A Neutrophil Elastase Inhibitor, Sivelestat, Reduces Lung Injury Following Endotoxin-Induced Shock in Rats by Inhibiting
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A Neutrophil Elastase Inhibitor, Sivelestat, Reduces Lung Injury Following Endotoxin-Induced Shock in Rats by Inhibiting HMGB1 Satoshi Hagiwara,1,2 Hideo Iwasaka,1 Kazumi Togo,1 and Takayuki Noguchi1
Abstract—Neutrophil elastase (NE) plays an important role in the progression of acute lung injury (ALI). Sivelestat sodium hydrate (Sivelestat) is a highly specific synthetic inhibitor of NE. High mobility group box 1 (HMGB1) is one of the key mediators in the development of sepsis. The aim of this study was to evaluate the effect of sivelestat and to determine whether it can reduce lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomly divided into a negative control group, an LPS-induced sepsis group, and a group treated with sivelestat prior to LPS administration. Animals in the sivelestat group received a bolus of 10 mg/kg of sivelestat injected into the intraperitoneal cavity before the LPS treatment. Furthermore, rats were administered sivelestat at 0, 1, 3, and 6 h following LPS treatment. We measured cytokine and HMGB1 levels in the serum after the induction of sepsis. In addition, we observed histopathology, wet/dry weight ratio, induc ible nitric oxide synthase and HMGB1 expression in the lung tissue. Lung histopathology was significantly improved in the sivelestat group compared to the LPS group. Serum and pulmonary HMGB1 levels were lower over time among sivelestat-treated animals. Furthermore, inhibition of NF-κB activity was observed with the administration of sivelestat. These results suggest that sivelestat reduces LPS-induced lung injury at least partially by inhibiting inflammation and NF-κB activity. KEY WORDS: inflammation; sepsis; high mobility group box 1; cytokine; NF-κB; nitric oxide.
well defined clinical disorders that are a significant cause of morbidity and mortality in intensive care units (ICU). The most frequent cause of ARDS and ALI is sepsis. [2]. Despite recent increases in our understanding of the molecular underpinnings of sepsis, most of these complications remain refractory to treatment [3]. The respiratory system in particular is severely affected and difficult to treat [4]. Neutrophil elastase (NE, also called leukocyte elastase) is a serine protease found primarily in the azurophilic granules of neutrophils. Intracellular NE is a key molecule of the innate immune system and is required for effective killing of phagocytosed bacterial and fungal pathogens [5, 6]. In addition, Moraes TJ et al. [7] reviewed the potentially pathologic role of NE in ARDS and ALI, including the ability of extracellular NE
INTRODUCTION The high case fatality rate of sepsis is due to complications throughout the major organ systems that can occur by various mechanisms. In spite of advances in therapy, the mortality rate for severe sepsis remains high, reaching 80% to 90% for septic shock with multiple organ dysfunction [1]. Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are 1
Department of Brain and Nerve Science, Anesthesiology, Oita University Faculty of Medic
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