The neutrophil elastase inhibitor, sivelestat, attenuates sepsis-related kidney injury in rats

Abstract

Sepsis-induced acute kidney injury (AKI) represents a major cause of mortality in intensive care units. Sivelestat, a selective inhibitor of neutrophil elastase (NE), can attenuate sepsis-related acute lung injury. However, whether sivelestat can preserve kidney function during sepsis remains unclear. In this study, we thus examined the effects of sivelestat on sepsis-related AKI. Cecal ligation and puncture (CLP) was performed to induce multiple bacterial infection in male Sprague-Dawley rats, and subsequently, 50 or 100 mg/kg sivelestat were administered by intraperitoneal injection immediately after the surgical procedure. In the untreated rats with sepsis, the mean arterial pressure (MAP) and glomerular filtration rate (GFR) were decreased, whereas serum blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels were increased. We found that sivelestat promoted the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels; specifically, the higher dose was more effective. In addition, sivelestat suppressed the CLP-induced macrophage infiltration, the overproduction of pro-inflammatory mediators (tumor necrosis factor-α, interleukin-1β, high-mobility group box 1 and inducible nitric oxide synthase) and serine/threonine kinase (Akt) pathway activation in the rats. Collectively, our data suggest that the inhibition of NE activity with the inhibitor, sivelestat, is beneficial in ameliorating sepsis-related kidney injury.

Anti-Inflammatory Pyranochalcone Derivative Attenuates LPS-Induced Acute Kidney Injury via Inhibiting TLR4/NF-κB Pathway

“…Numerous studies have demonstrated that proinflammatory cytokines have prominent roles in sepsis-induced AKI [ 19 , 20 ]. Excessive release of inflammatory factors, such as IL-1β, IL-6, and TNF-α, triggered pathophysiological abnormities of sepsis [ 19 , 21 , 22 , 23 ]. Therefore, anti-inflammatory therapy could be effective for the treatment of septic AKI, and novel chemical entities or drug candidates with anti-inflammatory activity would be beneficial for sepsis-induced AKI [ 6 , 8 , 19 , 24 , 25 ].…”

Characterization and functional analysis of cathelicidin-MH, a novel frog-derived peptide with anti-septicemic properties

“…Therefore, fibrinolytic enzymes and chymase closely correlate with disease severity and fatality in sepsis ( Zeerleder et al, 2007 ). Furthermore, neutrophil elastase is associated with pulmonary endothelial injury under LPS-induced endotoxemic conditions ( Suzuki et al, 2019 ), and inhibitors such as sivelestat can attenuate sepsis-related acute tissue injury ( Li et al, 2016 ). Finally, β-tryptase promotes early pulmonary fibrosis in sepsis-induced lung injury and anti-tryptase treatment has a therapeutic effect in experimental colitis ( Isozaki et al, 2006 ; Villar et al, 2015 ).…”

Role of using two-route ulinastatin injection to alleviate intestinal injury in septic rats

“…In addition, NE, a serine protease that propagates persistent neutrophilic inflammation by attacking host proteins of neutrophils or accelerating pro-inflammatory cytokine production, may also participate in the development of sepsis. 16 , 17 Such proteolysis may change the protein pattern of an inflammatory focus depending on the number of neutrophils involved and the duration of inflammation. 14 Of note, Suda et al.…”

“…confirmed using the sepsis shock model that intraintestinal administration of proteinase inhibitors 6-amidino-2-naphthyl p -guanidinobenzoatedimethanesulfate or tranexamic acid could inhibit the activities of digestive enzymes, ameliorate the expression of inflammatory mediators, and increase the survival rate. In addition, NE, a serine protease that propagates persistent neutrophilic inflammation by attacking host proteins of neutrophils or accelerating pro-inflammatory cytokine production, may also participate in the development of sepsis 16, 17. Such proteolysis may change the protein pattern of an inflammatory focus depending on the number of neutrophils involved and the duration of inflammation 14 .…”