fk-706 and sivelestat

The present study was conducted to elucidate the role of neutrophil elastase in lipopolysaccharide (LPS)-induced hepatic microvascular injury by using in vivo microscopy. The intravenous (i.v.) injection of LPS (0.1 mg/kg) in male C3H/HeN mice caused significant hepatic microcirculatory dysfunction: leukocyte adhesion to the sinusoids as well as to the venule, and reduced sinusoidal perfusion, in comparison with vehicle-treated mice. Concomitantly, the serum alanine aminotransferase (ALT) activity at 4 h after LPS injection was significantly increased. The serum concentrations of tumor necrosis factor (TNFalpha) and interleukin-1beta (IL-1beta) at 1 h and at 4 h after LPS injection, respectively, were significantly elevated. Neutrophil elastase inhibitors, ONO-5046 (30 and 90 mg/kg, i.v., 0 and 2 h after LPS injection) or FK706 (30 and 100 mg/kg, i.v., 0 and 2 h after LPS injection) minimized the LPS-induced hepatic microcirculatory dysfunction in a dose-dependent manner. Treatment with ONO-5046 and FK706 significantly reduced the ALT level as well as the serum concentrations of TNFalpha and IL-1beta. In addition, ONO-5046 and FK706 attenuated both hepatic microcirculatory dysfunction and liver injury mediated by TNFalpha and IL-1beta (10 microg/kg i.v.). Furthermore, both ONO-5046 and FK706 improved human neutrophil elastase (10 microg/kg i.v.)-induced hepatic microcirculatory dysfunction, although neutrophil elastase did not increase the levels of TNFalpha and IL-1beta. These results suggest that neutrophil elastase aggravates the LPS-induced hepatic microvascular dysfunction. Neutrophil elastase inhibitors attenuate hepatic microvascular dysfunction in response to LPS by inhibiting TNFalpha and IL-1beta production. Neutrophil elastase inhibitors also reduce the microvascular dysfunction mediated by TNFalpha and IL-1beta as well as by neutrophil elastase.

Topics: Analysis of Variance; Animals; Benzoates; Cytokines; Disease Models, Animal; Drug Interactions; Glycine; Injections, Intravenous; Interleukin-1; Lipopolysaccharides; Liver Circulation; Liver Diseases; Male; Mice; Mice, Inbred C57BL; Microcirculation; Microscopy; Probability; Pyrrolidines; Random Allocation; Reference Values; Sensitivity and Specificity; Sulfonamides; Treatment Outcome; Tumor Necrosis Factor-alpha