Abstract
BackgroundEndothelial injury is one of the predominant pathophysiological characteristics of sepsis and is the major cause of sepsis-induced multiple organ failure. Endothelial pyroptosis is a fatal mechanism of endothelial injury in sepsis, and specific, effective therapies are lacking. Although hepatocyte growth factor (HGF) has been shown to have anti-apoptotic and anti-necrotic effects, whether it prevents pyroptosis to improve endothelial injury in sepsis remains unclear.MethodsRecombinant HGF was intravenously injected into mice with sepsis caused by caecal ligation puncture (CLP). Histopathological examination and transmission electron microscopy (TEM) were used to measure lung vascular endothelial injury. Lipopolysaccharide (LPS) was transfected into EA.hy926 cells to induce endothelial pyroptosis, and the cells were treated with HGF in the presence of inhibitors of c-Met and mTOR, namely, PHA-665752 and rapamycin, respectively. The mTOR signalling pathway and mitochondrial physiology were assessed using Western blot and flow cytometry.ResultsIntravenous HGF effectively alleviated pulmonary vascular endothelial injury and acute lung injury in the septic mice. The TEM results of lung tissue revealed that HGF attenuated pulmonary vascular endothelial pyroptosis, which was confirmed in vitro. Transfected LPS induced the pyroptosis of EA.hy926 cells and damaged their paracellular permeability, and these effects were ameliorated by treating the cells with recombinant HGF. The protective effect of HGF against pyroptosis was dependent on c-Met/mTOR signalling. mTOR activation effectively protected mitochondrial physiology and decreased reactive oxygen species (ROS) production in EA.hy926 cells in vitro.ConclusionsThese results demonstrated that HGF protected mitochondrial physiology by activating mTOR signalling to partially ameliorate endothelial pyroptosis and attenuate vascular endothelial injury and acute lung injury in sepsis animal model.
Highlights
Sepsis is a common clinical syndrome defined as lifethreatening organ dysfunction caused by a dysregulated host response to infection [1]
With the use of animal models, imaging studies, biochemical assays, and molecular inhibition approaches, we show that hepatocyte growth factor (HGF) ameliorates septic endothelial pyroptosis in vivo and in vitro and that the mammalian target of rapamycin signalling pathway plays a central role in this process
HGF effectively alleviated acute lung injury in sepsis To explore the effect of HGF on acute lung injury (ALI) in sepsis, we intravenously injected recombinant HGF into mice with sepsis caused by caecal ligation puncture (CLP) (Fig. 1a)
Summary
Sepsis is a common clinical syndrome defined as lifethreatening organ dysfunction caused by a dysregulated host response to infection [1]. Anticoagulant therapy and nitric oxide synthase inhibitors have shown protective effects in the endothelium, effective treatments for endothelial cell injury in sepsis that improve prognosis are lacking [6]. It is of great significance and translational value to explore mechanisms and novel therapeutic options of endothelial cell injury. Endothelial pyroptosis is a fatal mechanism of endothelial injury in sepsis, and specific, effective therapies are lacking. Hepatocyte growth factor (HGF) has been shown to have anti-apoptotic and anti-necrotic effects, whether it prevents pyroptosis to improve endothelial injury in sepsis remains unclear
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