Acute lung injury and septic shock : the new therapeutic strategies based on the pathomechanism

Abstract

Although septic shock is frequently developed in patients with acute respiratory distress syndrome (ARDS), why these two pathologic conditions are associated is not known at present. Prostacyclin plays important roles in prevention of pulmonary vascular injury and shock responses by inhibiting increases in lung tissue levels of tumor necrosis factor (TNF) in rats administered endotoxin. Neutorphil elastase has been shown to decrease the endothelial production of prostacyclin. We attempted to determine whether sivelestat, a neutrophil elastase inhibitor. reduce the pulmonary vascular injury and hypotension by inhibiting the decrease in the pulmonary endothelial production of prostacyclin in rats administered endotoxin. Animals were pretreated with a neutrophil elastase inhibitor, sivelestat, before endotoxin administration. Lung tissue levels of 6-keto-PGF_1α were markedly increased after endotoxin administration, followed by the rapid decrease. Sivelestat inhibited these decreases and increases in both lung tissue levels of TNF and lung wet-to-dry weight ratio in animals administered endotoxin. Sivelestat also reduced hypotension and inhibited increases in lung tissue levels of mRNA of iNOS, iNOS activity, and those in plasma levels of NO₂-/NO₃- in animals administered endotoxin. These effects of sivelestat were completely reveresd by pretreatment with indomethacin, a non-specific cyclooxygenase inhibitor. These observations suggested that neutrophil elastase might decrease the pulmonary endothelial production of prostacyclin, thereby increasing lung tissue levels of TNF, contributing to the development of pulmonary vascular injury and shock in rats administered endotoxin. Thus, it is likely that the activated neutrophil-induced pulmonary endotherial cell dysfunction leading to decrease in prostacyclin is a common cause for development of both ARDS and septic shock. This notion might explain why ARDS and septic shock are frequently associated in the clinical setting.