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.

Alpha-lipoic acid (ALA) reportedly has protective effects against sepsis, which is a leading cause of mortality worldwide and is associated with multiple organ dysfunction. The present study aimed to investigate further the possible action mechanisms of ALA. Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) in order to establish a sepsis model. The rats received an oral gavage of 200 mg/kg ALA or saline immediately after surgery. The heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and maximum rising and lowering rates of left ventricular pressure (±dp/dt) were examined for assessing the cardiac function. Blood urea nitrogen (BUN) and serum creatinine levels were assessed for evaluating renal function. Neutrophil gelatinase-associated lipocalin (NAGL) was examined for reflecting acute renal injury. Histopathological alterations of the small intestine were examined by hematoxylin-eosin staining. The ultrastructure of the small intestine and kidney was observed under electron microscopy. The levels of autophagy- and inflammation-associated proteins were determined via western blot analysis. The binding of nuclear factor-kappa B (NF-κB) to DNA was tested via an electrophoretic mobility shift assay. Cell apoptosis was examined using TUNEL staining. ALA treatment improved the survival rate, restored the loss of body weight and pro-inflammatory cytokines production in the serum of CLP-induced septic rats. ALA improved the cardiac and renal functions, downregulated the expression levels of interleukin-1β, tumor necrosis factor-α, and inducible nitric oxide synthase in the myocardium and small intestine of septic rats. ALA treatment also inactivated the NF-κB signaling pathway in the small intestine. An examination of autophagy showed that ALA increased the LC3II/I ratio, upregulated Atg5, Atg7, and beclin-1 and downregulated p62 protein levels in the myocardium, kidney, and small intestine of septic rats, and further promoted autophagosome accumulation in the kidney and small intestine. In addition, ALA could also reduce cell apoptosis in myocardium, kidney and small intestine tissues. These effects can be completely or party inhibited by 3-MA. Our findings suggest that autophagy enhancing may contribute to the organ protective effect of ALA in septic rats.

Acute kidney injury is a frequent and serious complication in patients with severe sepsis. α-Lipoic acid (ALA), a naturally occurring dithiol compound, has been shown to possess anti-inflammatory and anti-oxidative properties. In the present study we investigated whether ALA could attenuate acute kidney injury and improve survival in a rat model of sepsis. Rats were subjected to caecal ligation and puncture (CLP) to induce sepsis. α-Lipoic acid (200 mg/kg) was administered by oral gavage either immediately (early treatment) or 12 h after the surgical procedure (delayed treatment). Both early and delayed ALA treatment effectively prolonged survival, improved pathological damage in kidney tissues and reduced serum blood urea nitrogen and creatinine levels in CLP-induced septic rats. Furthermore, early treatment with ALA markedly inhibited the release of tumour necrosis factor-α, interleukin (IL)-6 and IL-1β into the serum and reduced mRNA and protein expression of inducible nitric oxide synthase and high mobility group box 1 in kidney tissues from CLP-induced rats. Finally, CLP-induced nuclear factor-κB activation in kidney tissues was significantly suppressed by early ALA treatment. Together, the results indicate that ALA is able to reduce mortality and attenuate acute kidney injury associated with sepsis, possibly by anti-inflammatory actions. α-Lipoic acid may be a promising novel agent for the treatment of conditions associated with septic shock.

Ventilator-induced lung injury is a severe complication mainly caused from mechanical ventilation (MV), associated with the upregulation of inflammation response. The mechanism still remains unclear. This study aims to explore the effects of pathological damage, neutrophil infiltration, expression of P 2 X 7 receptor, and activation of Caspase-1 in lung tissue using a rat model. Sprague Dawley (SD) rats were randomly divided into sham group, conventional MV group, and high-tidalvolume ventilation group and fed with clean water and rat food. The sham group received tracheotomy without MV; conventional MV group was given 7 mL/kg tidal volume ventilation, and high-tidal-volume MV group was given 28 mL/kg tidal volume ventilation. All the rats were sacrificed after 4 h of ventilation or spontaneous breath. Lung wet/dry ratio was measured, and paraffin sections were prepared for pathological injury assessment and immunohistochemistry of P 2 X 7 and myeloperoxidase levels. Lung homogenate was used for Western blot analysis of P 2 X 7 receptor and Caspase-1 levels and real-time polymerase chain reaction (PCR) analysis of P 2 X 7 gene expression level. Compared to sham group and conventional MV group, high-tidal-volume MV led to an increase in lung wet/dry ratio and histology score. High-tidalvolume ventilation also led to chemotaxis of neutrophils. The expression levels of protein and messenger RNA (mRNA) of P 2 X 7 receptor were significantly upregulated. Cleaved-caspase-1 expression was also upregulated. All data provide the evidence that high-tidal-volume MV can lead to lung injury, neutrophils infiltration, and upregulation of cleaved-Caspase-1 level. This result may be related to the upregulation of P 2 X 7 receptor expression.