内源性ghrelin与急性胰腺炎炎症反应及代谢异常的关系研究
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摘要
第一部分
内源性ghrelin在大鼠急性坏死性胰腺炎的动态变化以及GHRP-2干预的影响
目的探讨内源性ghrelin在大鼠急性坏死性胰腺炎(ANP)发病后的动态变化以及GHRP-2前干预对ANP的影响。
方法90只SD大鼠分为C组、A组、G组。C组为假手术组,仅开腹后翻动胰腺。A组逆行胰胆管注射2%牛磺胆酸钠诱导大鼠ANP模型,G组在诱导模型前30分钟腹腔注射GHRP-2(200μg/kg),C组、A组腹腔注射生理盐水对照。分别在第3、6、12、24、48小时处死大鼠,称量腹水重量、取胰腺组织进行组织病理学检查进行病理学评分；分装血清分别应用底物酶法检测淀粉酶(AMS),ELISA法检测血清ghrelin、IL-β浓度；应用荧光定量PCR检测胰腺组织ghrelin mRNA表达。
结果①A组、G组大鼠胰腺有明显坏死,光镜下见胰腺水肿、炎症细胞浸润、出血、坏死,病理评分均高于C组；A组与G组病理评分无差异；②A组、G组腹腔内有清亮腹水,腹水重量均高于C组,以第3小时统计学差异最明显(P＜0.01)；③A组、G组AMS高于C组(P＜0.05或P＜0.01),高峰出现在第6小时,A组与G组无差异；④A组、G组血清ghrelin含量均高于C组,G组第3小时的ghrelin高于A组(593.19±265.97pg/ml Vs310.82±148.64pg/ml, P<0.05),其余时间点无差异；⑤A组血清IL-1β在第3、6小时高于C组、G组(P＜0.05)；A组血清IL-1β随着时间延长而有所下降,高峰出现在第3小时；⑥血清ghrelin含量分别与血清IL-1β、胰腺炎症细胞浸润病理评分正相关；⑦A组各时点的胰腺组织ghrelin mRNA表达随着时间延长呈增高趋势,在第6、12、24小时高于C组。
结论①实验性ANP大鼠血清ghrelin水平增高,与血清IL-1β、胰腺炎症细胞浸润程度呈正相关；②实验性ANP大鼠的胰腺组织ghrelin mRNA表达水平在发病早期增高；③GHRP-2前干预的早期可以降低ANP大鼠的血清IL-1β、提高血清ghrelin水平,对胰腺病理损伤无影响。
第二部分
血清ghrelin、obestatin与急性胰腺炎患者代谢异常的相关性研究
目的观察血清ghrelin、obestatin在AP发病早期的动态变化并探讨两者与急性胰腺炎(AP)患者代谢异常的相关性。
方法以83例AP患者作为观察组,24例其他疾病者为对照组。收集患者的入院前、入院后第1天、第3天、第5天的临床资料与入院后血清样本,比较重症急性胰腺炎(SAP)与轻症急性胰腺炎(MAP)生化检查项目的差异和两组间代谢异常的发生率。EIA法检测观察组与对照组的血清ghrelin、obestatin浓度,对比发生高血糖、高脂血症、低蛋白血症、低钙血症的AP患者血清ghrelin、obestatin与未发生代谢异常患者的差异,分析两者与代谢异常的相关性。
结果①83例AP患者中有35例MAP,48例SAP,高血糖、高脂血症、低蛋白血症、低钙血症的总发生率分别为56.63%、48.19%、40.96%、27.71%；SAP组高脂血症、低蛋白血症、低钙血症的发生率分别为58.33%、54.17%、39.58%,显著高于MAP组的34.29%、22.86%、11.43%(P＜0.05或P＜0.01)；SAP组的血清白蛋白、血钙水平分别为33.95±6.62g/L、1.98±0.24mmol/L,均低于MAP组的37.93±4.63g/L、2.16±0.21mmol/L (P<0.01);②SAP患者入院后第1天的血清ghrelin水平低于对照组(58.81±79.36pg/ml vs79.31±26.03pg/ml, P<0.05), MAP组与对照组无差异；MAP组入院第1天的血清obestatin水平(16.96±40.28pg/ml)高于对照组(16.96±40.28pg/ml vs8.87±2.21pg/ml, P<0.01),SAP组与对照组无差异；③AP患者血清ghrelin、 obestatin水平随着时间延长逐渐增高,第5天MAP组ghrelin水平高于SAP组(P＜0.05),第1、3天MAP组obestatin水平高于SAP组(P＜0.01)；④低蛋白血症AP患者第5天ghrelin水平较低,与ALB水平正相关(r=0.317,P＜0.01)；高脂血症AP患者第1天obestatin水平较低,与甘油三酯水平呈负相关(r=-0.263,P＜0.05)；⑤血糖≥11.1mmol/L的患者入院第5天血清ghrelin水平和第1、3天obestatin水平均低于血糖<11.1mmol/L的患者。
结论①AP患者的代谢异常发生率由高到低依次为高血糖、高脂血症、低蛋白血症、低钙血症,SAP组更易发生代谢异常,且代谢异常的程度较重；②AP患者血清ghrelin、obestatin水平随时间逐渐上升；③AP患者血清ghrelin、obestatin与AP发病后的代谢异常密切相关：ghrelin与白蛋白浓度正相关,obestatin与甘油三酯负相关,显著高血糖的AP患者血清ghrelin、 obestatin水平下降。
CHARPTER ONE
THE DYNAMIC CHANGES OF ENDOGENOUS GHRHELIN AND THE EFFECT OF GHRP-2INTERVENTION IN ACUTE NECROTIZING PANCREATITIS RAT
Objective To investigate the dynamic changes of endogenous ghrelin and the effect of growth hormone releasing peptide-2(GHRP-2) pre-intervention in acute necrotizing pancreatitis (ANP) rats.
