PAI-1 in tissue fibrosis

Abstract

Fibrosis is defined as a fibroproliferative or abnormal fibroblast activation-related disease. Deregulation of wound healing leads to hyperactivation of fibroblasts and excessive accumulation of extracellular matrix (ECM) proteins in the wound area, the pathological manifestation of fibrosis. The accumulation of excessive levels of collagen in the ECM depends on two factors: an increased rate of collagen synthesis and or decreased rate of collagen degradation by cellular proteolytic activities. The urokinase/tissue type plasminogen activator (uPA/tPA) and plasmin play significant roles in the cellular proteolytic degradation of ECM proteins and the maintenance of tissue homeostasis. The activities of uPA/tPA/plasmin and plasmin-dependent MMPs rely mostly on the activity of a potent inhibitor of uPA/tPA, plasminogen activator inhibitor-1 (PAI-1). Under normal physiologic conditions, PAI-1 controls the activities of uPA/tPA/plasmin/MMP proteolytic activities and thus maintains the tissue homeostasis. During wound healing, elevated levels of PAI-1 inhibit uPA/tPA/plasmin and plasmin-dependent MMP activities, and, thus, help expedite wound healing. In contrast to this scenario, under pathologic conditions, excessive PAI-1 contributes to excessive accumulation of collagen and other ECM protein in the wound area, and thus preserves scarring. While the level of PAI-1 is significantly elevated in fibrotic tissues, lack of PAI-1 protects different organs from fibrosis in response to injury-related profibrotic signals. Thus, PAI-1 is implicated in the pathology of fibrosis in different organs including the heart, lung, kidney, liver, and skin. Paradoxically, PAI-1 deficiency promotes spontaneous cardiac-selective fibrosis. In this review, we discuss the significance of PAI-1 in the pathogenesis of fibrosis in multiple organs.

Copyright © 2011 Wiley Periodicals, Inc.

Figures

Figure 1. PAI-1 deficiency and spontaneous cardiac fibrosis

Images show the Masson’s Trichrome staining of myocardial tissues derived from 24-m old wildtype mice and PAI-1 knockout mice. Note the excessive perivascular and interstitial collagen deposition (blue color) in aged PAI-1 knockout mice in heart (middle and right) and no such pathologic manifestation of fibrosis is present in aged wildtype heart (left).

Figure 2. Possible role of PAI-1 in induced fibrosis in different organs: involvement of fibrin

PAI-1 controls uPA/tPA/plasmin/MMPs proteolytic activity, levels of fibrin and the migration of inflammatory- and collagen-producing cells. In PAI-1−/− mice, more fibrinolytic activity leads to a lack of fibrin, impaired cellular migration/adhesion, and less inflammation and collagen production. In the PAI-1+/+ mice, the elevated level of fibrin causes increased adhesion and migration of inflammatory- and collagen-producing cells and tissue fibrosis.

Figure 3. PAI-1 and EndMT

Model showing possible role of PAI-1 deficiency in EndMT. Exogenous TGF-β activates both wildtype and PAI-1 deficient endothelial cells. However, in the absence of PAI-1, autocrine TGF-β signaling is higher in PAI-1 null cells compared to wildtype cells. Increased autocrine TGF-β signaling may contribute to faster EndMT in PAI-1 deficient endothelial cells.

Figure 4. Model demonstrating possible molecular basis of induced tissue fibrosis and role of PAI-1

Different extracellular and intracellular stresses induce ROS production; inflammation and inflammatory mononuclear cells secrete profibrotic cytokines such as TGF-β which activates Smad and MAPK, which in turn activates resident fibroblasts as well as induces EMT/EndMT. Resident and EMT/EndMT-derived fibroblasts differentiate to myofibroblasts and produce collagen and other ECM proteins. ROS and TGF-β also induce PAI-1, which inhibits proteolytic activities and prevents collagen/ECM degradation. Additionally, PAI-1 contributes in tissue fibrosis by influencing EMT/EndMT and the migration of inflammatory/collagen producing cells.

Figure 5. Significance of PAI-1 in injury or stress–induced tissue fibrosis and in age-dependent spontaneously developed tissue fibrosis

While PAI-1 deficiency protects organs from induced fibrosis except skin, PAI-1 deficiency develops spontaneous cardiac-selective fibrosis in aged mice. Role of PAI-1 is organ specific.