Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

Abstract

Background Sivelestat sodium hydrate (sivelestat) is a specific neutrophil elastase inhibitor that is effective in treating acute lung injury associated with systemic inflammatory response syndrome. As such, it may be useful in treating hepatic ischemia-reperfusion injury (IRI), a condition in which neutrophils transmigrate into the interstitium, leading to release of neutrophil elastase from neutrophils and consequent damage to the affected tissue, particularly in cases of hepatic failure after liver transplantation or massive liver resection. Aims The purpose of this study was to examine whether treatment with sivelestat inhibits neutrophil adhesion and migration to the vessel wall and suppresses hepatic IRI. Methods Whether and, if so, the extent to which sivelestat suppresses the adhesion and migration of neutrophils and reduces liver damage in hepatic IRI was examined in a human umbilical vein endothelial cell (HUVEC) model and a rat hepatic IRI model. Results In the HUVEC model, the extent of the adhesion and migration of neutrophils stimulated by platelet-activating factor were found to be dose-dependently inhibited by sivelestat treatment (p \ 0.05). In the rat model, serum liver enzyme levels were significantly lower at 12 h after reperfusion, and the number of neutrophils that had migrated to extravascular sites was significantly less in the treatment group compared to the control group (p \ 0.05). Conclusion Sivelestat inhibits the adhesion and migration of neutrophils to vascular endothelium in hepatic IRI, thereby suppressing liver injury.

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

“…In all models, a dramatic suppression of tissue infiltration of neutrophils was noted, with some indications of concomitant inhibition of acute tissue injury. Similar results were obtained using an NE inhibitor, observations that are in agreement with previously published works using different models of I/R injury and confirming the efficacy of sivelestat in the treatment of perioperative acute inflammatory responses in the clinic . In sharp contrast, the use of NE‐deficient mice has led to conflicting and varied results regarding the functions of this protease in neutrophil infiltration, questioning the efficacy and specificity of existing NE inhibitors.…”

“…sivelestat) inhibitors of NE . The use of sivelestat, in particular, confirmed the potential of targeting NE for the treatment of disorders such as acute lung injury , complications arising from myocardial surgery , organ transplantation and several model of I/R injury . However, at present the specific role(s) of NE in I/R injury remains poorly understood.…”

Extravasated platelet aggregation in the livers of rats with drug-induced hepatic sinusoidal obstruction syndrome

“…NETs, however, have been reported to contribute to organ damage in patients with infectious diseases (30) Furthermore, sivelestat sodium, a neutrophil elastase inhibitor, was found to inhibit neutrophil adhesion and migration to vascular endothelium during hepatic ischemia reperfusion and prevent liver injury (31). Platelets are not stained by H&E. because they lack nuclei.…”

Structural Diversity and Anticancer Activity of Marine‐Derived Elastase Inhibitors: Key Features and Mechanisms Mediating the Antimetastatic Effects in Invasive Breast Cancer

“…One study demonstrated the ability of sivelestat to inhibit the NE‐induced migration of the TE‐13 esophageal cancer cell line . Additionally, sivelestat was reported to inhibit the migration of neutrophils in a human umbilical vein endothelial cell (HUVEC) model . The migration inhibitory ability of other NE inhibitors was also reported .…”