Protective effect of Sivelestat in a porcine hepatectomy model prepared using an intermittent Pringle method

The effect of Sivelestat, a neutrophil elastase inhibitor, on hepatic ischemia–reperfusion injury was examined in a pig hepatectomy model. An internal jugular vein–splenic vein bypass was prepared in male pigs and about 40% hepatic resection (left lobe) was performed under 15-min liver ischemia and 5-min intermittent reperfusion. Six animals received Sivelestat (10 mg/kg/h) intravenously and six control animals received physiological saline (10 mg/kg/h) from commencement of laparotomy. Hemodynamics, blood chemistry, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), lactic acid, hyaluronic acid, nitrite/nitrate (NOS), and tumor necrosis factor-α (TNF-α) were compared between the groups. The effects of Sivelestat on NOS generation and expression of iNOS mRNA and TNF-α mRNA were also assessed in J774 cells. Expression of TNF-α mRNA in hepatic tissues was examined using RT-PCR. The blood pressure of control animals was significantly lower immediately and 3 h after ischemia–reperfusion, compared with that at commencement of laparotomy, whereas there was no decrease of blood pressure in animals administered Sivelestat. Serum AST (P = 0.0045), NOS (P = 0.0098), and TNF-α (P = 0.041) levels were significantly lower 3 h after hepatectomy in animals receiving Sivelestat. Sivelestat inhibited NOS production in J774 cells, but did not inhibit expression of iNOS mRNA or TNF-α mRNA. In hepatic tissues, Sivelestat showed a greater tendency to inhibit expression of TNF-α mRNA and fewer TUNEL-positive cells were present in the hepatic sinusoidal endothelium after Sivelestat treatment, although these differences were not statistically significant. We conclude that Sivelestat inhibits production of TNF-α and NO by inhibiting neutrophil elastase, and thus reduces hepatic injury and stabilizes hemodynamics after ischemia–reperfusion.