PAI‐1 in tissue fibrosis

Abstract

1. Summary 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 extracellular matrix depends on two factors: an increased rate of collagen synthesis and or decreased rate of collagen degradation by cellular proteolytic activities. The urokinase-type/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.

Adipose-Derived Mesenchymal Stromal Cells From Aged Patients With Coronary Artery Disease Keep Mesenchymal Stromal Cell Properties but Exhibit Characteristics of Aging and Have Impaired Angiogenic Potential

“…PAI-1 controls the activities of uPA/plasmin/MMP proteolytic activities and thus maintains the tissue homeostasis; it also has a great impact in pathogenesis of multiple age-related diseases, such as cardiovascular pathologies and tumors [56,57]. Increased PAI-1 expression in adipose tissues plays a significant role in cardiovascular diseases and obesity.…”

Lung Pericytes and Resident Fibroblasts

“…26,28,93 In addition, myofibroblasts are a major source of plasminogen activator inhibitor 1; plasminogen activator inhibitor 1 inhibits the conversion of plasminogen to plasmin, and plasmin stimulates PGE 2 synthesis by lung epithelial cells. 15,94,95 Thus, the PGE 2 -dependent negative feedback loop may serve as an informative example of how regeneration occurs from a self-limited wound healing response, whereas an imbalance in feedback inhibition…”

4G/4G PAI-1 gene variant in a patient with non-healing ulcers

“…PAI-1 is released from platelets, hepatocytes, macrophages, vascular endothelial cells and smooth muscle cells, and is secreted in response to cytokines, specifically interleukin 1, tumor necrosis factor-alpha, and transforming growth factor-beta. [1][2][3] PAI-1 binds irreversibly t-PA and u-PA in circulation which inhibits their binding with and conversion of plasminogen into plasmin on the fibrin clot surface. [1,4] Plasmin promotes fibrinolysis by directly degrading the cross-linked fibrin into fibrin degradation products.…”

“…[1,4] Plasmin promotes fibrinolysis by directly degrading the cross-linked fibrin into fibrin degradation products. PAI-1 can also inhibit fibrinolysis by binding to and protecting the fibrin clot from degradation while complexed with t-PA or u-PA [1,2] (see Figure 4). Single nucleotide insertion or deletions at the PAI-1 promoter sequence create PAI-1 gene polymorphisms with varying phenotypes.…”

“…Increased PAI-1 has been implicated in both coronary arteries disease and venous thromboembolic events, by promoting plaque formation and venous thrombosis. [2,3,7,8] PAI-1 has also been shown to delay wound healing in vitro mostly through impairing angiogenesis and by inhibiting integrinvitronectin and vitronectin-vitronectin which are essential for cell migration and angiogenesis though activation of vascular endothelial growth factor receptor 2. [9][10][11] Our patient presents with multiple, chronic, non-healing wounds of varying locations and depths.…”