Methods Ninety male SD rats were randomly divided into three groups: group control (group C)、group ANP (group A) and group GHRP-2(group G). Rats in group C received sham operation and pancreas flipping. ANP model was induced by injecting2%sodium taurocholate retrogradely into biliopancreatic duct in group A and G, while rats in group G received GHRP-2(200μg/kg) intraperitoneal injection (i.p)30minutes before inducing ANP model. Rats in group C and group A received saline i.p instead. All the rats were sacrificed at3rd、6th、12th、24th、48th hour after ANP induction. Ascites were measured and pathological changes in pancreatic tissue were observed and scored. Serum AMS was detected by substrate enzymatic assay and serum ghrelin and IL-β were determined by ELISA. The expressions of ghrelin mRNA in pancreas were evaluated by quantitative PCR.
Results①With obvious necrosis in general and edema, infiltration of inflammatory cell, hemorrhage, necrosis under microscope in rats of group A and G, the pathologic scores of pancreas were significantly higher than those of group C, but there was no difference between group A and G.②The weight of ascites was less in group C than those in group A and G, which was clear and reached the peak at3rd and6th hour.③The serum AMS levels of group A and G were higher than those of group C (P<0.05or P<0.01). The peak time points of group A was6th hour, which had no difference with group G④The mean levels of ghrelin in group A and G were higher than those in group C. Except the ghrelin levels at the3rd hour of group G were higher than those of group A (593.19±265.97pg/ml vs310.82±148.64pg/ml, P<0.05), the other time points of group A and G had no significant difference.⑤The levels of serum IL-1β at3rd and6th hour in group C and G were lower than those in group A (P<0.05), which reaching the peak and decreasing with time.⑥The positive correlation was found between serum ghrelin and serum IL-1β, pathologic score of pancreatic inflammatory cell infiltration.⑦The expressions of ghrelin mRNA in pancreas of group A were increased gradually with time, and were higher than those of group C at6th、12th and24th hour.
Conclusions①The increasing levels of serum ghrelin in rats were positively related to serum IL-1β and pancreatic inflammatory cell infiltration.②The expressions of ghrelin mRNA in pancreas tissue were increased at early onset of ANP in rats.③The pre-interventions of GHRP-2decreased the level of serum IL-1β and increase the serum ghrelin in ANP rats, but had no effect to the pancreatic injury.
CHARPTER TWO
THE RELATIONSHIP BETWEEN SERUM GHRELIN, OBESTATIN AND ABNORMAL METABOLISM OF PATIENTS WITH ACUTE PANCREATITIS
Objective To observe the dynamic changes of serum ghrelin, obestatin concentration in patients with acute pancreatitis(AP) and investigate their relationship with abnormal metabolism of AP.
Methods The serum sample and data of clinical, biochemical tests of83patients with AP were studied on the1st,3rd,5th day after admission, contrasted with24patients without infection as control group. Serum concentration of ghrelin, obestatin was detected by the enzyme-linked immune assay (EIA). The levels of ghrelin, obestatin, biochemical tests and the incidence of hyperglycemia, hyperlipidemia, hypoproteinemia, hypocalcaemia were compared between group mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP), respectively. The correlation between ghrelin, obestatin with abnormal metabolism of AP was investigated.
