| PAI-1 Promotes the Accumulation of Exudate Macrophages and Worsens Pulmonary Fibrosis Following Type II Alveolar Epithelial Cell Injury. | |
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MedLine Citation:
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PMID: 22262246 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Fibrotic 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 (AEC) are specifically injured by administering diphtheria toxin (DT) to mice genetically engineered to express the human DT receptor (DTR) off of 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. |
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Authors:
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John J Osterholzer; Paul J Christensen; Vibha Lama; Jeffrey C Horowitz; Noboru Hattori; Natalya Subbotina; Andrew Cunningham; Yujing Lin; Benjamin J Murdock; Roger E Morey; Michal A Olszewski; Daniel A Lawrence; Richard H Simon; Thomas H Sisson |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-19 |
Journal Detail:
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Title: The Journal of pathology Volume: - ISSN: 1096-9896 ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-20 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0204634 Medline TA: J Pathol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
Affiliation:
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Division of Pulmonary and Critical Care Medicine. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI. 48109; Research Service, Ann Arbor VA Health System, Department of Veterans Affairs Health System. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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