Effect Of Alteration Of Sympathetic Nerve Activity On Inflammatory Response And Organ Function In Severe Acute Pancreatitis

Severe acute pancreatitis(SAP)is characterized by an overwhelming inflammatory reaction in early period.Mortality in SAP occurs either early,due to the over activated inflammatory response or late,owing to infection.Controlling excessive inflarmation is an key point in treating SAP patients.Signs of sympathetic activation:tachycadia,fever,high peripheral vascular resistance and oliguria can often be observed in the acute phase of SAP patients.However,this phenomenon could either be induced by the inframmatory reaction,or activation of sympathetic nerve.Also,we do not know if there is a connection between sympathetic nerve activity and inflammation in SAP patients.Elevated sympathetic activation occurs during several distinct,pro-inflammatory disease states,including sepsis.Researches have demonstrated autonomic activity is closely related to systemic inflammatory response syndrome(SIRS)and organ failure in sepsis.Clinical trials and animal studies have proved that suppression of sympathetic nerve activity in sepsis could attenuate systemic inflammation,organ function and improve survival.However,whether there is a relationship between sympathetic nerve activity and inflammation in SAP is unknown.We design this experiment to see if sympathetic activity is increased in SAP.If the hypothesis is true,suppression of sympathetic nerve activity may have some beneficial effect on SAP.Aim of our study:1.evaluate autonomic function in SAP to see if there is a link between autonomic nerve activity and severity of SAP;2.study the influence of sympathetic suppression on inflammatory reaction and organ function in SAP rats and its possible mechanisms.Our research consisted of three parts.In the first part,we evaluated autonomic nerve activity in 41 SAP patients.In the second part,sympathetic nerve activity was detected in SAP rats.As to the third part,we studied the effect of sympathetic inhibition on inflammation and organ function in SAP rats and its possible mechanisms.Part ? Relation of sympathetic nerve activity to inflammation and prognosis in SAP patientsObjectives:To evaluate relation of HRV to inflammatory response and disease severity in SAP.Methods:41 SAP patients within 72 hours of symptoms onset admitted at surgical intensive care unit of Jinling hospital were included in this prospective,observational study.5-minute ECG signals were obtained at admission for HRVanalyses to assess SAP severity.General demographies and the acute physiology and chronie health evaluation(APACHE)? were recorded at admission.Blood sample were obtained within 24 hours after admission to detect TNF-?,IL-6 and PCT levels.Plasma TNF-?and IL-6 were detected by ELISA.PCT levels were measured by chemoluminescentimmunoassay.Data were presented as median and interquartile range(25th-75th percentiles).Descriptive data were described as absolute numbers or percentages.Mann-Whitney U-test was used to compare continuous variables.Relationship between cytokines and HRV was carried out by Pearson correlation.The area under the receiver operating characteristic curve(ROC)was calculated to compare the effectiveness of IPN and MODS prediction.The significance level was accepted at P<0.05.Results:The frequency index of HRV in 41 SAP patients was lower than normal value.The frequency domain index:nHF exhibited significant positive correlations with LF(r=0.849).LF/HF correlated negatively with TNF-?(r=-0.525).IL-6 correlated well with nHF(r=0.761)and LF/HF(r=-0.708).In SAP patients who developed IPN or MODS,lower LF and LF/HF levels were found as compared to patients in whom these complications were absent.Moreover,nHF levels were significantly higher in patients who developed IPN or MODS(P<0.01).nLF levels were lower in MODS patients than patients who didn't present with MODS.But LF levels did not show any difference in patients with or without IPN.Values of nLF and LF/HF of nonsurvivals were lower,whereas nHF was significantly higher than those of survivals.No difference was found in time domain indexes.Both nHF and LF/HF were superior to APACHE ? score(AUC=0.785)and PCT(AUC=0.709)for the prediction of IPN.In the prediction of MODS,area under ROC curves of nHF and LF/HF were 0.837 and 0.821.Usefulness of nHF and LF/HF for differentiating of MODS from non-MODS was comparable with APACHE ?score(AUC=0.899),and better than PCT(AUC=0.722)Conclusions:Sympathetic nerve activity was activated in SAP patients.The frequency domain indexes of HRV correlated well with inflammatory cytokines and prognosis in SAP patients.Part ? Relation of sympathetic nerve activity to inflammation in SAP ratsObjectives:To evaluate sympathetic nerve activity in SAP rats and the relationship between autonomic activity and serum cytokines in SAP rats.Methods:Twelve