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.