Effect Of TLR4 Gene Knockout On Acute Liver Injury And Myocardial Damage And Its Mechanism In Septic Mice

BackgroundSepsis is one of the most severe diseases in the world.It is usually accompanied by multiple organ failure,which is mainly caused by the body’s disordered inflammatory response to infection.Heart and liver are the two most vulnerable organs during sepsis.The occurrence and development of sepsis myocardial injury and acute liver injury are critical to the prognosis of sepstic patients.In recent years,a large number of studies have shown that TLR4 plays a vital role in the regulation of inflammatory response and apoptosis in septic multiple organ injury,but the exact mechanism of how TLR4 signaling pathway regulates sepsis acute liver injury and myocardial injury is still unclear.ObjectiveThis study intends to study the effect of TLR4 gene knockout on acute liver injury and myocardial injury in sepsis by establishing a mouse model of sepsis induced by LPS,and to explore the mechanism of TLR4 gene knockout and its effect pathway in regulating inflammatory factor release and cell apoptosis,as to clarify the specific role and mechanism of TLR4 on acute liver injury and myocardial injury in sepsis,and provide a new direction for the treatment of acute liver injury and myocardial injury in sepsis.MethodsAccording to random number method,32 male adult TLR4 knockout mice(TLR4-/-)and 32 male adult wild-type mice(WT)were randomly divided into 4 groups:WT group,WT-LPS group,TLR4-/-group,TLR4-/--LPS group.The LPS-challenged group was injected intraperitoneally with a dose of 4 mg/kg of LPS to establish a model of sepsis multiple organ injury,and the control group was intraperitoneally injected with the same dose of saline.Six hours after the administration,we used echocardiography,HE staining,liver biochemical detection,ELISA,Immunohistochemistry,RT-PCR,Western Blot et al,to detect the effect of TLR4 gene knockout on LPS-induced sepsis mice with acute liver injury and myocardial injury and to explore whether the TLR4 signaling pathway plays a role in acute liver injury and myocardial injury in sepsis by regulating the release of inflammatory factors and the activation of apoptotic pathways.ResultsThe study found that:1.LPS could induce severe liver and myocardial injury in mice,while TLR4 gene knockout could improve liver function damage and heart failure in LPS-induced sepsis mice;2.TLR4 gene knockout not only attenuated the adverse changes of liver tissue and myocardial histomorphology,but also reduced the content of protein oxidized carbonyl in liver tissue and heart tissue of LPS-induced sepsis mice;3.TLR4 gene knockout eliminated LPS-induced activation of the TLR4/MyD88/NF-κB molecular pathway;4.TLR4 gene knockout reduced the expression levels of inflammatory factors in serum,liver and heart tissues of LPS-induced sepsis mice;5.TLR4 gene knockout inhibited the level of cell apoptosis and increased the expression of anti-apoptotic protein Bcl-2,while downregulated the expression of apoptotic protein Bax in liver and heart tissues of LPS-induced sepsis mice.ConclusionTLR4 gene knockout could attenuate LPS-induced acute liver injury and myocardial injury in sepsis mice.The mechanism may be through inhibiting the release of inflammatory factors and activation of the apoptosis.