Results①A total35cases of MAP and48cases of SAP was recruited. The total incidence of hyperglycemia, hyperlipidemia, hypoproteinemia and hypocalcaemia was56.63%,48.19%,40.96%and27.71%, respectively. Except hyperglycemia, the others were more common in SAP. The incidence of hyperlipidemia, hypoproteinemia and hypocalcaemia of patients with SAP was58.33%,54.17%and39.58%, higher than them of patients with MAP(34.29%,22.86%,11.43%, P<0.05or P<0.01).The serum albumin and calcium level in group SAP was33.95±6.62g/L and1.98±0.24mmol/L, that was lower than group MAP(37.93±4.63g/L and2.16±0.21mmol/L, P<0.01).②The level of serum ghrelin in group SAP was lower than group control (58.81±79.36pg/ml vs79.31±26.03pg/ml, P<0.05) on the1st day after admission, whereas the level of serum obestatin in group MAP (16.96±40.28pg/ml) was higher than both group control (8.87±2.21pg/ml, P<0.01) and SAP (9.81±27.25pg/ml, P<0.05).③he serum ghrelin, obestatin levels gradually increased with time after admission. The level of serum ghrelin in group MAP was higher than group SAP (P<0.05) on the5th day, whereas the level of serum obestatin in group MAP was higher than group SAP both on the1st and3rd day after admission (P<0.01).④Serum ghrelin on the5th day was higher in patients with hypoproteinemia and it was positively correlated to serum albumin(r=0.317, P<0.01), however the serum obestatin on the1st day was lower in patients with hyperlipidemia and negatively correlated to serum triglyceride(r=-0.263, P<0.05).⑤The serum ghrelin on the5th day and serum obestatin on the1st,3rd day in patients with significant hyperglycemia (FBG≥11.1mmol/L) was lower than the others with FBG<11.1mmol/L.
Conclusions①The incidence of abnormal metabolism in patients with AP were successively hyperglycemia, hyperlipidemia, hypoproteinemia and hypocalcaemia and it was more common and serious in SAP.②Serum ghrelin, obestatin in AP patients gradually increased with time.③Endogenous ghrelin and obestatin is correlated to abnormal metabolism of acute pancreatitis:serum ghrelin was positively correlated to serum albumin, while serum obestatin was negatively correlated to serum triglyceride conversely. Serum ghrelin and obestatin was lower in patients with significant hyperglycemia.
内源性ghrelin在大鼠急性坏死性胰腺炎的动态变化以及GHRP-2干预的影响
目的探讨内源性ghrelin在大鼠急性坏死性胰腺炎(ANP)发病后的动态变化以及GHRP-2前干预对ANP的影响。
方法90只SD大鼠分为C组、A组、G组。C组为假手术组,仅开腹后翻动胰腺。A组逆行胰胆管注射2%牛磺胆酸钠诱导大鼠ANP模型,G组在诱导模型前30分钟腹腔注射GHRP-2(200μg/kg),C组、A组腹腔注射生理盐水对照。分别在第3、6、12、24、48小时处死大鼠,称量腹水重量、取胰腺组织进行组织病理学检查进行病理学评分；分装血清分别应用底物酶法检测淀粉酶(AMS),ELISA法检测血清ghrelin、IL-β浓度；应用荧光定量PCR检测胰腺组织ghrelin mRNA表达。
