Differential expression time course and the distribution of 4 PARs in rats with endotoxin-induced acute lung injury.

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The lung and liver can be injured and their functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the study was to: 1) investigate the pattern of protease-activated receptors (PARs) over time in a model of acute lung and liver injuries induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of TNF-a were significantly expressed 1 h after LPS administration followed by: 1) an increase in levels of tissue factor, factor Vila, thrombin and plasminogen activator inhibitor-1; 2) unchanged or steady levels of tissue factor pathway inhibitor; and 3) subsequent deposition of fibrin in the lung and liver tissues, that led to the amelioration of blood gas analysis and the elevation of AST and ALT, which are associated with lung and liver injuries. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization in the tissues of lung and liver, and a time-dependent pattern of expression. Interestingly, PAR2 blocking peptide (BP) improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. Our study reveals a distinct chronological expression and cellular localization of PARs-in LPS-mediated lung and liver injuries and shows that blockade of PAR2 play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.These results clearly suggest that cross-talk between inflammation and coagulation has pivotal roles in sepsis-induced organ dysfunctions.