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: Koichi Suda, Hiroya Takeuchi, Tomoko Hagiwara, Taku Miyasho, Minoru Okamoto, Kazufumi Kawasako, Shingo Yamada, Kazuhiro Suganuma, Norihito Wada, Yoshiro Saikawa, Koichi Fukunaga, Yosuke Funakoshi, Satoru Hashimoto, Hiroshi Yokota, Ikuro Maruyama, Akitoshi Ishizaka, Yuko Kitagawa
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 33 Issue 5 Pg. 526-31 (May 2010) ISSN: 1540-0514 [Electronic] United States
• PMID: 19953005 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation, Myelomonocytic
• CD68 protein, rat
• HMGB1 Protein
• Hbp1 protein, rat
• Interleukin-8
• Proteinase Inhibitory Proteins, Secretory
• Sulfonamides
• sivelestat
• Glycine

Topics

• Animals
• Antigens, CD (metabolism)
• Antigens, Differentiation, Myelomonocytic (metabolism)
• Cecum (pathology)
• Disease Models, Animal
• Glycine (analogs & derivatives, therapeutic use)
• HMGB1 Protein (metabolism)
• Inflammation (drug therapy)
• Interleukin-8 (metabolism)
• Ligation
• Lung (pathology)
• Male
• Proteinase Inhibitory Proteins, Secretory (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sepsis (drug therapy)
• Sulfonamides (therapeutic use)
• Survival Analysis