Effect Of5-AIQ, PARP Inhibitor, On Severe Acute Pancreatitis Associated Lung Injury And The Mechanisms

Part1. The optimal dosage of5-AIQ, a PARP inhibitor, of its protective effects in severe acute pancreatitis.Objective: This study is to investigate the optimal dose of5-AIQ, a PARP inhibitor, for treatment on severe acute pancreatitis-associated lung injury in rats.Methods: Fifty-six male Wistar rats, were randomly divided into8groups (N=8), Control group (CON group), Sham group (SO group), Severe acute pancreatitis group(SAP group),5-AIQ treatment groups (groups with different does of5-AIQ, O.lmg/kg,0.5mg/kg,1.5mg/kg,5mg/kg),5-AIQ vehicle group (Vehicle group). SAP model was induces by retrograde injection of5%sodium taurocholate (0.1ml/100g) in biliopancreatic duct. Various doses (0.1,0.5,1.5and5mg/kg) of5-AIQ were administered via femoral vein instantly after modeling. All rats were sacrificed and harvest at12h after modeling. Ascitic fluid and dry/wet ratio were recorded, AMY, LIP, ALT and Creatinine were measured and pancreas slides with H&E stain were evaluated.Results: the serum levels of AMY, LIP, ALT and Creatinine in SAP group, along with wet/dry ratio, ascetic fluid volumes and pathological scores of pancreases were higher than CO,SO and Vehicle groups. P<0.05; In5-AIQ treatment group, ALY, LIP, ALT, Creatinine and lung wet/dry ratio were significantly decreased in O.lmg/kg group than SAP group. P<0.05; All indications were decreased in0.5mg/kg and1.5mg/kg groups than SAP group.P<0.05;Indications beside ALT and Cr were decreased in5.0mg/kg group. ALT and Cr were higher than1.5mg/kg group and the differences were statistically significant. P<0.05; But verses SAP group, not significant, P>0.05.Conclusions:Administrate5-AIQ in doses of5mg/kg can alleviate the severity of pancreatitis, but not sufficient.0.5mg/kg and1.5mg/kg5-AIQ have better outcomes, more sufficient in1.5mg/kg group. Despite the good outcome of5.0mg/kg group, the toxic effects of live and kidney is higher, it’s not recommended. Therefore, the1.5mg/kg5-AIQ is the optimal, effective dosage. Part2. Effect of5-AIQ on severe acute ancreatitis-associated lung injury in ratsObjective: This study is to investigate the effect of5-AIQ, a PARP inhibitor, of its treatment on lung injury in severe acute pancreatitis rats.Method: Eighty male Wistar rats, were randomly divided into7groups: Control group (CON group)(N=10), Sham Group (N=10), severe acute pancreatitis group (SAP group)(N=40),5-AIQ treatment group (5-AIQ group)(N=14). Severe acute pancreatitis group (SAP group) was divided into four time points of1h,3h,6h and12h (N=10each time point). Severe acute pancreatitis model was induced by retrograde injection of5%sodium taurocholate (0.1ml/100g) through biliopancreatic duct in SAP group and5-AIQ group.1.5mg/kg5-AIQ was administered via femoral vein instantly after modeling. All rats except SAP group were sacrificed and harvest at12h after modeling while SAP group at its time point respectively. Ascitic fluid and lung dry/wet ratio were recorded, serum AMY and LIP were measured, The MPO of lung tissue, protein level of bronchoalveolar lavage fluid, pancreas and lung tissue slides with H&E stain were evaluated.Results:All indications were increased with modeling time. The indications of SAP group in12h verses CO and SO group were significantly different. P<0.05; The indications of5-AIQ group were decreased significantly. P<0.05Conclusion:1.5mg/kg5-AIQ can reduce the mortality and ascites, effectively alleviate the enzyme and pathological injury in pancreatic and lung tissue in severe acute pancreatitis of rats. Part3.The mechanism of5-AIQ on severe acute pancreatitis associated lung injury in ratsObjective: To investigate the possible mechanism of5-AIQ protection of the severe acute pancreatitis associated lung injury.Method: Seventy male Wistar rats, were randomly divided into six groups: Control group (CON group)(N=10), Severe acute pancreatitis group (SAP group)(N=40),5-AIQ treatment group (5-AIQ group)(N=14). Severe acute pancreatitis group(SAP group) was divided into four time points of1h,3h,6h and12h (1h N=10,3h N=12,6h N=14,12h N=14). Severe acute pancreatitis model was induced by retrograde injection of5%sodium taurocholate (O.1ml/100g) in biliopancreatic duct in SAP group and5-AIQ group.1.5mg/kg5-AIQ was administered via femoral vein instantly after modeling in5-AIQ group. All rats except SAP group were sacrificed and harvest at12h after modeling while SAP group at its time point respectively, as described earlier. Use western blot assay to measure IL-6levels and ICH to detect PARP-1and NF-kappa B in lung tissue.Results: The Expression of PARP-1, NF-κB and IL-6in lung tissue of SAP group were elevated verse CO group. All indications were gradually increased with modeling time, the differences are significant, P<0.05; Indications in5-AIQ group were lower than12h SAP group, P<0.05.Conclusions:5-AIQ inhibits PARP-1in lung tissue, down-regulates NF-κB levels and lower downstream inflammatory factor like IL-6to attenuate lung injury in SAP.