Effects Of Kynurenine-3-monooxygenase Inhibitor GSK180 On Sepsis-induced Acute Lung Injury In A Mouse Model

Background:Acute lung injury(ALI)or acute respiratory distress syndrome(ARDS)is a clinical syndrome induced by various pathological factors,which is characterized by persistent inflammation,acute respiratory distress,and non-cardiogenic pulmonary edema.It has become one of the most important causes of death in severe infection,severe trauma,and elderly patients.Although the mechanism remains unclear,accumulating evidence has demonstrated that excessive inflammatory response and oxidative stress play key roles in the development of ALI/ARDS.Tryptophan-kynurenine pathway is one important signal pathway responsible for proinflammatory cytokine production and consequently results in multiple organ dysfunctions.Among them,kynurenine-3-monooxygenase(KMO)is the key limiting enzyme in the metabolism of tryptophan,which can lead to enhanced inflammatory response and oxidative damage.Therefore,reducing the activity of KMO may provide a new way for the treatment of ALI/ARDS.However,the role and mechanism of KMO in sepsis induced ALI/ARDS remains unclear.In the present study,ALI/ARDS model induced by cecal ligation and puncture(CLP)was used to investigate the effects of KMO inhibitor GSK180 on ALI/ARDS and its possible mechanism,so as to provide evidence for the effective prevention and treatment of ALI/ARDS.Objectives:The current study aimed to investigate the effects of KMO inhibitor GSK180 on ALI/ARDS and its possible mechanism.In addition,we studied whether GSK180 can protect ALI/ARDS.For this purpose,we established the ALI model of sepsis by cecal ligation and puncture(CLP)in mice,to verify the effects of GSK180 on ALI induced by sepsis in mice,and to explore the potential mechanism and the protective effect of ALI/ARDS,so as to provide an important theoretical basis for better prevention and treatment of ALI/ARDS.Methods:The animal model of sepsis-induced ALI in mice was established by CLP.In the first set of experiment,56 adult mice were randomly assigned to the following four groups:sham + vehicle group(n=10),sham + GSK180 group(n=10),CLP +vehicle group(n=18),and CLP + GSK180 group(n=18).At 0 or 5 h after CLP or sham operation,animals received an intraperitoneal injection of GSK180(30 mg/kg of body weight)or the equal volume of normal saline.Pulmonary histological scores,wet-to-dry ratio(W/D),myeloperoxidase activity(MPO),TUNEL positive cells,tumor necrosis factor alpha(TNF-a),interleukin(IL)-6,IL-10,malondialdehyde(MDA)and superoxide dismutase activities(SOD)were measured at 24 h after operation.In addition,we also observed the 7 day survival rate in another set of experiment using the same protocol.Results:The survival rate of mice in sham + vehicle group and sham + GSK180 groups was 100%,CLP + vehicle group was 53.3%,CLP+ GSK180 group was 59.3%,and there was no significant difference in survival rate between CLP+ vehicle group and CLP+ GSK180 group(P>0.05).When compared with sham + vehicle group,sepsis significantly increased the pulmonary histological scores,W/D ratio,MPO activity,TUNEL positive cells,IL-6,and MDA levels in the CLP + vehicle group(P<0.05).However,GSK180 treatment decreased these parameters significantly as compared with the CLP + vehicle group(P<0.05).However,no significant difference was observed in pulmonary levels of TNF-a,IL-10,and SOD among the four groups(P>0.05).Conclusion:The present study suggested that although GSK180 did not significantly improve the survival rate of mice with sepsis,it can improve the sepsis-induced ALI/ARDS in mice by CLP,probably by down-regulating the inflammation and oxidative stress responses.