The Role Of CD4+T Lymphocytes In The Pathogenesis Of Severe Acute Pancreatitis

Most cases of acute pancreatitis(AP)are mild with no organs failure,and are often self-limited.While other cases of AP are characterized with a 20%mortality,following by complication with organs failure,which are severe acute pancreatitis(SAP).They are the same disease,why is there so much difference between their disease process?After the revision of the Atlanta classification of AP was published,the "immune disorder theory" was propounded to explaine this question.And it is considered that AP was essentially a systemic inflammatory disorder,and the severity of AP depended on the intensity of the inflammatory immune response,immune cells and inflammatory factors derived from immune cells contained.Firstly,together with nuclear factor-?B in the pancreatic acinar cells,immune cells and inflammatory factors released by immune cells formed a vicious circle of the pancreatic acinar cells injury,which would magnify the local inflammation of the pancreas.What's more,they could transfer the local inflammation to the systemic by the circulation system,and lead to the distant organs injury.Immune cells thus play an important role in the pathgenesis of SAP,and are the potential target for the treatment of SAP.Previous research showed that CD4+T lymphocytes played a pivotal role in the development of tissue injury during SAP.Therefore,we speculated that CD4+T lymphocytes might play a pivotal role in the inflammatory immune response in the early phase of SAP.Based on the "immune disorder theory",in the study we observed the change of CD4+T lymphocytes in the early phase of SAP dynamically and analyzed the relationship between the pancreas injury and CD4+T lymphocytes.Afterwards,an immunosuppressant was administrated in the early phase of SAP to inhibit the egress of CD4+T lymphocytes,and we observed its effect on the inflammatory response,the pancreas injury and the distant organs injury.Therefore,this thesis contained two parts as follows:Part ?:The change of CD4+T lymphocytes in the early phase of SAP and the relationship between CD4+T lymphocytes and the inflammatory responseObjectives:To observe the dynamic change of CD4+T lymphocytes in the early phase of SAP and analyze the relationship between CD4+T lymphocytes and the pancreas injury,inflammatory response.Methods:AP was induced by giving four or eight intraperitoneal injections of caerulein(50 ?g/kg/h)at hourly intervals.The mice were sacrificed at 5h,9h,13h,18h,24h,and 48h after the first intraperitoneal injection respectively.Levels of serum TNF-a and IL-6,the percentage of CD3e+T lymphocytes and CD4+T lymphocytes in peripheral blood lymphocytes,the ratio of CD4+T lymphocytes/CD8a+T lymphocytes,the histological scores of pancreas,and the CD4+T lymphocytes infiltration in pancreas and colon mucosa were assessed.Results:Compared with the control group,at 5h after the first intraperitoneal injection,the serum levels of TNF-a and IL-6 were significantly higher(p<0.05),so were the percentage of CD3e+ T lymphocytes and CD3e+CD4+ T lymphocytes in peripheral blood lymphocytes and the ratio of CD4+/CD8a+(p<0.05),and the number of the CD4+ T lymphocytes infiltrated in pancreas and colon mucosa were obviously more(p<0.05),and all of them reached the maximun at the 13h or 18h.The pathological damage of pancreas aggravated gradually after the injection of cearulein,and reached the peak at the 18h.The histological scores of pancreas were well related with the indicators of the inflammatory immune response(p<0.001,r>0.5),especially with the infiltration of CD4+T lymphocytes in the peripheral tissue(blood,pancreas and colon mucosa)(p<0.001,r>0.7).Conclusions:As the inflammatory response began in the early phase of SAP,the infiltration of CD4+T lymphocytes in the peripheral tissue gradually increased,and the inflammatory immune response increasingly enhanced.The pancreas injury was well related with the status of the inflammatory immune response,especially with the infiltration of CD4+T lymphocytes in the peripheral tissue.Part ?:The effect of inhibiting CD4+T lymphocytes on the inflammatory response in the early phase of SAPObjectives:By inhibiting the egress of CD4+T lymphocytes in the early phase of SAP with an immunosuppressant,we observed its effect on the inflammatory response,the pancreas injury and the distant organs injury.Methods:SAP was induced by giving eight intraperitoneal injections of caerulein(50?g/kg/h)at hourly intervals.SEW2871 was administered by gavage,at a dose of 20mg/kg,at Oh and 12h after the first intraperitoneal injection of caerulein.The mice were sacrificed at 24h.CD45+CD4+T lymphocytes in blood,CD4+ T lymphocytes infiltration in pancreas,the pathological damage of pancreas and lung,serum amylase and lipase activity,levels of serum IL-6 and TNF-?,myeloperoxidase(MPO)activity in tissues(liver,lung and pancreas),and proinflammatory cytokine productions associated with CD4+T lymphocytes were assessed.Furthermore,the expression of signal transducer and activator of transcription(STAT)3 and phospho-STAT3(p-STAT3)in pancreas was also evaluated.Results:The early administration of SEW2871 inhibited the infiltration of CD4+T lymphocytes in the peripheral tissue(blood,pancreas and colon mucosa),and obviously ameliorated the pancreas and lung injury of SAP mice,reduced the serum pancreatic enzymes activity and levels of cytokines,suppressed the MPO activity in tissues(liver,lung and pancreas).Furthermore,the proinflammatory cytokines mRNA associated with CD4+T lymphocytes and p-STAT3 expression in pancreas were also suppressed by SEW2871 treatment.Conclusions:The early administration of SEW2871 inhibited the infiltration of CD4+T lymphocytes in the peripheral tissue,and provided the protective effect on the pancreas and distant organs.Through this study,we found that CD4+T lymphocytes played an important role in the inflammatory immune response in the early phase of SAP.The pancreas injury was well related with the infiltration of CD4+T lymphocytes in the peripheral tissue.In the early phase of SAP,inhibiting the infiltration of CD4+T lymphocytes in the peripheral tissue can obviously reduce the inflammatory response and alleviate the injury of pancreas and distant organs.