Effects of a synthetic protease inhibitor (gabexate mesilate) and a neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury in rats

Abstract

The present study was designed to examine the combined effects of a synthetic protease inhibitor (gabexate mesilate) with a specific neutrophil elastase inhibitor (sivelestat sodium) on acid-induced lung injury. Adult male Sprague-Daley rats weighing 300-350 g were anesthetized intraperitoneally with pentobarbital sodium and the right jugular vein was cannulated. Following tracheostomy, rats were ventilated mechanically and underwent intratracheal instillation of hydrochloric acid (HCl, 0.1N 1.5 ml/kg) or normal saline. Thirty minutes before HCl instillation, gabexate mesilate (10 mg/kg, i.p.) and/or sivelestat sodium (10mg/kg/h, i.v.) were administered. Bronchoalveolar lavage fluid samples were obtained 5 h after HCl instillation. In bronchoalveolar lavage fluid, the HCl-induced increases in total nucleated cell counts, neutrophil counts, optical density at 412 nm, as an index of pulmonary hemorrhage, concentrations of albumin and cytokine-induced neutrophil chemoattractant (CINC) were significantly attenuated by either gabexate mesilate or sivelestat sodium treatment. Gabexate mesilate or sivelestat sodium treatment also significantly attenuated the wet to dry weight ratio induced by HCl. However, combined treatment with both gabexate mesilate and sivelestat sodium did not exhibit additive effects on HCl-induced lung injury, compared with the single treatment. These findings suggest that gabexate mesilate and sivelestat sodium each exhibited protective effects on acid-induced lung injury, respectively, but that synergistic effects of both agents are limited in this acid-induced lung injury model. Word counts: 216

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.…”

Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19

“…NE is a protease capable of degrading multiple protein targets, including extracellular matrix proteins such as elastin, collagen and fibronectin, which are abundant proteins of the alveolar basement membrane. NE inhibitors, e.g., sivelestat sodium (ONO Pharmaceuticals), have been evaluated in clinical trials in patients with COPD (Hayakawa et al, 2010;Morjaria et al, 2010), and in acute lung injury patients (Yoshikawa et al, 2010). The use of sivelestat together with oseltamivir effectively reduced lung injury in a patient infected with the 2009 pandemic swine-influenza virus (Yokoyama et al, 2010).…”

Neutrophil elastase inhibitors

“…The HNE acylating agent par excellence continues to be Sivelestat (Elaspol R ) (Figure 4) (89), marketed in Japan and Korea for the treatment of acute lung injury associated with systemic inflammatory response syndrome and is currently explored for a range of other indications, including sepsis associated with acute respiratory distress syndrome and disseminated intravascular coagulation (90–92). …”