Activated protein C reduces stress-induced gastric mucosal injury in rats by inhibiting the endothelial cell injury

Abstract

Background and objective: Activated protein C (APC) is a natural anticoagulant with anti-inflammatory activity. APC inhibits neutrophil activation through inhibition of tumor necrosis factor (TNF)-α production. Such anti-inflammatory activity of APC has recently been shown to be critical in the treatment of patients with severe sepsis. We previously demonstrated that activated neutrophils play a crucial role in the development of stress-induced gastric mucosal injury. Thus, inhibition of neutrophil activation by APC should reduce endothelial cell damage, maintain gastric blood flow, and lessen gastric mucosal injury. In the present study, we examined this possibility by using a rat model of water-immersion restraint stress (WIRS)-induced gastric mucosal injury. Methods and results: Gastric mucosal injury was observed 4 h after WIRS, without increases in gastric mucosal levels of either myeloperoxidase activity or TNF-α, but with significant increases in plasma levels of TNF-α 1 h after WIRS. Intravenous administration of APC (100 μg kg-1) significantly reduced WIRS-induced gastric mucosal injury by inhibiting decrease in gastric mucosal blood flow. Administration of APC also inhibited both the decrease in gastric tissue levels of 6-keto-prostaglandin F1α and the increase in gastric mucosal micorvascular permeability in animals subjected to WIRS. Furthermore, APC inhibited WIRS-induced increases in plasma levels of TNF-α. Neither active site-blocked factor Xa, which is a selective inhibitor of thrombin generation, nor active site-blocked APC had any effect on these events. Intraperitoneal administration of anti-rat TNF-α antibody produced effects similar to those of APC. Conclusions: The observations in the present study strongly suggest that APC reduces stress-induced gastric mucosal injury by inhibiting the decrease in gastric mucosal blood flow through attenuation of the activated neutrophil-induced endothelial cell injury via inhibition of TNF-α production. In addition, we show that serine protease activity of APC, rather than its anticoagulant activity, is critical for the protective mechanism(s) by which TNF-α production could be inhibited. © 2003 International Society on Thrombosis and Haemostasis.