title: A neutrophil elastase inhibitor, sivelestat, ameliorates lung injury after hemorrhagic shock in rats.
abstract: Hemorrhagic shock followed by resuscitation (HSR) causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30+/-5 mm Hg for 60 min followed by resuscitation with the shed blood. HSR-treated animals received a bolus injection of sivelestat (10 mg/kg) intravenously at the start of resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the resuscitation phase, or the vehicle. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, myeloperoxidase (MPO) activity, gene expression of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS), DNA binding activity of nuclear factor (NF)-kappaB, and immunohistochemical analysis of intercellular adhesion molecule (ICAM)-1. HSR treatment induced lung injury, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of TNF-alpha and iNOS, and DNA-binding activity of NF-kappaB, and enhanced expression of ICAM-1. In contrast, sivelestat treatment significantly ameliorated the HSR-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that sivelestat attenuated HSR-induced lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.
authors.affiliation: Department of Anesthesiology and Resuscitology, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Toda
authors.forename: Toru
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Maeshima
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimizu
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Inoue
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morimatsu
authors.forename: Emiko
authors.initials: E
authors.lastname: Omori
authors.forename: Mamoru
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Reiko
authors.initials: R
authors.lastname: Akagi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Morita
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D055370:Lung Injury; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012151:Resuscitation; D012771:Shock, Hemorrhagic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D016328:NF-kappa B; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D004247:DNA; C069195:sivelestat; D052247:Nitric Oxide Synthase Type II; D019272:Leukocyte Elastase; D005998:Glycine