The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice

Courey, Anthony J.; Horowitz, Jeffrey C.; Kim, Kevin K.; Koh, Timothy J.; Novak, Margaret L.; Subbotina, Natalya; Warnock, Mark; Xue, Bing; Cunningham, Andrew K.; Lin, Yujing; Goldklang, Monica; Simon, Richard H.; Lawrence, Daniel A.; Sisson, Thomas H.

doi:10.1182/blood-2010-12-324574

Cited by 52 publications

(49 citation statements)

References 35 publications

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“…Studies in lung (70) and liver (180) fibrosis models have shown that the profibrotic effect of PAI-1 depends on its inhibition of tPA or uPA and support the notion that impairment of normal extracellular collagen breakdown pathways can lead to pathologic fibrosis. However, another recent study on PAI-1 Ϫ/Ϫ mice that had been transgenically engineered to selectively express PAI-1 protein constructs including or lacking PAI-1's antiprotease domain concluded that the major contribution of PAI-1 to fibrogenesis rests not on its antiproteolytic function but its ability to bind vitronectin (30). PAI-1 is clearly important in the development and resolution of fibrosis.…”

Section: Extracellular Pathway Of Collagen Degradationmentioning

confidence: 99%

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

McKleroy

Lee

Atabai

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

210

169

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Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production.

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Section: Extracellular Pathway Of Collagen Degradationmentioning

confidence: 99%

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

McKleroy

Lee

Atabai

2013

American Journal of Physiology-Lung Cellular and Molecular Phys

210

169

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“…Plasminogen activator inhibitor (PAI)-1 concentrations in cell supernatants were measured using a carboxylated microsphere-based ELISA (Luminex) (8).…”

Section: Pai-1 Concentrationsmentioning

confidence: 99%

Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis

Naik

Bozyk

Bentley

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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235

232

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective therapeutics. Periostin has been reported to be elevated in IPF patients relative to controls, but its sources and mechanisms of action remain unclear. We confirm excess periostin in lungs of IPF patients and show that IPF fibroblasts produce periostin. Blood was obtained from 54 IPF patients (all but 1 with 48 wk of follow-up). We show that periostin levels predict clinical progression at 48 wk (hazard ratio = 1.47, 95% confidence interval = 1.03–2.10, P < 0.05). Monocytes and fibrocytes are sources of periostin in circulation in IPF patients. Previous studies suggest that periostin may regulate the inflammatory phase of bleomycin-induced lung injury, but periostin effects during the fibroproliferative phase of the disease are unknown. Wild-type and periostin-deficient (periostin−/−) mice were anesthetized and challenged with bleomycin. Wild-type mice were injected with bleomycin and then treated with OC-20 Ab (which blocks periostin and integrin interactions) or control Ab during the fibroproliferative phase of disease, and fibrosis and survival were assessed. Periostin expression was upregulated quickly after treatment with bleomycin and remained elevated. Periostin−/− mice were protected from bleomycin-induced fibrosis. Instillation of OC-20 during the fibroproliferative phase improved survival and limited collagen deposition. Chimeric mouse studies suggest that hematopoietic and structural sources of periostin contribute to lung fibrogenesis. Periostin was upregulated by transforming growth factor-β in lung mesenchymal cells, and periostin promoted extracellular matrix deposition, mesenchymal cell proliferation, and wound closure. Thus periostin plays a vital role in late stages of pulmonary fibrosis and is a potential biomarker for disease progression and a target for therapeutic intervention.

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“…There exist many plausible mechanisms by which PAI-1 might influence this monocyte recruitment. For example, PAI-1 may enhance the transendothelial migration of Ly6C high monocytes across the pulmonary vasculature (perhaps through its vitronectinbinding function) [42]. Alternatively, PAI-1 may alter the expression or recognition of monocyte/macrophage chemotactic factors (ie CCL2 or CCL7).…”

Section: Discussionmentioning

confidence: 99%

“…This induction of PAI-1 expression mimics the elevated levels of intrapulmonary PAI-1 observed in patients with pulmonary fibrosis of varying aetiologies [14][15][16]18]. PAI-1 production is also increased in the lung following bleomycin-mediated injury [19,20,[22][23][24][25][26]42]. To determine whether the enhanced PAI-1 production following type II AEC injury was required for fibro-genesis, we generated transgenic mice that expressed human DTR on their type II AECs and were deficient in PAI-1.…”

Section: Discussionmentioning

confidence: 99%

PAI-1 Promotes The Accumulation Of Exudate Macrophages And Worsens Pulmonary Fibrosis Following Type II Alveolar Epithelial Cell Injury

Sisson¹,

Osterholzer²,

Christensen³

et al. 2012

C68. Old and New Pathways to Pulmonary Fibrosis

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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 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...

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The vitronectin-binding function of PAI-1 exacerbates lung fibrosis in mice

Cited by 52 publications

References 35 publications

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis

PAI-1 Promotes The Accumulation Of Exudate Macrophages And Worsens Pulmonary Fibrosis Following Type II Alveolar Epithelial Cell Injury

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