Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia.
Sepsis is associated with a systemic activation of coagulation and an excessive inflammatory response. Anticoagulants have been shown to inhibit both coagulation and inflammation in sepsis. In this study, we used both genetic and pharmacologic approaches to analyze the role of tissue factor and protease-activated receptors in coagulation and inflammation in a mouse endotoxemia model. We used mice expressing low levels of the procoagulant molecule, tissue factor (TF), to analyze the effects of TF deficiency either in all tissues or selectively in hematopoietic cells. Low TF mice had reduced coagulation, inflammation, and mortality compared with control mice. Similarly, a deficiency of TF expression by hematopoietic cells reduced lipopolysaccharide (LPS)-induced coagulation, inflammation, and mortality. Inhibition of the down-stream coagulation protease, thrombin, reduced fibrin deposition and prolonged survival without affecting inflammation. Deficiency of either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) alone did not affect inflammation or survival. However, a combination of thrombin inhibition and PAR-2 deficiency reduced inflammation and mortality. These data demonstrate that hematopoietic cells are the major pathologic site of TF expression during endotoxemia and suggest that multiple protease-activated receptors mediate crosstalk between coagulation and inflammation.
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA.
Rafal
R
Pawlinski
Brian
B
Pedersen
Gernot
G
Schabbauer
Michael
M
Tencati
Todd
T
Holscher
William
W
Boisvert
Patricia
P
Andrade-Gordon
Rolf Dario
RD
Frank
Nigel
N
Mackman
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D005337:Fibrin / Q000378:metabolism; D006410:Hematopoiesis / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020239:Receptor Cross-Talk / Q000502:physiology; D044463:Receptor, PAR-1 / Q000378:metabolism*; D044464:Receptor, PAR-2 / Q000378:metabolism; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D015996:Survival Rate; D013925:Thromboplastin / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D008070:Lipopolysaccharides; C115084:Pard3 protein, mouse; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D044462:Receptors, Proteinase-Activated; C481942:protease-activated receptor 4, mouse; D005337:Fibrin; D013925:Thromboplastin