| Objective:Acute pancreatitis(AP)is a common clinical disease,and some patients progress to severe acute pancreatitis(SAP),which has an acute onset and many complications,a high mortality rate,the ability to damage the intestine,increased cell death,and a reduced intestinal barrier.It is capable of damaging the intestine with increased cell death and reduced intestinal barrier function.Recent studies have shown that the stimulator of interferons genes(STING)signaling pathway is activated and plays an important role in several inflammatory diseases,and the role of STING in intestinal mucosal barrier damage in SAP is currently unknown.We investigated whether the STING signaling pathway is activated in intestinal epithelial cells(IECs)when SAP-related intestinal barrier dysfunction occurs,whether activation of the STING signaling pathway can aggravate intestinal barrier damage,and whether inhibition of the STING signaling pathway can improve intestinal barrier damage.Methods:Forty healthy male Wistar rats were divided into four groups: sham-operated group(SO group),severe acute pancreatitis group(SAP group),STING activator DMXAA treatment group(SAP+DMXAA group),and STING inhibitor C-176 treatment group(SAP+C-176 group).The retrograde puncture method of bile-pancreatic duct was adopted,and sodium taurocholate solution(5% concentration,1 ml/kg)was injected into the bile-pancreatic duct to make the SAP rat model.STING activator DMXAA(10mg/kg)was given intraperitoneally 0.5 h before the establishment of SAP model and labeled as SAP+DMXAA group.STING inhibitor C-176(6.7 mg/kg)was injected into the bile-pancreatic duct 0.5 h before the establishment of SAP model,and labeled as SAP+DMXAA group.C-176(6.7 mg/kg)was administered intraperitoneally 0.5 hours before SAP model establishment and labeled as SAP+C-176 group.Rats were anesthetized again 24 hours after SAP establishment.Serum lipase and serum amylase were analyzed using an automated biochemical analyzer,and endotoxin,diamine oxidase(DAO),tumor necrosis factor-α(TNF-α),fatty acid binding protein(FABP2),interferon-β(INF-β),interleukin-6(IL-6);pancreatic and terminal ileal pathological changes were assessed and scored pathologically using HE staining;terminal ileal STING,p-interferon regulatory factor 3(p-IR)Regulatory Factor 3(p-IRF3),p-nuclear facto-κB(p-NF-κB,p-P65)and tight junction(TJ)proteins,Occludin,Zonula occluden-1(ZO-1)protein levels in the ileum were measured using The distribution of STING,tight junction,Occludin and ZO-1 in the terminal ileum was measured by immunofluorescence.Results:All serological parameters detected in the SAP group were significantly higher.serum lipase,serum amylase,TNF-α,IL-6,DAO,IFN-β,FABP2 and endotoxin levels were significantly higher in the SAP group than in the SO group(p<0.01).intestinal pathological damage was significantly increased in the SAP group compared to the SO group.Compared with the SAP group,the expression and protein levels of STING-related genes were significantly higher in the SAP+DMXAA group(p<0.01)and significantly lower in the SAP+C-176 group(p<0.01).serum amylase,serum lipase,TNF-α,IL-6,DAO,FABP2 and endotoxin levels were significantly higher in the SAP+DMXAA group compared with the SO group(p<0.01).The levels of serum amylase,serum lipase,TNF-α,IL-6,DAO,INF-β,FABP2 and endotoxin were increased in the SAP+C-176 group compared with the SAP group(p<0.01).The pancreatic and intestinal tissues in the SAP group showed significant signs of injury by HE staining,and the pancreatic and intestinal tissues in the SAP+DMXAA group had heavier histological injury changes and higher pathological scores(p<0.05),while the pancreatic and intestinal tissues in the SAP+C-176 group had lighter histological injury changes and lower pathological scores(p<0.05).The expression of tight junction protein ZO-1 and occludin was lower in the SAP group than in the SO group(p<0.01).Compared with the SAP group,the expression of ZO-1 and occludin was decreased in the SAP+DMXAA group(p<0.05),and the expression of ZO-1 and occludin was increased in the SAP+C-176 group(p<0.05).Conclusion:This study confirms that STING signaling pathway plays an important role in intestinal mucosal injury in SAP,and activation of STING signaling pathway can aggravate intestinal mucosal injury and aggravate intestinal barrier damage,and inhibition of STING signaling pathway can alleviate intestinal mucosal injury and reduce intestinal barrier damage. |
