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 Copyright © 2012 Author contributionsJJO planned and performed experiments to quantify macrophage accumulation and to analyse macrophage expression of PAI-1 and collagen, and also assisted with manuscript preparation; PJC planned and performed experiments to analyse PAI-1 expression by injured type II alveolar epithelial cells; VL planned and performed experiments to co-immunostain PAI-1 and surfactant protein C; JCH assisted in experimental planning and data interpretation for the entire manuscript, and also assisted with manuscript preparation; NH assisted in experimental planning and data interpretation for the entire manuscript; NS performed all of the in vivo experiments; AC assisted with all of the in vivo experiments and managed the breeding colonies for the DTR mice; YL assisted with all of the in vivo experiments and managed the breeding colonies for the DTR mice; BJM assisted with experiments to quantify macrophage accumulation and to analyse macrophage expression of PAI-1 and collagen; REM assisted with experiments to quantify macrophage accumulation and to analyse macrophage expression of PAI-1 and collagen; MAO assisted with experiments to quantify macrophage accumulation and to analyse macrophage expression of PAI-1 and collagen; DAL performed experiments to quantify PAI-1 levels in DTR mice following targeted epithelial cell injury; RHS assisted in experimental planning and data interpretation for the entire manuscript, and also assisted with manuscript preparation; THS generated the hypothesis, planned the experiments, interpreted the data for the entire manuscript and was also the primary author. SUPPORTING INFORMATION ON THE INTERNETThe following supporting information may be found in the online version of this article: Supplementary materials and methods Figure S1. PAI-1 is associated with decreased survival following type II AEC injury. NIH Public AccessAuthor Manuscript J Pathol. Author manuscript; available in PMC 2013 October 01. 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 compa...