结果①A组、G组大鼠胰腺有明显坏死,光镜下见胰腺水肿、炎症细胞浸润、出血、坏死,病理评分均高于C组；A组与G组病理评分无差异；②A组、G组腹腔内有清亮腹水,腹水重量均高于C组,以第3小时统计学差异最明显(P＜0.01)；③A组、G组AMS高于C组(P＜0.05或P＜0.01),高峰出现在第6小时,A组与G组无差异；④A组、G组血清ghrelin含量均高于C组,G组第3小时的ghrelin高于A组(593.19±265.97pg/ml Vs310.82±148.64pg/ml, P<0.05),其余时间点无差异；⑤A组血清IL-1β在第3、6小时高于C组、G组(P＜0.05)；A组血清IL-1β随着时间延长而有所下降,高峰出现在第3小时；⑥血清ghrelin含量分别与血清IL-1β、胰腺炎症细胞浸润病理评分正相关；⑦A组各时点的胰腺组织ghrelin mRNA表达随着时间延长呈增高趋势,在第6、12、24小时高于C组。
结论①实验性ANP大鼠血清ghrelin水平增高,与血清IL-1β、胰腺炎症细胞浸润程度呈正相关；②实验性ANP大鼠的胰腺组织ghrelin mRNA表达水平在发病早期增高；③GHRP-2前干预的早期可以降低ANP大鼠的血清IL-1β、提高血清ghrelin水平,对胰腺病理损伤无影响。
第二部分
血清ghrelin、obestatin与急性胰腺炎患者代谢异常的相关性研究
目的观察血清ghrelin、obestatin在AP发病早期的动态变化并探讨两者与急性胰腺炎(AP)患者代谢异常的相关性。
方法以83例AP患者作为观察组,24例其他疾病者为对照组。收集患者的入院前、入院后第1天、第3天、第5天的临床资料与入院后血清样本,比较重症急性胰腺炎(SAP)与轻症急性胰腺炎(MAP)生化检查项目的差异和两组间代谢异常的发生率。EIA法检测观察组与对照组的血清ghrelin、obestatin浓度,对比发生高血糖、高脂血症、低蛋白血症、低钙血症的AP患者血清ghrelin、obestatin与未发生代谢异常患者的差异,分析两者与代谢异常的相关性。
结果①83例AP患者中有35例MAP,48例SAP,高血糖、高脂血症、低蛋白血症、低钙血症的总发生率分别为56.63%、48.19%、40.96%、27.71%；SAP组高脂血症、低蛋白血症、低钙血症的发生率分别为58.33%、54.17%、39.58%,显著高于MAP组的34.29%、22.86%、11.43%(P＜0.05或P＜0.01)；SAP组的血清白蛋白、血钙水平分别为33.95±6.62g/L、1.98±0.24mmol/L,均低于MAP组的37.93±4.63g/L、2.16±0.21mmol/L (P<0.01);②SAP患者入院后第1天的血清ghrelin水平低于对照组(58.81±79.36pg/ml vs79.31±26.03pg/ml, P<0.05), MAP组与对照组无差异；MAP组入院第1天的血清obestatin水平(16.96±40.28pg/ml)高于对照组(16.96±40.28pg/ml vs8.87±2.21pg/ml, P<0.01),SAP组与对照组无差异；③AP患者血清ghrelin、 obestatin水平随着时间延长逐渐增高,第5天MAP组ghrelin水平高于SAP组(P＜0.05),第1、3天MAP组obestatin水平高于SAP组(P＜0.01)；④低蛋白血症AP患者第5天ghrelin水平较低,与ALB水平正相关(r=0.317,P＜0.01)；高脂血症AP患者第1天obestatin水平较低,与甘油三酯水平呈负相关(r=-0.263,P＜0.05)；⑤血糖≥11.1mmol/L的患者入院第5天血清ghrelin水平和第1、3天obestatin水平均低于血糖<11.1mmol/L的患者。
结论①AP患者的代谢异常发生率由高到低依次为高血糖、高脂血症、低蛋白血症、低钙血症,SAP组更易发生代谢异常,且代谢异常的程度较重；②AP患者血清ghrelin、obestatin水平随时间逐渐上升；③AP患者血清ghrelin、obestatin与AP发病后的代谢异常密切相关：ghrelin与白蛋白浓度正相关,obestatin与甘油三酯负相关,显著高血糖的AP患者血清ghrelin、 obestatin水平下降。
CHARPTER ONE
THE DYNAMIC CHANGES OF ENDOGENOUS GHRHELIN AND THE EFFECT OF GHRP-2INTERVENTION IN ACUTE NECROTIZING PANCREATITIS RAT
Objective To investigate the dynamic changes of endogenous ghrelin and the effect of growth hormone releasing peptide-2(GHRP-2) pre-intervention in acute necrotizing pancreatitis (ANP) rats.
Methods Ninety male SD rats were randomly divided into three groups: group control (group C)、group ANP (group A) and group GHRP-2(group G). Rats in group C received sham operation and pancreas flipping. ANP model was induced by injecting2%sodium taurocholate retrogradely into biliopancreatic duct in group A and G, while rats in group G received GHRP-2(200μg/kg) intraperitoneal injection (i.p)30minutes before inducing ANP model. Rats in group C and group A received saline i.p instead. All the rats were sacrificed at3rd、6th、12th、24th、48th hour after ANP induction. Ascites were measured and pathological changes in pancreatic tissue were observed and scored. Serum AMS was detected by substrate enzymatic assay and serum ghrelin and IL-β were determined by ELISA. The expressions of ghrelin mRNA in pancreas were evaluated by quantitative PCR.
