Abstract 1711: Blockade of Protease Activated Receptor-2 Ameliorates Acute Liver Injury through The Suppression of Upregulated Levels of Endothelin-1 And TNF-α in a Rat Model of Endotoxemia
Septic shock, the severe form of sepsis, is associated with the development of progressive damage in multiple organs, and is the leading cause of patient mortality in intensive care units. The liver can be injured and its functions altered by activation of coagulation, vasoactive-peptide and inflammatory processes in sepsis. Endothelin (ET)-1, a potent vasoconstrictor, is implicated in the pathogenesis of a number of diseases. Here, we examined the time-dependent alterations of ET-1, NO and inflammatory cytokine, such as TNF-α in liver tissue in a septic rat model. Normal male Wistar rats at age 8 wks were administered with lipopolysaccharide (LPS : 15 mg/kg) and then sacrificed at different time points (1h, 3h, 6h and 10h). The classical features of acute liver injury, such as infiltration of inflammatory cells, hepatocytic necrosis, were seen in LPS administered rats. Furthermore, plasma bilirubin, GOT and GPT levels were also significantly changed. A 28-fold increase in ET-1 level was observed in liver tissue at 10 h after LPS administration, while a peak increase of 14-fold ET-1 mRNA level was seen 1 hour after LPS administration in liver tissue. Levels of hepatic TNF- α peaked (4.5-fold) at 1 hour of sepsis. Endotoxemia often triggers exuberant inflammatory responses and activation of the coagulation cascade, and interactions between inflammation and coagulation may be important in this setting. Protease-activated receptors (PARs) connect coagulation proteases to cellular responses and represent one mechanism by which coagulation might affect inflammation. Of the 4 mammalian PARs, PAR1, PAR3, and PAR4 are activated by thrombin, and PAR2 can be activated by coagulation proteases VIIa and Xa but not thrombin. Interestingly, PAR2 blocking peptide improved the status of liver injury morphologically with a normalization of plasma GOT and GPT levels, and this improvement of liver injury was associated with suppression of TNF-α elevation, and normalization of ET-1 at both systemic and hepatic levels. The present study reveals a distinct chronological expression of ET-1 in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and vaso-active peptide.