Gabexate mesilate, a synthetic protease inhibitor, prevents ischemia/reperfusion injury of rat uver by increasing hepatic tissue blood flow

Introduction: Gabexate mesilate (GM), a synthetic pnxease inhibitor, inhibits TNF-α production by monocytes, thereby preventing the activated neutrophil-induced tissue injury. Activated neutrophils impair the endothelial prostacyclin production by releasing neutrophil elastase (NE). We have previously demonstrated that NE is implicated in ischemia/reperfusion (I/R)-induced hepatic damage in rats. Based on these observations, we examined whether GM might prevent l/R-induced hepatic damage by inhibiting neutrophil activation in the present study. Methods: Hepatic damage was induced in male Wistar rats by 60 min-ischemia and the subsequent reperfusion. Hepatic damage was evaluated by effects on bite formation capacity (n = 40) and serum arninotransfense lewis (n = 40). Hepatic 6-keto-PGF,a levels were measured by enzyme-linked immunosorbent assay (n = 40). Hepatic tissue blood flow was measured by laser-Doppler fiowmeier (n = 40). Refaits: GM significantly prevented the Mi-induced hepatic damage. l/R-mdnced reduction of hepatic tissue blood flow was inhibited by GM administration. GM as well as ONO-5046 (a specific inhibitor of neotrophil elastase) significantly inhibited the I/R-induced reduction of hepatic levels of 6-keto-PGF₁α. Both ONO-5046 and iloprost (a stable analog of prostacyclin) inhibited the I/R-indaced redaction of hepatic tissue blood flow, lloprost prevented the t/R-induced hepatic damage. Hepatic tissue blood flow (% of initial value) Time after reperfusion 1 hr 2hr 3hr I/R (n=6) 48.86±4.08 57.44±3.14 56.00±3.76 GM (n=6) 63.68±4.80 * 73.37±5.81 * 75.00± 4.71 * Iloprost (n=6) 71.76±3.45 * 77.26±2.81 * 85.55±2.79 * ONO-5046 (n=6) 79.63±9.02 * 84.63±6.74 * 84.04± 8.18 * (Data are expressed as mean ±SD. *, p<0.01 vs I/R. The resaks were compated using an analysis of variance followed by SchefK's (post hoc) test) Conclusion: These results suggest that GM prevents the I/R-indoced hepatic damage by inhibiting neutrophil elastase-tnduced decrease in hepatic prostacyclin production, which may prevent the reduction of hepatic tissue blood flow.