Figure 2.

PAI-1 is a critical factor in the regulation of pericellular proteolysis and tissue fibrosis. Plasminogen activators (urokinase, uPA; tissue-type, tPA) are the physiologically relevant plasmin-generating proteinases that impact ECM homeostasis through a complex and interdependent proteolytic cascade. uPA-stimulated conversion of plasminogen to plasmin leads to an increased downstream activation of matrix metalloproteinases (MMPs). Collectively, plasmin and MMPs dictate the locale and extent of ECM remodeling. Increased PAI-1 expression and/or activity facilitates ECM accumulation and attenuates ECM degradation which, if prolonged or chronic, results in the onset and progression of fibrotic disease (reviewed in Flevaris and Vaughan, 2016; Rabieian et al., 2018; Milenkovic et al., 2017; Higgins et al., 2018).