Hydrogen sulfide (H(2) S) can induce a reversible hypometabolic state, which could protect against hypoxia. In this study we investigated whether H(2) S could protect livers from ischemia/reperfusion injury (IRI). Male C57BL/6 mice were subjected to partial hepatic IRI for 60 min. Animals received 0 (IRI) or 100 ppm H(2) S (IRI + H(2) S) from 30 min prior to ischemia until 5 min before reperfusion. Core body temperature was maintained at 37 degrees C. Animals were sacrificed after 1, 6 or 24 h. Hepatic ischemia caused extensive hepatic necrosis in the IRI animals which coincided with an increase in ALT and AST serum levels. Animals treated with H(2) S showed attenuated serum ALT and AST levels and reduced necrotic lesions after 24 h. IRI animals had increased Bcl-2 mRNA expression and increased active Caspase 3 protein, which were both significantly lower in H(2) S treated animals. Increased TNFalpha and IL-6 mRNA in the IRI livers was significantly attenuated by H(2) S treatment, as was hepatic influx of Ly-6G positive granulocytes. Hepatic superoxide production after ischemia was attenuated by H(2) S treatment. In hepatic ischemia/reperfusion injury, gaseous H(2) S treatment is highly protective, substantially reducing necrosis, apoptosis and inflammation. Gaseous H(2) S is therefore a very promising treatment for reducing IRI during hepatic transplantation.