. Paper presented at European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.. European Respiratory Journal, 54
Öppna denna publikation i ny flik eller fönster >>Exposure to wood smoke induced activation of lymphocyte subtypes in peripheral blood
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2019 (Engelska)Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
Sheffield: European Respiratory Society Journals, 2019
Nyckelord
Air pollution, Systemic effect, Inflammation
Nationell ämneskategori
Lungmedicin och allergi
Identifikatorer
urn:nbn:se:umu:diva-168164 (URN)10.1183/13993003.congress-2019.PA1983 (DOI)000507372402143 ()
Konferens
European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.
Projekt
Bio4Energy
Forskningsfinansiär
Bio4Energy
Anmärkning

Supplement: 63. Meeting Abstract: PA1983.

Tillgänglig från: 2020-03-17 Skapad: 2020-03-17 Senast uppdaterad: 2023-05-09Bibliografiskt granskad
Muala, A., Österdahl, R., Sehlstedt, M., Rankin, G., Pourazar, J., Bosson, J. A., . . . Öhberg, F. (2019). Small airways effects of exposure to wood smoke. Paper presented at European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.. European Respiratory Journal, 54
Öppna denna publikation i ny flik eller fönster >>Small airways effects of exposure to wood smoke
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2019 (Engelska)Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
Sheffield: European Respiratory Society Journals, 2019
Nyckelord
Asthma, Air pollution
Nationell ämneskategori
Lungmedicin och allergi
Identifikatorer
urn:nbn:se:umu:diva-168166 (URN)10.1183/13993003.congress-2019.PA2829 (DOI)000507372403325 ()
Konferens
European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.
Projekt
Bio4Energy
Forskningsfinansiär
Bio4Energy
Tillgänglig från: 2020-03-17 Skapad: 2020-03-17 Senast uppdaterad: 2023-05-09Bibliografiskt granskad
Hansson, A., Rankin, G., Uski, O., Sehlstedt, M., Bosson, J. A., Pourazar, J., . . . Muala, A. (2019). Wood smoke effects on epithelial cell lines and human airway cells. Paper presented at European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.. European Respiratory Journal, 54
Öppna denna publikation i ny flik eller fönster >>Wood smoke effects on epithelial cell lines and human airway cells
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2019 (Engelska)Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
European Respiratory Society Journals, 2019
Nyckelord
Bronchoscopy, Immunology, Air pollution
Nationell ämneskategori
Lungmedicin och allergi
Identifikatorer
urn:nbn:se:umu:diva-168169 (URN)10.1183/13993003.congress-2019.PA5448 (DOI)000507372407158 ()
Konferens
European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.
Projekt
Bio4Energy
Forskningsfinansiär
Bio4Energy
Anmärkning

Supplement: 63. Meeting Abstract: PA5448.

Tillgänglig från: 2020-03-17 Skapad: 2020-03-17 Senast uppdaterad: 2023-05-09Bibliografiskt granskad
Sehlstedt, M., Muala, A., Pourazar, J., Rankin, G., Uski, O., Behndig, A. F., . . . Blomberg, A. (2019). Wood smoke exposure induces the activation of bronchoalveolar lavage lymphocytes. Paper presented at European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.. European Respiratory Journal, 54
Öppna denna publikation i ny flik eller fönster >>Wood smoke exposure induces the activation of bronchoalveolar lavage lymphocytes
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2019 (Engelska)Ingår i: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 54Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Ort, förlag, år, upplaga, sidor
European Respiratory Society Journals, 2019
Nyckelord
Air pollution, Bronchoalveolar lavage, Inflammation
Nationell ämneskategori
Lungmedicin och allergi
Identifikatorer
urn:nbn:se:umu:diva-168165 (URN)10.1183/13993003.congress-2019.PA2828 (DOI)000507372403324 ()
Konferens
European-Respiratory-Society (ERS) International Congress, Madrid, SPAIN, SEP 28-OCT 02, 2019.
Projekt
Bio4Energy
Forskningsfinansiär
Bio4Energy
Anmärkning

Supplement: 63. Meeting Abstract: PA2828.

Tillgänglig från: 2020-03-17 Skapad: 2020-03-17 Senast uppdaterad: 2023-05-09Bibliografiskt granskad
Gouveia-Figueira, S. C., Karimpour, M., Bosson, J. A., Blomberg, A., Unosson, J., Sehlstedt, M., . . . Nording, M. L. (2018). Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust. Analytica Chimica Acta, 1018, 62-69
Öppna denna publikation i ny flik eller fönster >>Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust
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2018 (Engelska)Ingår i: Analytica Chimica Acta, ISSN 0003-2670, E-ISSN 1873-4324, Vol. 1018, s. 62-69Artikel i tidskrift (Refereegranskat) Published
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.

