20-HETE Mediates Ozone-Induced, Neutrophil-Independent Airway Hyper-Responsiveness in Mice

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20-HETE Mediates Ozone-Induced, Neutrophil-Independent Airway Hyper-Responsiveness in Mice

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dc.contributor.author Cooper, Philip R.
dc.contributor.author Mesaros, A. Clementina
dc.contributor.author Stark, Christopher M.
dc.contributor.author Douaidy, Karim
dc.contributor.author Mittelman, Michael A.
dc.contributor.author Blair, Ian A.
dc.contributor.author Panettieri, Reynold A.
dc.contributor.author Zhang, Jie
dc.contributor.author Christmas, Peter
dc.contributor.author Soberman, Roy Jason
dc.date.accessioned 2012-02-19T23:35:33Z
dc.date.issued 2010
dc.identifier.citation Cooper, Philip R., A. Clementina Mesaros, Jie Zhang, Peter Christmas, Christopher M. Stark, Karim Douaidy, Michael A. Mittelman, Roy J. Soberman, Ian A. Blair, and Reynold A. Panettieri. 2010. 20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice. PLoS ONE 5(4): e10235. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:8191180
dc.description.abstract Background Ozone, a pollutant known to induce airway hyper-responsiveness (AHR), increases morbidity and mortality in patients with obstructive airway diseases and asthma. We postulate oxidized lipids mediate in vivo ozone-induced AHR in murine airways.Methodology/Principal Findings Male BALB/c mice were exposed to ozone (3 or 6 ppm) or filtered air (controls) for 2 h. Precision cut lung slices (PCLS; 250 µm thickness) containing an intrapulmonary airway (∼0.01 mm\(^2\) lumen area) were prepared immediately after exposure or 16 h later. After 24 h, airways were contracted to carbachol (CCh). Log EC\(_{50}\) and E\(_{\text{max}}\) values were then calculated by measuring the airway lumen area with respect to baseline. In parallel studies, dexamethasone (2.5 mg/kg), or 1-aminobenzotriazol (ABT) (50 mg/kg) were given intraperitoneal injection to naïve mice 18 h prior to ozone exposure. Indomethacin (10 mg/kg) was administered 2 h prior. Cell counts, cytokine levels and liquid chromatography-mass spectrometry (LC-MS) for lipid analysis were assessed in bronchoalveolar lavage (BAL) fluid from ozone exposed and control mice. Ozone acutely induced AHR to CCh. Dexamethasone or indomethacin had little effect on the ozone-induced AHR; while, ABT, a cytochrome P450 inhibitor, markedly attenuated airway sensitivity. BAL fluid from ozone exposed animals, which did not contain an increase in neutrophils or interleukin (IL)-6 levels, increased airway sensitivity following in vitro incubation with a naïve PCLS. In parallel, significant increases in oxidized lipids were also identified using LC-MS with increases of 20-HETE that were decreased following ABT treatment.Conclusions/Significance These data show that ozone acutely induces AHR to CCh independent of inflammation and is insensitive to steroid treatment or cyclooxygenase (COX) inhibition. BAL fluid from ozone exposed mice mimicked the effects of in vivo ozone exposure that were associated with marked increases in oxidized lipids. 20-HETE plays a pivotal role in mediating acute ozone-induced AHR. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0010235 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857875/pdf/ en_US
dash.license LAA
dc.title 20-HETE Mediates Ozone-Induced, Neutrophil-Independent Airway Hyper-Responsiveness in Mice en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Soberman, Roy Jason
dc.date.available 2012-02-19T23:35:33Z
dash.affiliation.other HMS^Medicine-Massachusetts General Hospital en_US

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