The Effects And Mechanisms Of FTY720 In Different Doses On Acute Lung Injury Induced By LPS In Rats

Objective:The acute lung injury model of rats induced by tracheal drip of LPS was established by exposure method,and different doses of FTY720 were given for intervention,to study the inhibitory effect of different doses of FTY720 on inflammatory response and its mechanism,and to explore the therapeutic effect of FTY720 on acute lung injury induced by LPS in rats.Methods:120 healthy adult male SD rats,weighing 160-240g,were divided into the control group(LPS+NS group,n=20)and the experimental group(LPS+FTY group,n=20/group)by random number table method,The experimental group was further divided into five subgroups:FTY 0.1 mg/kg group(FTY-0.1),0.2mg/kg group(FTY-0.2),0.5mg/kg group(FTY-0.5),1mg/kg group(FTY-1)and 2mg/kg group(FTY-2).FTY720 0.1mg/kg,0.2mg/kg,0.5mg/kg,lmg/kg,2mg/kg were given intraperitoneally injected after acute lung injury induced by intratracheal infusion of 10mg/kg LPS by exposure,The LPS+NS group was injected with the corresponding dose of NS.After intraperitoneal injection,routine feeding was performed to observe and compare the general changes in each group.Lung CT and blood gas analysis were performed at the time points of 6h,24h and 48h after treatment,and the lung tissues were extracted to prepare paraffin sections for histopathological observation,Levels of inflammatory cytokines(TNF-?,IL-6,IL-1?)were detected by ELISA,and to detect the expression of inflammatory pathway protein by Western-blot.All the results were statistically analyzed.Results:(1)General condition of rats,PaO2 and Lung tissues wet-dry ratio(W/D):Compared with LPS+NS group,the respiratory distress symptoms of the LPS+FTY group were alleviated,The PaO2 and W/D of the rats in each group were improved,and the improvement degree of the low-dose groups(FTY-0.1,FTY-0.2,FTY-0.5)were more obvious(P<0.05),and the FTY-0.1 group was closer to normal(P>0.05).(2)Lung histopathology and lung CT:Compared with LPS+NS group,lung injury scores in the low-dose groups(FTY-0.1,FTY-0.2,FTY-0.5)were decreased(_P<0.05),CT images showed the reduction of pulmonary inflammation,but the effect was not significant in FTY-1 and FTY-2 groups.(3)The levels of inflammatory cytokines was measured by ELISA:Compared with the LPS+NS group,the level of inflammatory cytokines(TNF-?,IL-6,IL-1?)in the low-dose groups(FTY-0.1,FTY-0.2,FTY-0.5)were decreased,and the lowest level was found in the FTY-0.5 group(P<0.05).(4)Western blot of lung tissues:Compared with the LPS+NS group,the p-NF-?Bp65/NF-?Bp65 ratio of lung tissues in the low-dose groups(FTY-0.1,FTY-0.2,FTY-0.5)were decreased,and the content of I?B? was increased(p<0.05),The activation of NF-?B was inhibited and was more obvious in FTY-0.5 group(P<0.05).However,with the increase of FTY720 dose,the inhibitory effect of FTY-1 and FTY-2 groups decreased.Conclusions:One-time intraperitoneal injection of FTY720 can protect ALI induced by LPS,and the effect of 0.5mg/kg is better.The protective mechanism may be achieved by inhibiting LPS-induced NF-?B activation and regulating the sphingosine-1-phosphate mechanism to improve barrier dysfunction of alveolus-capillary.