Effects of specific neutrophil elastase inhibitor, sivelestat sodium hydrate, in murine model of severe pneumococcal pneumonia.
An excessive amount of neutrophil elastase (NE) released from neutrophils accumulated in the lung can cause tissue damage, despite its importance to host defense against microbial pathogens in severe pneumonia. Therefore, NE inhibitors may reduce tissue damage in lungs with severe pneumonia. In this study, the efficacy of a specific NE inhibitor, sivelestat sodium hydrate (sivelestat), was examined using a murine model of severe pneumonia with Streptococcus pneumoniae. Male mice (CBA/JNCrj, aged 5 weeks) were inoculated intranasally with penicillin-susceptible S. pneumonia (1.0 x 10(5) CFU/mouse). Sivelestat (3 mg/kg) or physiological saline was administered every 12 hours beginning at 12 hours after inoculation. Survival was primarily evaluated. Bronchoalveolar lavage fluid (BALF) and blood were collected at 30 hours after inoculation. Thus, cell counts in BALF and numbers of viable bacteria in blood were determined. Histopathological analysis was also performed. Sivelestat significantly prolonged survival when compared with the control group (P < .05), although all animals died within 4 days. Cell count and histopathological analysis indicated that sivelestat prevented the progression of lung inflammation, such as alveolar neutrophil infiltration and hemorrhage. Furthermore, the number of viable bacteria in blood was significantly lower in the sivelestat group than in the control group (5.69 +/- 0.27 and 6.75 +/- 0.32 log CFU/mL, respectively; mean +/- SEM, P < .01). Sivelestat prolonged survival in this model. A possible explanation for the improved survival is that sivelestat prevents tissue damage by inhibiting NE activity in the lung. Therefore, NE inhibitors may be useful for treating with patients with severe pneumonia.
Yanagihara
Katsunori
K
Second Department of Internal Medicine, University Graduate School of Biomedical Sciences, Nagasaki, Japan. kyana-ngs@umin.ac.jp
Fukuda
Yuichi
Y
Seki
Masafumi
M
Izumikawa
Koichi
K
Miyazaki
Yoshitsugu
Y
Hirakata
Yoichi
Y
Tsukamoto
Kazuhiro
K
Yamada
Yasuaki
Y
Kamhira
Shimeru
S
Kohno
Shigeru
S
D000818:Animals; D001769:Blood / Q000382:microbiology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D004195:Disease Models, Animal; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D015996:Survival Rate
D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine