Neutralization of the anti-fibrinolytic function of plasminogen activator inhibitor-1 resolves skin fibrosis.

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Neutralization of the anti-fibrinolytic function of plasminogen activator inhibitor-1 resolves skin fibrosis.

Arthritis Rheumatol. 2015 Sep 28;

Authors: Lemaire R, Burwell T, Sun H, Delaney T, Bakken J, Cheng L, Rebelatto MC, Czapiga M, de-Mendez I, Coyle AJ, Herbst R, Lafyatis R, Connor J

Abstract
Background - Systemic scleroderma (SSc) is a fibrotic disease featuring an obliterative vasculopathy with thrombosis and impairment of the coagulation-fibrinolysis balance. Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of profibrinolytic plasminogen activators (PAs). This study evaluates the contribution of PAI-1 to SSc pathology in the skin.
METHODS: PAI-1 was evaluated in diffuse and limited SSc skin by IHC. PAI-1 contribution to SSc pathology was tested in vivo in murine Graft-vs-Host (GVH) and bleomycin models of progressive skin fibrosis and in vitro in dermal human microvascular endothelial cells (HMVEC) using a monoclonal antibody that selectively prevents PAI-1-to-PA binding. Results - Skin from diffuse and limited SSc patients showed increased PAI-1 levels in the epidermis and microvessel endothelium. PAI-1 neutralization in the GVH model led to dramatic, dose-dependent clinical skin score improvement, concomitant with vasculopathy resolution, including reduction of fibrinolysis regulators and vascular injury markers, as well as reduction of inflammation. Resolution of vasculopathy and inflammation was associated with skin fibrosis resolution, as assessed by reduction of collagen content and expression of key profibrotic mediators, including Transforming Growth Factor-β1 (TGF-β1) and Tissue Inhibitor of Metalloproteinase-1 (TIMP-1). Similar to the GVH model, PAI-1 neutralization reduced dermal inflammation and fibrosis in the bleomycin model. PAI-1 neutralization stimulated plasmin-mediated Metallopeptidase-1 (MMP-1) activation in dermal HMVECs. Conclusion - Neutralization of the anti-fibrinolytic function of PAI-1 resolved skin fibrosis by limiting the extent of initial vascular injury and connective tissue inflammation. These data suggest that PAI-1 represents an important checkpoint in disease pathology in human SSc. This article is protected by copyright. All rights reserved.

PMID: 26414805 [PubMed - as supplied by publisher]