Oxidative stress, plasminogen activator inhibitor 1, and lung fibrosis

Abstract

Fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) in basement membranes and interstitial tissues, resulting from increased synthesis or decreased degradation of ECM or both. The plasminogen activator/plasmin system plays an important role in ECM degradation, whereas the plasminogen activator inhibitor 1 (PAI-1) is a physiologic inhibitor of plasminogen activators. PAI-1 expression is increased in the lung fibrotic diseases and in experimental fibrosis models. The deletion of the PAI-1 gene reduces, whereas the overexpression of PAI-1 enhances, the susceptibility of animals to lung fibrosis induced by different stimuli, indicating an important role of PAI-1 in the development of lung fibrosis. Many growth factors, including transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha), as well as other chemicals/agents, induce PAI-1 expression in cultured cells and in vivo. Reactive oxygen and nitrogen species (ROS/RNS) have been shown to mediate the induction of PAI-1 by many of these stimuli. This review summarizes some recent findings that help us to understand the role of PAI-1 in the development of lung fibrosis and ROS/RNS in the regulation of PAI-1 expression during fibrogenesis.

FIG. 1. Plasminogen activation system and extracellular matrix (ECM) degradation

Plasminogen is converted to plasmin by tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Plasmin then degrades ECM components directly or indirectly by activating matrix metallo-proteinases (MMPs). Under physiologic conditions, the activities of tPA and uPA are controlled by plasminogen activator inhibitor 1 (PAI-1).

FIG. 2. Potential mechanisms whereby PAI-1 promotes ECM deposition

PAI-1 promotes ECM deposition by (a) inhibiting tPA and uPA activities and thereby plasminogen activation and ECM degradation; (b) recruiting inflammatory cells to the sites and therefore increasing profibrogenic cytokines; and (c) suppressing the release of antifibrogenic growth factors from the sequestered sites on the ECM.

FIG. 3. Potential mechanism whereby GSH inhibits TGF-β–induced collagen accumulation in NIH3T3 cells

GSH inhibits TGF-β-–induced PAI-1 expression and therefore increases plasmin formation and collagen degradation.

FIG. 4. Potential signaling pathways mediating ROS induction of PAI-1 by TGF-β and TNF-α

TGF-β and TNF-α increase ROS production, which, by activating the MAPK pathways and/or the NF-κB pathway, increase the transcription rate of the PAI-1 gene.