Neutrophil Elastase Inhibitor Improves Survival of Rats With Clinically Relevant Sepsis

Abstract

Sivelestat sodium hydrate is a selective inhibitor of neutrophil elastase, which is effective in acute lung injury associated with systemic inflammatory response syndrome. However, the effectiveness of sivelestat in sepsis has not been fully examined. In the present study, the effect of sivelestat on severe sepsis in a rat cecal ligation and puncture (CLP) model was investigated. Adult male Sprague-Dawley rats underwent CLP and were randomly divided into two groups: sivelestat-treated group and saline-treated controls. The serum concentrations of several inflammatory mediators were measured. Hematoxylin-eosin staining, and immunohistochemical staining for high-mobility group box chromosomal protein 1 (HMGB1), IL-8, and CD68 were performed on the lungs to assess pathological changes found 12 h after the CLP procedure. Treatment with sivelestat significantly improved the survival rate of the post-CLP septic animals (P = 0.030). Sivelestat also induced a significant reduction in serum IL-1beta (P = 0.038) and IL-10 (P = 0.008) levels in these CLP rats. Serum HMGB1 levels had no significant difference between the sivelestat-treated and the control group. The lungs from sivelestat-treated rats exhibited less severe pathological changes and decreased the numbers of HMGB1, IL-8, and CD68-positive cells (P < 0.001). Sivelestat significantly improved survival rate of rats with clinically relevant sepsis, possibly by attenuating sepsis-induced systemic inflammatory response and lung injury. This may explain the implicated health benefits of sivelestat in reducing morbidity and mortality from sepsis.

Hydrogen-rich saline ameliorates lung injury associated with cecal ligation and puncture-induced sepsis in rats

“…Neutrophils are considered to be central to the pathogenesis of most forms of ALI (Suda et al, 2010). Lung MPO activity is an indicator of neutrophil accumulation.…”

“…It is a leading cause of morbidity and mortality in severely ill patients (Raghavendran and Napolitano, 2011a,b;Ware and Matthay, 2000). The major pathological changes of ALI include impaired gas exchange, neutrophil accumulation, increased vascular permeability and parenchyma injury (Wu et al, 2009;Lee and Downey, 2001;Suda et al, 2010). Endotoxin (LPS), derived from the cell wall of gram-negative bacteria, is thought to be the most important pathogen that leads to the development of ALI.…”

High-dose immunoglobulin preparations improve survival in a CLP-induced rat model of sepsis

“…CLP in rodents results in an early hyperdynamic phase what is followed by a hypodynamic phase, similar to human sepsis [8]. We previously reported the efficacy of sivelestat (a synthetic, specific, low molecular weight neutrophil elastase inhibitor, which has been used clinically for the treatment of acute lung injury) in clinically relevant sepsis using this model [9].…”

In vivo efficacy of KRP-109, a novel elastase inhibitor, in a murine model of severe pneumococcal pneumonia

“…In addition, it has been reported that NE induces the release of IL-8 from cells [15]. Furthermore, NE inhibitor has been reported to induce a significant reduction in serum IL-1β in rats with relevant sepsis [16]. IL-1β acts locally to stimulate chemotaxis and activate neutrophils in ALI and also stimulates the production of extracellular matrix by fibroblasts [17].…”