Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice

• Published in: Shock (Augusta, Ga.) Ga.), 2002-08, Vol.18 (2), p.163-168
• Main Authors: ISHII, Ken-Ichiro, ITO, Yoshiya, KATAGIRI, Hiroyuki, MATSUMOTO, Yutaka, KAKITA, Akira, MAJIMA, Masataka
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Benzoates - pharmacology; Biological and medical sciences; Cytokines - drug effects; Cytokines - metabolism; Disease Models, Animal; Drug Interactions; Gastroenterology. Liver. Pancreas. Abdomen; Glycine - analogs & derivatives; Glycine - pharmacology; Injections, Intravenous; Interleukin-1 - metabolism; Lipopolysaccharides; Liver Circulation - drug effects; Liver Diseases - drug therapy; Liver Diseases - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microcirculation - drug effects; Microscopy; Other diseases. Semiology; Probability; Pyrrolidines - pharmacology; Random Allocation; Reference Values; Sensitivity and Specificity; Sulfonamides - pharmacology; Treatment Outcome; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/00024382-200208000-00013

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.