Ort, förlag, år, upplaga, sidor
Elsevier, 2018
Nyckelord
Oxylipin, Endocannabinoid, Eicosanoid, Mass spectrometry, Rapeseed methyl ester, Inflammation
Nationell ämneskategori
Arbetsmedicin och miljömedicin Lungmedicin och allergi
Identifikatorer
urn:nbn:se:umu:diva-148622 (URN)10.1016/j.aca.2018.02.032 (DOI)000428798200008 ()29605135 (PubMedID)2-s2.0-85042661500 (Scopus ID)
Forskningsfinansiär
Vetenskapsrådet, 2010-303AFA Försäkring, 130320
Tillgänglig från: 2018-06-26 Skapad: 2018-06-26 Senast uppdaterad: 2023-05-09Bibliografiskt granskad
Pfeffer, P. E., Ho, T. R., Mann, E. H., Kelly, F. J., Sehlstedt, M., Pourazar, J., . . . Hawrylowicz, C. M. (2018). Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes. Immunology, 153(4), 502-512
Öppna denna publikation i ny flik eller fönster >>Urban particulate matter stimulation of human dendritic cells enhances priming of naive CD8 T lymphocytes
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2018 (Engelska)Ingår i: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 153, nr 4, s. 502-512Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Epidemiological studies have consistently shown associations between elevated concentrations of urban particulate matter (UPM) air pollution and exacerbations of asthma and chronic obstructive pulmonary disease, which are both associated with viral respiratory infections. The effects of UPM on dendritic cell (DC) -stimulated CD4 T lymphocytes have been investigated previously, but little work has focused on CD8 T-lymphocyte responses despite their importance in anti-viral immunity. To address this, we examined the effects of UPM on DC-stimulated naive CD8 T-cell responses. Expression of the maturation/activation markers CD83, CCR7, CD40 and MHC class I on human myeloid DCs (mDCs) was characterized by flow cytometry after stimulation with UPM in vitro in the presence/absence of granulocyte-macrophage colony-stimulating factor (GM-CSF). The capacity of these mDCs to stimulate naive CD8 T-lymphocyte responses in allogeneic co-culture was then assessed by measuring T-cell cytokine secretion using cytometric bead array, and proliferation and frequency of interferon-γ (IFN-γ)-producing T lymphocytes by flow cytometry. Treatment of mDCs with UPM increased expression of CD83 and CCR7, but not MHC class I. In allogeneic co-cultures, UPM treatment of mDCs enhanced CD8 T-cell proliferation and the frequency of IFN-γ+ cells. The secretion of tumour necrosis factor-α, interleukin-13, Granzyme A and Granzyme B were also increased. GM-CSF alone, and in concert with UPM, enhanced many of these T-cell functions. The PM-induced increase in Granzyme A was confirmed in a human experimental diesel exposure study. These data demonstrate that UPM treatment of mDCs enhances priming of naive CD8 T lymphocytes and increases production of pro-inflammatory cytokines. Such UPM-induced stimulation of CD8 cells may potentiate T-lymphocyte cytotoxic responses upon concurrent airway infection, increasing bystander damage to the airways.

Ort, förlag, år, upplaga, sidor
John Wiley & Sons, 2018
Nyckelord
CD8(+) T lymphocyte, dendritic cells, granulocyte-macrophage colony-stimulating factor, granzyme, lung, particulate matter
Nationell ämneskategori
Immunologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-146142 (URN)10.1111/imm.12852 (DOI)000426728600010 ()29044495 (PubMedID)2-s2.0-85036569704 (Scopus ID)
Tillgänglig från: 2018-05-15 Skapad: 2018-05-15 Senast uppdaterad: 2023-03-24Bibliografiskt granskad
Muala, A., Rankin, G., Sehlstedt, M., Unosson, J., Bosson, J. A., Behndig, A., . . . Sandström, T. (2015). Acute exposure to wood smoke from incomplete combustion - indications of cytotoxicity. Particle and Fibre Toxicology, 12, Article ID 33.
Öppna denna publikation i ny flik eller fönster >>Acute exposure to wood smoke from incomplete combustion - indications of cytotoxicity
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2015 (Engelska)Ingår i: Particle and Fibre Toxicology, E-ISSN 1743-8977, Vol. 12, artikel-id 33Artikel i tidskrift (Refereegranskat) Published
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.

Nyckelord
Air pollution, Biomass, Bronchoscopy, Cytotoxicity, Neutrophils, Lymphocytes, Mast cells
Nationell ämneskategori
Miljövetenskap
Identifikatorer
urn:nbn:se:umu:diva-111761 (URN)10.1186/s12989-015-0111-7 (DOI)000363833500001 ()26511835 (PubMedID)2-s2.0-84945908415 (Scopus ID)
Tillgänglig från: 2015-11-25 Skapad: 2015-11-23 Senast uppdaterad: 2023-07-07Bibliografiskt granskad
Pourazar, J., Behndig, A. F., Helleday, R., Muala, A., Rankin, G., Sehlstedt, M., . . . Bosson, J. A. (2015). Airway Inflammatory Response In Healthy Subjects Following Chamber Exposure To 100% Rme Biodiesel. Paper presented at International Conference of the American-Thoracic-Society (ATS), MAY 15-20, 2015, Denver, CO. American Journal of Respiratory and Critical Care Medicine, 191, Article ID A5252.
Öppna denna publikation i ny flik eller fönster >>Airway Inflammatory Response In Healthy Subjects Following Chamber Exposure To 100% Rme Biodiesel
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2015 (Engelska)Ingår i: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 191, artikel-id A5252Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Lungmedicin och allergi
Identifikatorer
urn:nbn:se:umu:diva-123483 (URN)000377582807072 ()
Konferens
International Conference of the American-Thoracic-Society (ATS), MAY 15-20, 2015, Denver, CO
Tillgänglig från: 2016-07-06 Skapad: 2016-07-04 Senast uppdaterad: 2023-05-09Bibliografiskt granskad
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