title: Effect of FR167653, a novel inhibitor of tumor necrosis factor-alpha and interleukin-1beta synthesis on lipopolysaccharide-induced hepatic microvascular dysfunction in mice.
abstract: Tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) have been recognized as key proinflammatory mediators in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury. In the present study we examined the effect of FR167653, a novel inhibitor of TNFalpha and IL-1 synthesis, on the hepatic microvascular response to LPS using in vivo microscopy. Significant hepatic microvascular responses comprising leukocyte adhesion to the sinusoidal wall and central venules and reduced sinusoidal perfusion appeared 2 and 4 h after LPS (0.1 mg/kg, i.v.) injection in male C3H/HeN mice (LPS sensitive) when compared with male C3H/HeJ mice (LPS resistant). The serum concentrations of TNFalpha at 1.5 h and IL-1beta at 4 h after injection of LPS, as determined by enzyme-linked immunosorbent assay, were significantly higher in C3H/HeN mice than in C3H/HeJ mice. Administration of murine TNFalpha or IL-1beta (10 microg/kg., i.v., respectively) in both C3H/HeN and C3H/HeJ mice elicited the hepatic microvascular responses that were similar to those produced by LPS injection in C3H/HeN mice. FR167653 (1 and 10 mg/kg, i.v., 0 and 2 h after LPS injection) significantly reduced leukocyte adhesion and restored sinusoidal perfusion in a dose-dependent manner in C3H/HeN mice 4 h after LPS injection. The levels of TNFalpha, IL-1beta, and alanine aminotransferase also were significantly lower in FR167653-treated endotoxemic C3H/HeN mice than those in vehicle-treated endotoxemic animals. The results suggest that the hepatic microvascular response to LPS is partly mediated by TNFalpha and IL-1beta, and that FR167653 prevents LPS-induced hepatic microcirculatory dysfunction by inhibiting the production of TNFalpha and IL-1beta.
authors.affiliation: Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Ito
authors.forename: Izumi
authors.initials: I
authors.lastname: Hayashi
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Ishii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Katagiri
authors.forename: Akira
authors.initials: A
authors.lastname: Kakita
mesh_terms: D000818:Animals; D019446:Endotoxemia / Q000188:drug therapy / Q000503:physiopathology; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology; D007962:Leukocytes / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008833:Microcirculation / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000494:pharmacology
chemical_list: C104334:FR 167653; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011500:Protein Synthesis Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha