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Semin Thromb Hemost 2017; 43(2): 169-177
DOI: 10.1055/s-0036-1586228
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Role of Plasminogen Activator Inhibitor Type-1 in Fibrosis

Panagiotis Flevaris
1   Department of Medicine, Northwestern University, Chicago, Illinois
,
Douglas Vaughan
1   Department of Medicine, Northwestern University, Chicago, Illinois
› Author Affiliations
Further Information

Publication History

Publication Date:
24 August 2016 (online)

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Abstract

Extracellular matrix (ECM) deposition during wound healing is a physiological response to an insult. Wound healing becomes deregulated in the setting of chronic injury or long-standing metabolic disease, leading to the accumulation of ECM components and fibrosis. Matrix protein turnover is determined by the rate of synthesis as well as the rate of proteolytic degradation and clearance by matrix metalloproteinases (MMPs). The persistent activation of interstitial myofibroblasts, coupled with defects in matrix proteolysis, ultimately disrupts tissue architecture and leads to biochemical and mechanical organ dysfunction with eventual organ failure. Plasminogen activator inhibitor type-1 (PAI-1) regulates tissue homeostasis and wound healing by inhibiting plasmin-mediated MMP activation. Multiple reports using models of liver, lung, and kidney fibrosis suggest that PAI-1 deficiency or inhibition of PAI-1 activity attenuates fibrosis. The disinhibition of plasmin-mediated MMP activation leads to collagen degradation and its diminished accumulation, resulting in the reduction of fibrotic matrix deposition in these organs. Paradoxically, homozygous deficiency of PAI-1 promotes age-dependent spontaneous cardiac fibrosis, suggesting a protective role for PAI-1 in the heart. It remains unclear whether PAI-1-deficient cardiac fibroblasts have increased proliferative, migratory, or differentiation capabilities, that allow them to overcome increased plasmin and MMP activity and matrix clearance. In this review, we examine the specific roles of PAI-1 in fibrosis of different organs including the lung, liver, kidney, and cardiovascular system.

Keywords

plasminogen - serpin - fibrosis - matrix - fibroblast
 

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