Neutrophil elastase inhibitor (sivelestat) attenuates subsequent ventilator-induced lung injury in mice

Abstract

Mechanical ventilation can paradoxically cause acute lung injury, which is termed ventilator-induced lung injury. Neutrophil recruitment and neutrophil elastase release play a central role in the pathogenesis of ventilator-induced lung injury including cell damage, extracellular matrix degradation and alveolar-capillary hyperpermeability. We therefore speculated that neutrophil elastase inhibition ameliorates ventilator-induced lung injury. Anesthetized C57/BL6 mice received mechanical ventilation with a high tidal volume (V(T); 20 ml/kg) for 4 h. The neutrophil elastase inhibitor (sivelestat, 100 mg/kg) or saline was given intraperitoneally (i.p.) 30 min before ventilation. Sivelestat completely inhibited both neutrophil elastase and myeloperoxidase activities that were increased by ventilation, and attenuated the histopathological degree of lung damage, neutrophil accumulation and lung water content, as well as the concentration of macrophage inflammatory protein (MIP)-2, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid and serum. Moreover, mechanical ventilation increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and the expression of early growth response gene-1 (Egr-1) mRNA, and these increases were also recovered by sivelestat. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed apoptotic cells mainly in alveolar epithelial cells and their numbers corresponded to histological damage. These data suggested that sivelestat could protect against ventilator-induced lung injury by suppressing apoptotic responses through mechanical stress-induced cell signaling in addition to inhibiting neutrophil chemotaxis.

Combined effects of a neutrophil elastase inhibitor (sivelestat sodium) and a free radical scavenger (edaravone) on lipopolysaccharide-induced acute lung injury in rats

“…In the present study, we found that therapeutic treatment of sivelestat, a small molecular weight inhibitor of neutrophil elastase, exhibited protective effects against LPS-induced lung injury. In agreement with our findings, previous studies have reported the protective effects of sivelestat against ALI/ARDS caused by other stimuli such as acid aspiration [29], mechanical ventilation [30], hemorrhagic shock [31], and hyperoxia [32]. Taken together, these findings support the idea that neutrophil elastase plays an important role in the pathogenesis of ALI/ ARDS.…”

Leukocyte Elastase Induces Lung Epithelial Apoptosis via a PAR-1–, NF-κB–, and p53-Dependent Pathway

“…In this regard, intratracheal administration of elastase into murine lungs induces apoptosis of lung epithelial cells (66,67), supporting the relevance of in vitro observations to events in intact animals. Second, inhibition of neutrophil elastase attenuates lung injury in several animal models (68)(69)(70)(71) and in patients with ALI after cardio-pulmonary bypass (72). However, treatment with a neutrophil elastase inhibitor was not effective in improving clinical outcomes in a multinational study of 492 patients with ALI (73).…”

Secondary necrosis in multicellular animals: an outcome of apoptosis with pathogenic implications

“…The effect of elastase inhibitors has been investigated in several situations with lung hyper inflammation, and some reports described beneficial results in patients with ALI/ ARDS or in rodent models of ALI further supporting the pathogenic role of released elastase (see for example [230][231][232] and references herein).…”