Results①With obvious necrosis in general and edema, infiltration of inflammatory cell, hemorrhage, necrosis under microscope in rats of group A and G, the pathologic scores of pancreas were significantly higher than those of group C, but there was no difference between group A and G.②The weight of ascites was less in group C than those in group A and G, which was clear and reached the peak at3rd and6th hour.③The serum AMS levels of group A and G were higher than those of group C (P<0.05or P<0.01). The peak time points of group A was6th hour, which had no difference with group G④The mean levels of ghrelin in group A and G were higher than those in group C. Except the ghrelin levels at the3rd hour of group G were higher than those of group A (593.19±265.97pg/ml vs310.82±148.64pg/ml, P<0.05), the other time points of group A and G had no significant difference.⑤The levels of serum IL-1β at3rd and6th hour in group C and G were lower than those in group A (P<0.05), which reaching the peak and decreasing with time.⑥The positive correlation was found between serum ghrelin and serum IL-1β, pathologic score of pancreatic inflammatory cell infiltration.⑦The expressions of ghrelin mRNA in pancreas of group A were increased gradually with time, and were higher than those of group C at6th、12th and24th hour.
Conclusions①The increasing levels of serum ghrelin in rats were positively related to serum IL-1β and pancreatic inflammatory cell infiltration.②The expressions of ghrelin mRNA in pancreas tissue were increased at early onset of ANP in rats.③The pre-interventions of GHRP-2decreased the level of serum IL-1β and increase the serum ghrelin in ANP rats, but had no effect to the pancreatic injury.
CHARPTER TWO
THE RELATIONSHIP BETWEEN SERUM GHRELIN, OBESTATIN AND ABNORMAL METABOLISM OF PATIENTS WITH ACUTE PANCREATITIS
Objective To observe the dynamic changes of serum ghrelin, obestatin concentration in patients with acute pancreatitis(AP) and investigate their relationship with abnormal metabolism of AP.
Methods The serum sample and data of clinical, biochemical tests of83patients with AP were studied on the1st,3rd,5th day after admission, contrasted with24patients without infection as control group. Serum concentration of ghrelin, obestatin was detected by the enzyme-linked immune assay (EIA). The levels of ghrelin, obestatin, biochemical tests and the incidence of hyperglycemia, hyperlipidemia, hypoproteinemia, hypocalcaemia were compared between group mild acute pancreatitis (MAP) and severe acute pancreatitis (SAP), respectively. The correlation between ghrelin, obestatin with abnormal metabolism of AP was investigated.
Results①A total35cases of MAP and48cases of SAP was recruited. The total incidence of hyperglycemia, hyperlipidemia, hypoproteinemia and hypocalcaemia was56.63%,48.19%,40.96%and27.71%, respectively. Except hyperglycemia, the others were more common in SAP. The incidence of hyperlipidemia, hypoproteinemia and hypocalcaemia of patients with SAP was58.33%,54.17%and39.58%, higher than them of patients with MAP(34.29%,22.86%,11.43%, P<0.05or P<0.01).The serum albumin and calcium level in group SAP was33.95±6.62g/L and1.98±0.24mmol/L, that was lower than group MAP(37.93±4.63g/L and2.16±0.21mmol/L, P<0.01).②The level of serum ghrelin in group SAP was lower than group control (58.81±79.36pg/ml vs79.31±26.03pg/ml, P<0.05) on the1st day after admission, whereas the level of serum obestatin in group MAP (16.96±40.28pg/ml) was higher than both group control (8.87±2.21pg/ml, P<0.01) and SAP (9.81±27.25pg/ml, P<0.05).③he serum ghrelin, obestatin levels gradually increased with time after admission. The level of serum ghrelin in group MAP was higher than group SAP (P<0.05) on the5th day, whereas the level of serum obestatin in group MAP was higher than group SAP both on the1st and3rd day after admission (P<0.01).④Serum ghrelin on the5th day was higher in patients with hypoproteinemia and it was positively correlated to serum albumin(r=0.317, P<0.01), however the serum obestatin on the1st day was lower in patients with hyperlipidemia and negatively correlated to serum triglyceride(r=-0.263, P<0.05).⑤The serum ghrelin on the5th day and serum obestatin on the1st,3rd day in patients with significant hyperglycemia (FBG≥11.1mmol/L) was lower than the others with FBG<11.1mmol/L.
Conclusions①The incidence of abnormal metabolism in patients with AP were successively hyperglycemia, hyperlipidemia, hypoproteinemia and hypocalcaemia and it was more common and serious in SAP.②Serum ghrelin, obestatin in AP patients gradually increased with time.③Endogenous ghrelin and obestatin is correlated to abnormal metabolism of acute pancreatitis:serum ghrelin was positively correlated to serum albumin, while serum obestatin was negatively correlated to serum triglyceride conversely. Serum ghrelin and obestatin was lower in patients with significant hyperglycemia.
引文
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