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PAI‐1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury

dc.contributor.authorOsterholzer, John Jen_US
dc.contributor.authorChristensen, Paul Jen_US
dc.contributor.authorLama, Vibhaen_US
dc.contributor.authorHorowitz, Jeffrey Cen_US
dc.contributor.authorHattori, Noboruen_US
dc.contributor.authorSubbotina, Natalyaen_US
dc.contributor.authorCunningham, Andrewen_US
dc.contributor.authorLin, Yujingen_US
dc.contributor.authorMurdock, Benjamin Jen_US
dc.contributor.authorMorey, Roger Een_US
dc.contributor.authorOlszewski, Michal Aen_US
dc.contributor.authorLawrence, Daniel Aen_US
dc.contributor.authorSimon, Richard Hen_US
dc.contributor.authorSisson, Thomas Hen_US
dc.date.accessioned2012-10-02T17:20:16Z
dc.date.available2013-11-04T19:53:16Zen_US
dc.date.issued2012-10en_US
dc.identifier.citationOsterholzer, John J; Christensen, Paul J; Lama, Vibha; Horowitz, Jeffrey C; Hattori, Noboru; Subbotina, Natalya; Cunningham, Andrew; Lin, Yujing; Murdock, Benjamin J; Morey, Roger E; Olszewski, Michal A; Lawrence, Daniel A; Simon, Richard H; Sisson, Thomas H (2012). "PAI‐1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury ." The Journal of Pathology 228(2): 170-180. <http://hdl.handle.net/2027.42/93723>en_US
dc.identifier.issn0022-3417en_US
dc.identifier.issn1096-9896en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/93723
dc.description.abstractFibrotic disorders of the lung are associated with perturbations in the plasminogen activation system. Specifically, plasminogen activator inhibitor‐1 (PAI‐1) expression is increased relative to the plasminogen activators. A direct role for this imbalance in modulating the severity of lung scarring following injury has been substantiated in the bleomycin model of pulmonary fibrosis. However, it remains unclear whether derangements in the plasminogen activation system contribute more generally to the pathogenesis of lung fibrosis beyond bleomycin injury. To answer this question, we employed an alternative model of lung scarring, in which type II alveolar epithelial cells (AECs) are specifically injured by administering diphtheria toxin (DT) to mice genetically engineered to express the human DT receptor (DTR) off the surfactant protein C promoter. This targeted AEC injury results in the diffuse accumulation of interstitial collagen. In the present study, we found that this targeted type II cell insult also increases PAI‐1 expression in the alveolar compartment. We identified AECs and lung macrophages to be sources of PAI‐1 production. To determine whether this elevated PAI‐1 concentration was directly related to the severity of fibrosis, DTR + mice were crossed into a PAI‐1‐deficient background (DTR + : PAI‐1 −/− ). DT administration to DTR + : PAI‐1 −/− animals caused significantly less fibrosis than was measured in DTR + mice with intact PAI‐1 production. PAI‐1 deficiency also abrogated the accumulation of CD11b + exudate macrophages that were found to express PAI‐1 and type‐1 collagen. These observations substantiate the critical function of PAI‐1 in pulmonary fibrosis pathogenesis and provide new insight into a potential mechanism by which this pro‐fibrotic molecule influences collagen accumulation. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.en_US
dc.publisherJohn Wiley & Sons, Ltd.en_US
dc.subject.otherPAI‐1en_US
dc.subject.otherFibrosisen_US
dc.subject.otherMacrophageen_US
dc.subject.otherLungen_US
dc.titlePAI‐1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injuryen_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelPathologyen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.peerreviewedPeer Revieweden_US
dc.contributor.affiliationumUniversity of Michigan Medical Center, Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, 1150 West Medical Center Drive, 6301 MSRB III, Ann Arbor, MI 48109‐5642, USA.en_US
dc.contributor.affiliationumDivision of Cardiology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USAen_US
dc.contributor.affiliationumDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USAen_US
dc.contributor.affiliationotherResearch Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System, Ann Arbor, MI, USAen_US
dc.contributor.affiliationotherDepartment of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Japanen_US
dc.identifier.pmid22262246en_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/93723/1/3992_ftp.pdf
dc.identifier.doi10.1002/path.3992en_US
dc.identifier.sourceThe Journal of Pathologyen_US
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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