male SD rats were randomized into two groups,control group and SAP group.SAP were induced by injecting taurocholate solution(3.5%,lml/kg)into the common bile duct.All animals received standard therapy for SAP,including fluid resuscitation.HRV was recorded 0h,3h,6h and 9h after induce of SAP model.Blood was drawn 0h,3h,6h and 9h after the induce of SAP model to detect TNF-? and IL-6 levels(ELISA).Serum was then analyzed by ELISA for measurement of catecholamine(9h).All data were presented as Mean ± SD.Data were analyzed by Mann-Whitney U-test.The significance level was accepted at P<0.05.Results:Plasma levels of epinephrine,norepinephrine and dopamine were significantly higher in SAP group than control group.As compared to control group,SDNN in SAP group were reduced at 0h,3h,6h and 9h after induction of SAP model.Serum TNF-? levels at 0h,3h,6h and 9h after SAP induction were 37.9±19.4 pg/ml,74.1 ±25.2 pg/ml,57.1±15.9 pg/ml and 68.3±11.1pg/ml,respectively.Serum IL-6 levels at 0h,3h,6h and 9h after SAP induction were 115.8±63.1 pg/ml,499.7±104.1 pg/ml,450.0±89.3 pg/ml,397.9±12.5pg/ml,respectively.Conclusions:Sympathetic nerve activity was increased in SAP rats.SDNN was associated with serum cytokines in SAP rats.Part ? Effect of sympathetic inhibition on inflammatory response and organ function in SAP ratsResearch 3.1 Effect of ?1 blocker on inflammatory response and organ function in SAP ratsObjectives:To establish whether inhibition of sympathetic activation in SAP has beneficial effects on organ function and inflammatory markers.Methods:Eighteen male SD rats were randomly assigned to one of three groups,control group,SAP or SAP+?-blocker group.In SAP+?-blocker group,after modeling,rats received continuously intravenous pumping of esmolol(15mg/kg.h).Heart rate(HR)and mean arterial pressure(MAP)were monitored continuously.Animals were decapitated at 9h for blood collection.Femoral arterial blood was taken before decapitated for blood gas analysis.The lungs were isolated 9h after the induction of SAP for the detection of lung water volume,pulmanary permreability index and histological damage evaluation.Plasma amylase and lipase,pancreatic myeloperoxidase activity and pancreas histologic damage were also assessed.All data are presented as Mean ± SD.Data were analyzed by LSD test.The significance level was accepted at P<0.05.Results:Blood gas analysis was worse in SAP groups than control group.As compared with SAP group,the oxygenation was improved and lactate was reduced in SAP+?-blocker group.Pulmanary permreability index was increased in SAP+?-blocker group than SAP group.Amylase and lipase levels were increased significantly after the induction of SAP model.However,amylase level in SAP+?-group was lower than SAP group.Plasma cytokine levels and pancreas/lung MPO activity were significantly attenuated in SAP+?-group as compared to SAP group.Moreover,plasma CysC levels were also lower in SAP+?-blocker group.Conclusions:Continuously intravenous pumping of esmolol could effectively improve tissue oxygenation and perfusion,increase pulmanary permreability index.Moreover,esmolol could reduce pancreatitis severity,alleviate renal injury and attenuate systemic inflammation.Research 3.2The possible mechanism of ?1 blocker in inflammation in SAP ratsObjectives:IL-22 is an important cytokine allowing for cross talk between leukocytes and epithelial cells.IL-22RA1 has a more restricted expression in pancreatic epithelial cells.In this research,we aim to study the effects of esmolol on IL-22RA1 and STAT3 expression in pancreas and lung in SAP rats.Methods:The animal models and grouping were the same as research 3.1.The lung and pancreas were isolated 9h after the induction of SAP for detection of IL-22RA1 and STAT3 expression(immunohistochemistry).All data are presented as Mean±SD.Data were analyzed by LSD test.The significance level was accepted at P<0.05.Results:IL-22RA1 expression in the pancreas and lungs was upregulated in SAP rats.Also,the expression of STAT3 in pancreas and lungs increased significantly in SAP group as compared with control group.IL-22RA1 and STAT3 expression were decreased in SAP+?-blocker group as compared with SAP group.Conclusions:Esmolol could reduce IL-22RA1 and STAT3 expression in pancreas and lung in SAP rats.Conclusions1.Sympathetic nerve activity was activated in SAP patients and correlated well with inflammatory cytokines and disease severity.2.In SAP rats,sympathetic nerve activity was increased.Autonomic function correalated with cytokines in SAP rats.3.Continuously intravenous pumping of ?1 blocker could effectively improve tissue oxygenation and perfusion,increase pulmanary permreability index.Moreover,?1 blocker could reduce pancreatitis severity,alleviate renal injury and attenuate systemic inflammation.4.?1 blocker could reduce IL-22RA1 and STAT3 expression in pancreas and lung in SAP rats.