The Role Of P2X7Receptor In Acute Dextran Sodium Sulfate Colitis

Background：Inflammatory bowel disease (IBD), is a chronic inflammatory disorder inintestine and colon. The etiology of IBD is still unclear, but it is suggested that theaberrant interactions between immune system in genetically susceptible individuals,and enteric commensal bacteria/pathogens, contribute to the development of IBD.During the process of inflammation, a large amount of ATP was released from thedamaged cells, which can further bind to P2X7receptor. Once activated by ATP,P2X7induces the rapid and robust assembly of the NLRP3inflammasome complexthat facilitates caspase-1-mediated processing and secretion of proinflammatorycytokines. ATP-P2X7purinoceptor cascade has been reported to contribute toinflammatory diseases, such as respiratory disease, neurological disease, rheumatoiddisease, kidney disease. However, it remains to be elucidated whether P2X7receptorplays an important role in the pathogenesis of inflammatory bowel disease.Objective:Explore the effect and mechanism of P2X7receptor on dextran sulfate sodium(DSS) induced murine colitis.Method:The mice were randomly divided into4groups: control, DSS, DSS+Suramin(P2X7receptor antagonist), DSS+BzATP (P2X7receptor agonist). The mice ingroups DSS, DSS+Suramin, DSS+BzATP were given ad libitum4%w/v dextransulphate sodium (DSS) dissolved in distilled water for seven consecutive days,followed by distilled water for another additional two days. Control group micereceived distilled water only. The group of DSS+Suramin and DSS+BzATP weregiven of Suramin1mg/day, BzATP1mg/day intraperitoneal injection respectivelyfrom day4to day8. All mice were sacrificed on day10. Disease activity index (DAI) was evaluated daily regarding disease symptoms including body-weight, diarrhea,hematochezia. Colon tissues were collected and cytokine levels, histologicalexaminations and MPO activity were performed, including the expression of CD68and caspase-1p10, MPO activity, TNF and IL-1β levels.Results:1. On the day10, the DAI of group control is0. group DSS (8.25±2.25) andDSS+BzATP (9.4±0.55) while higher than control and group Suramin (p<0.05).2. The histological score of group Suramin (3.63±0.74) is lower than group DSS(8.25±1.58) and DSS+BzATP (9.2±2.17)(p<0.05), while higher than control(p<0.05).3. The MPO activity in colonic tissue of group DSS+Suramin (0.33±0.06U/g) islower than group DSS (0.49±0.07U/g) and DSS+BzATP (0.54±0.10U/g)(p<0.05),but no obvioushigher than control (0.23±0.03U/g)(p<0.05).4. The levels of TNF in colonic tissue of group DSS+Suramin (163.68±24.51pg/ml) is lower than group DSS （281.35±30.32pg/ml） and DSS+BzATP（305.48±65.16pg/ml）（p<0.05），but higher than control（126.18±23.24pg/ml）（p<0.05).5.The levels of IL-1β in colonic tissue of group DSS+Suramin（85.88±12.17pg/ml) is lower than group DSS (146.21±27.99pg/ml) and DSS+BzATP（197.60±41.80pg/ml)(p<0.05),but no obvious higher than control (67.38±9.36pg/ml)(p>0.05).6. The number of CD68positive cells in colonic tissue of group DSS+Suramin issignificantly lower than group DSS and DSS+BzATP (p<0.05), higher than controlgroup (p<0.05).7.The number of caspase-1p10positive cells in colonic tissue of DSS+Suraminis significantly lower than group DSS and DSS+BzATP (p<0.05), higher than controlgroup (p<0.05). Conclusion:P2X7receptor contributes to the pathogenesis of DSS induced colitis, viapromoting caspase-1activation, inducing cytokine production, and boosting immuneresponses in mice with colitis.