TY - JOUR
T1 - Neutrophil elastase inhibitor improves survival of rats with clinically relevant sepsis
AU - Suda, Koichi
AU - Takeuchi, Hiroya
AU - Hagiwara, Tomoko
AU - Miyasho, Taku
AU - Okamoto, Minoru
AU - Kawasako, Kazufumi
AU - Yamada, Shingo
AU - Suganuma, Kazuhiro
AU - Wada, Norihito
AU - Saikawa, Yoshirou
AU - Fukunaga, Koichi
AU - Funakoshi, Yosuke
AU - Hashimoto, Satoru
AU - Yokota, Hiroshi
AU - Maruyama, Ikuro
AU - Ishizaka, Akitoshi
AU - Kitagawa, Yuko
PY - 2010/5
Y1 - 2010/5
N2 - 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-1β (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.
AB - 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-1β (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.
KW - Cecal ligation and puncture
KW - Cytokine
KW - High-mobility group box chromosomal protein 1
KW - Sivelestat
KW - Systemic inflammatory response syndrome
UR - http://www.scopus.com/inward/record.url?scp=77951476335&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77951476335&partnerID=8YFLogxK
U2 - 10.1097/SHK.0b013e3181cc064b
DO - 10.1097/SHK.0b013e3181cc064b
M3 - Article
C2 - 19953005
AN - SCOPUS:77951476335
SN - 1073-2322
VL - 33
SP - 526
EP - 531
JO - Shock
JF - Shock
IS - 5
ER -