The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability

Abstract

The urokinase-type plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) are key components of the fibrinolytic system and are expressed by lung epithelial cells. uPA, uPAR, and PAI-1 have been strongly implicated in the pathogenesis of acute lung injury (ALI) and pulmonary fibrosis. Recently, it has become clear that regulation of uPA, uPAR, and PAI-1 occurs at the posttranscriptional level of mRNA stability in lung epithelial cells. uPA further mediates its own expression in these cells as well as that of uPAR and PAI-1 through induction of changes in mRNA stability. In addition, uPA-mediated signaling controls the expression of the tumor suppressor protein p53 in lung epithelial cells at the posttranslational level. p53 has recently been shown to be a trans-acting uPA, uPAR, and PAI-1 mRNA-binding protein that regulates the stability of these mRNAs. It is now clear that signaling initiated by uPA mediates dose-dependent regulation of lung epithelial cell apoptosis and likewise involves changes in p53, uPA, uPAR, and PAI-1 expression. These findings demonstrate that the uPA-uPAR-PAI-1 system of lung epithelial cells mediates a broad repertoire of responses that encompass but extend well beyond traditional fibrinolysis, involve newly recognized interactions with p53 that influence the viability of the lung epithelium, and are thereby implicated in the pathogenesis of ALI and its repair.

Loss of SerpinA5 protein expression is associated with advanced-stage serous ovarian tumors

“…A feedback loop between TP53 and uPA expression has been demonstrated in lung epithelial cells. 27,28 Reintroduction of TP53 in TP53-deficient lung epithelial cells suppressed uPA expression. PAI-1, a family member of SerpinA5, was shown to be minimally expressed in TP53-deficient lung carcinoma cells.…”

“…PAI-1, a family member of SerpinA5, was shown to be minimally expressed in TP53-deficient lung carcinoma cells. 28 In serous carcinomas, TP53 mutations occur in up to 80% of cases. It is reasonable that SerpinA5 is downregulated in serous carcinomas as a result of this mutation.…”

Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice

“…This association has been investigated in animal models with a number of different causes of lung injury, such as endotoxin, hyperoxia, trauma, hemorrhage, or pneumonia (2,7,8,14,44,54), but not in Cl 2 -induced lung injury. Moreover, pulmonary inflammation can cause local disturbances in fibrin turnover whereas increased intra-alveolar fibrin deposition with decreased breakdown may induce inflammation (44). Given this tight cross talk between coagulation and inflammation, the administration of an agent (such as heparin) that has both anti-coagulant as well as anti-inflammatory properties (53) may reduce the disturbance in pulmonary coagulopathy and inflammation, thereby ameliorating the clinical course of ALI.…”

Urokinase Plasminogen Activator Regulates Pulmonary Arterial Contractility and Vascular Permeability in Mice

“…The fibrinolytic system helps limit the deposition of fibrin in the small airways and alveolar compartment of the normal lung (1). Bronchoalveolar lavage (BAL) fluid from healthy individuals contains detectable amounts of urokinase-type plasminogen activator (uPA) (2,3).…”

“…Bronchoalveolar lavage (BAL) fluid from healthy individuals contains detectable amounts of urokinase-type plasminogen activator (uPA) (2,3). The exuberant expression of plasminogen activator inhibitor-1 (PAI-1) and the inhibition of plasmin are characteristic of the fibrinolytic defect in patients with acute respiratory distress syndrome (ARDS) and various forms of lung injury associated with the persistence of alveolar hyaline membranes and disordered lung remodeling (1,4). Furthermore, intraalveolar fibrin fails to deposit in response to hyperoxia in mice deficient in PAI-1, suggesting that the balance between plasminogen activators and their major inhibitor plays a crucial role in preventing the clearance of alveolar fibrin (5).…”