title: PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury.
abstract: 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 (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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Christensen
authors.forename: Vibha
authors.initials: V
authors.lastname: Lama
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Horowitz
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.forename: Natalya
authors.initials: N
authors.lastname: Subbotina
authors.forename: Andrew
authors.initials: A
authors.lastname: Cunningham
authors.forename: Yujing
authors.initials: Y
authors.lastname: Lin
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Murdock
authors.forename: Roger E
authors.initials: RE
authors.lastname: Morey
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Richard H
authors.initials: RH
authors.lastname: Simon
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Sisson
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D024042:Collagen Type I / Q000378:metabolism; D004167:Diphtheria Toxin / Q000633:toxicity; D004195:Disease Models, Animal; D005122:Exudates and Transudates / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis / Q000378:metabolism*; D011042:Poisons / Q000633:toxicity; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D004167:Diphtheria Toxin; D017395:Plasminogen Activator Inhibitor 1; D011042:Poisons; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C051321:SERPINE1 protein, human