Effects of Selective Cyclooxygenase Inhibitors on Ischemia/Reperfusion-Induced Hepatic Microcirculatory Dysfunction in MiceIto Y.a · Katagiri H.a · Ishii K.a · Kakita A.a · Hayashi I.b · Majima M.b
Departments of aSurgery and bPharmacology, Kitasato University School of Medicine, Sagamihara, Japan
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We examined the effects of selective cyclooxygenase (COX) inhibition on hepatic warm ischemia/reperfusion (I/R) injury in mice. A selective COX-1 inhibitor, SC-560, selective COX-2 inhibitors, NS-398 and celecoxib, and indomethacin were administered 30 min before ischemia. Four hours after reperfusion, an in vivo microscopic study showed that I/R caused significant accumulation of leukocytes adhering to the hepatic microvessels and nonperfused sinusoids. Levels of plasma alanine transaminase (ALT) and tumor necrosis factor (TNF)-α also showed increases. SC-560, NS-398, celecoxib and indomethacin significantly reduced hepatic responses to I/R including microcirculatory dysfunction and release of ALT and TNF-α. Moreover, the effects of the thromboxane (TX) A2 (TXA2) synthase inhibitor OKY-046 and the TXA2 receptor antagonist S-1452 on hepatic responses to I/R exhibited results similar to those obtained with COX inhibitors. These results suggest that COX-1 and COX-2 contribute to I/R-induced hepatic microvascular and hepatocellular injury partly through TNF-α production, and that TXs derived from COX are partly responsible for I/R-induced liver injury.
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