title: Sivelestat, a neutrophil elastase inhibitor, attenuates neutrophil priming after hepatoenteric ischemia in rabbits.
abstract: Neutrophils play an important role in ischemia-reperfusion injury. The neutrophil elastase not only causes tissue damage, but also mediates neutrophil priming. In the present study, we use a rabbit model of hepatoenteric ischemia-reperfusion to test the hypothesis that neutrophil elastase inhibition ameliorates an ischemia-reperfusion injury by attenuating neutrophil priming and suppressing enzymatic activity. Twenty-four Japanese white rabbits underwent 30 min of supraceliac aortic cross-clamping and 180 min of reperfusion under isoflurane anesthesia. The rabbits randomly received the neutrophil elastase inhibitor, sivelestat (n = 10), or saline (n = 14). Neutrophil priming was then assayed with luminol-dependent neutrophil chemiluminescence. Hepatic, intestinal, renal, and pulmonary damages were assessed with serum transaminase, lactate dehydrogenase concentrations, urinary N-acetyl glucosaminidase activity, and protein concentration in post mortem bronchoalveolar lavage fluid. We discovered that neutrophil elastase inhibition suppressed plasma neutrophil elastase, and that lipid peroxide concentrations increased after reperfusion. It improved ischemia-reperfusion injuries in the liver, intestine, kidney, and lung. Furthermore, inhibition of neutrophil elastase with sivelestat significantly attenuated post-reperfusion neutrophil priming. The results of this study demonstrate that neutrophil elastase inhibition could effectively attenuate an ischemia-reperfusion injury caused by supraceliac aortic cross-clamping, most likely from the attenuation of neutrophil priming.
authors.affiliation: Department of Anesthesiology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan. ykotake@sc.itc.keio.ac.jp
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Kotake
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Midori
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morisaki
authors.forename: Junzo
authors.initials: J
authors.lastname: Takeda
mesh_terms: D000118:Acetylglucosaminidase / Q000097:blood; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007511:Ischemia; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007773:Lactates / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000473:pathology*; D008163:Luminescent Measurements; D008297:Male; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D015427:Reperfusion Injury; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013270:Stomach / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors; D000637:Transaminases / Q000097:blood
chemical_list: D007773:Lactates; D008054:Lipid Peroxides; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D007770:L-Lactate Dehydrogenase; D000637:Transaminases; D000118:Acetylglucosaminidase; D019272:Leukocyte Elastase; D005998:Glycine