Study On The Protective Effect Of Linezolid Plus Fosfomycin On Liver Injury In Sepsis And Part Of Its Mechanisms

Objectives:The aim of the study was to observe the therapeutic effect of linezolid combined with fosfomycin on septic mice and to study its effect on oxidative stress,inflammation and apoptosis of macrophages.Methods:Experimental mice were randomly divided into control group,model group,linezolid group,fosfomycin group and two drug combination groups,and two sepsis mouse models were established by cecum ligation puncture surgery(CLP)and intraperitoneal injection of lipopolysaccharide(LPS).Drug administration was started 1 hour after the implementation of CLP and LPS injection,and the administration lasted for 3 days,and the therapeutic dose of the drug was injected intraperitoneally every 12 hours in each administration group,and the survival curves of the mice were recorded to establish the mice and their body temperatures were measured.The liver and serum were taken at 24 hours after modeling,and the levels of inflammatory factors(IL-6,TNF-α and IL-1β)in the blood were measured by ELISA.The pathological damage to the liver was observed by H&E staining,and the expression of inflammatory factors and inducible nitric oxide synthase(i NOS),malondialdehyde(MDA),and the expression of MDA in the liver were measured.malondialdehyde(MDA)content and superoxide dismutase(SOD)activity were measured to compare inflammation and oxidative stress in the liver.Bone marrow macrophages from induced mice were extracted and cell viability was determined by CCK8 method.The expression and secretion of cellular inflammatory factors were determined by q PCR,protein blotting(Western blot)and ELISA.The expression of cellular i NOS,ROS production,NO release and SOD activity were measured to compare the antioxidant effects of linezolid combined with fosfomycin on macrophages by Western blot was used to detect apoptosis-related proteins and to examine the effect of the combination of the two drugs on macrophage apoptosis.Results:Both linezolid and fosfomycin improved the survival rate of mice with LPS and CLP-induced sepsis,and the combination of the two drugs showed superior results to those of the single drug,significantly increasing the survival rate,restoring hypothermia and reducing liver damage in septic mice.The combination of the two drugs significantly reduced the plasma levels of inflammatory factors and the expression of inflammatory factors in the liver of septic mice,reduced MDA levels in the liver and significantly enhanced SOD activity,reducing inflammation and oxidative stress in mice.The results of cellular experiments showed that linezolid combined with fosfomycin significantly inhibited the expression and secretion of LPS-induced inflammatory factors,suppressed NO production by down-regulating the expression of i NOS,enhanced the antioxidant capacity of macrophages by inhibiting the production of ROS and increasing the activity of SOD,and promoted the apoptosis of activated macrophages and reduced inflammation by inhibiting the expression of BCL2.Conclusion:Linezolid combined with fosfomycin significantly improved the survival of septic mice,ameliorated liver inflammatory infiltration and pathological injury,and could further inhibit inflammation and oxidative stress in mice by promoting apoptosis of activated macrophages and enhancing their antioxidant capacity to suppress cellular inflammation and oxidative stress.