title: Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice.
abstract: 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.
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Akira
authors.initials: A
authors.lastname: Kakita
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007275:Injections, Intravenous; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides; D008102:Liver Circulation / Q000187:drug effects; D008107:Liver Diseases / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects*; D008853:Microscopy; D011336:Probability; D011759:Pyrrolidines / Q000494:pharmacology*; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D001565:Benzoates; D016207:Cytokines; C109799:FK 706; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011759:Pyrrolidines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C069195:sivelestat; D005998:Glycine