Hemorrhagic shock followed by
resuscitation (HSR) causes neutrophil sequestration in the lung which leads to
acute lung injury (ALI).
Neutrophil elastase (NE) is thought to play a pivotal role in the pathogenesis of ALI. This study investigated whether
sivelestat, a specific NE inhibitor, can attenuate ALI induced by HSR in rats. Male Sprague-Dawley rats were subjected to
hemorrhagic shock by withdrawing blood so as to maintain a mean arterial blood pressure of 30+/-5 mm Hg for 60 min followed by
resuscitation with the shed blood. HSR-treated animals received a bolus injection of
sivelestat (10 mg/kg) intravenously at the start of
resuscitation followed by continuous infusion for 60 min (10 mg/kg/h) during the
resuscitation phase, or the vehicle.
Lung injury was assessed by pulmonary histology,
lung wet-weight to dry-weight (W/D) ratio,
myeloperoxidase (MPO) activity, gene expression of
tumor necrosis factor (
TNF)-alpha and
inducible nitric oxide synthase (iNOS),
DNA binding activity of nuclear factor (
NF)-kappaB, and immunohistochemical analysis of
intercellular adhesion molecule (ICAM)-1. HSR treatment induced
lung injury, as demonstrated by
pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, MPO activity, gene expression of
TNF-alpha and iNOS, and
DNA-binding activity of
NF-kappaB, and enhanced expression of
ICAM-1. In contrast,
sivelestat treatment significantly ameliorated the HSR-induced
lung injury, as judged by the marked improvement in all these indices. These results indicate that
sivelestat attenuated HSR-induced
lung injury at least in part through an inhibition of the inflammatory signaling pathway, in addition to the direct inhibitory effect on NE.