Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis.
Inhibition of the tissue factor-factor VIIa complex reduces coagulation and inflammation in animal models of endotoxemia and sepsis and in patients with severe sepsis. However, the mechanism by which tissue factor-dependent activation of the coagulation cascade enhances inflammation is not known. We tested the hypothesis that coagulation proteases enhance inflammation during endotoxemia by activating protease-activated receptors (PARs) within the vasculature. We found that genetically modified mice expressing low levels of tissue factor exhibited reduced interleukin-6 expression and increased survival in a mouse model of endotoxemia compared with control mice. In contrast, hirudin inhibition of thrombin or a deficiency in either PAR-1 or PAR-2 did not affect interleukin-6 expression or mortality. However, combining hirudin treatment to inhibit thrombin signaling through PAR-1 and PAR-4 with PAR-2 deficiency reduced lipopolysaccharide-induced interleukin-6 expression and increased survival. Taken together, our results suggest that activation of multiple PARs by coagulation proteases enhances inflammation during endotoxemia.
Pawlinski
Rafal
R
Departments of Immunology and Cell Biology, the Scripps Research Institute, La Jolla, CA, USA.
Mackman
Nigel
N
D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation; D010450:Endopeptidases / Q000502:physiology*; D019446:Endotoxemia / Q000276:immunology*; D005337:Fibrin / Q000502:physiology; D006801:Humans; D011486:Protein C / Q000502:physiology; D044462:Receptors, Proteinase-Activated / Q000502:physiology*; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology*; D013917:Thrombin / Q000502:physiology; D013925:Thromboplastin / Q000502:physiology*
D000925:Anticoagulants; D011486:Protein C; D044462:Receptors, Proteinase-Activated; D005337:Fibrin; D013925:Thromboplastin; D010450:Endopeptidases; D013917:Thrombin