title: Neutrophil elastase inhibitor improves survival of rats with clinically relevant sepsis.
abstract: Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.
authors: Department of Surgery, School of Medicine, Keio University, Shinanomachi 35, Shinjuku-ku, Tokyo, Japan.
authors: Koichi
authors: K
authors: Suda
authors: Hiroya
authors: H
authors: Takeuchi
authors: Tomoko
authors: T
authors: Hagiwara
authors: Taku
authors: T
authors: Miyasho
authors: Minoru
authors: M
authors: Okamoto
authors: Kazufumi
authors: K
authors: Kawasako
authors: Shingo
authors: S
authors: Yamada
authors: Kazuhiro
authors: K
authors: Suganuma
authors: Norihito
authors: N
authors: Wada
authors: Yoshiro
authors: Y
authors: Saikawa
authors: Koichi
authors: K
authors: Fukunaga
authors: Yosuke
authors: Y
authors: Funakoshi
authors: Satoru
authors: S
authors: Hashimoto
authors: Hiroshi
authors: H
authors: Yokota
authors: Ikuro
authors: I
authors: Maruyama
authors: Akitoshi
authors: A
authors: Ishizaka
authors: Yuko
authors: Y
authors: Kitagawa
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D002432:Cecum / Q000473:pathology; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy; D016209:Interleukin-8 / Q000378:metabolism; D008026:Ligation; D008168:Lung / Q000473:pathology; D008297:Male; D053491:Proteinase Inhibitory Proteins, Secretory / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000188:drug therapy*; D013449:Sulfonamides / Q000627:therapeutic use*; D016019:Survival Analysis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005998:Glycine; D024243:HMGB1 Protein; D016209:Interleukin-8; D053491:Proteinase Inhibitory Proteins, Secretory; D013449:Sulfonamides; C539355:CD68 protein, rat; D000097382:CD68 Molecule; C104200:Hbp1 protein, rat; C069195:sivelestat