Protein C inhibitor as an anti-disseminated intravascular coagulation agent--mechanism and modification.
Gram-negative sepsis is associated with disseminated intravascular coagulation (DIC) due to endothelial damage, which is induced by inflammatory mediators released from phagocytes activated by lipopolysaccharide (LPS). DIC is a systemic hemorrhagic syndrome, which results from the consumption of coagulation factors for the formation of multiple thrombi in the systemic microvessels; it is associated with multiple organ failure. Therefore, not only the systemic activation of coagulation but also the inflammatory response has been perceived as the therapeutic target for DIC in sepsis. We gave attention that protein C inhibitor (PCI) acts as an inhibitor of both plasma kallikrein and thrombin, which are known to act not only as procoagulant proteases but also as chemotactic factors toward phagocytes. Then, we hypothesized that PCI possibly acts as an anti-DIC agent rather than an inhibitor of the protein C anticoagulant pathway under the pathophysiology of DIC, accompanied by the decrease in the thrombomodulin expression on endothelial cells. Our studies have suggested that PCI purified from human urine (uPCI) improves the pathophysiology of DIC through the inhibition of activities of plasma kallikrein and thrombin, and the activities of PCI are regulated by N-glycans. This review introduces the anti-DIC action of PCI and about the modification of N-glycosylation site(s) of PCI to heighten the value of PCI as an anti-DIC agent.
Pharmacological Science, Research Center, Research and Development Division, JCR Pharmaceuticals Co Ltd, 2-2-10 Murotani, Nishi-ku, Kobe 651-2241, Japan. fujita@jcrpharm.co.jp
M
M
Fujita
W
W
Izutani
K
K
Takahashi
D000818:Animals; D002986:Clinical Trials as Topic; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000097:blood; D011134:Polysaccharides / Q000502:physiology; D018046:Protein C Inhibitor / Q000494:pharmacology* / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018180:Thrombomodulin / Q000096:biosynthesis
D011134:Polysaccharides; D018046:Protein C Inhibitor; D018180:Thrombomodulin; D007610:Kallikreins; D013917:Thrombin