罗格列酮对急性坏死性胰腺炎及其肺损伤保护作用的实验研究
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摘要
第一部分罗格列酮对急性坏死性胰腺炎保护作用的实验研究
目的探讨罗格列酮对急性坏死性胰腺炎(ANP)的保护作用及其作用机制。
方法72只健康SD大鼠随机分为3组:假手术组(SO组)、ANP组及罗格列酮处理组。采用经十二指肠胰胆管逆行注射5%牛磺胆酸钠诱导大鼠ANP模型,于模型制作前30分钟腹腔内注射罗格列酮(10mg/kg)进行预处理。各组于术后3h、6h和12h分批处死动物,观测各组各时点大鼠血浆淀粉酶、胰腺组织髓过氧化物酶(MPO)的变化,采用酶联免疫吸附试验(ELISA)检测血浆TNF‐α、IL‐6水平,免疫组化法检测胰腺组织NF‐κB的表达,采用半定量逆转录聚合酶链反应(RT‐PCR)胰腺组织中PPARγmRNA、HSP‐70mRNA的表达,光镜下观察胰腺组织病理变化,根据Schmidt的评分标准对胰腺组织进行病理学评分。
结果(1)ANP组各时间点血浆淀粉酶、TNF‐α、IL‐6、胰腺组织MPO均较SO组明显升高(P<0.05),胰腺组织NF‐κB的表达较SO组显著增加(P<0.01),3h、6h、12h胰腺组织病理损伤呈进行性加重,各时间点胰腺组织病理评分均显著高于SO组(P<0.01)(2)罗格列酮处理组各时间点血浆淀粉酶、TNF‐α、IL‐6、胰腺组织MPO水平均较ANP组显著降低(P<0.05),各时间点胰腺组织NF‐κB表达均较ANP组显著降低(P<0.05),罗格列酮处理组各时点PPARγmRNA和HSP‐70mRNA表达水平均较ANP组增强,6h、12h胰腺组织病理评分均显著低于ANP组(P<0.05),各时间点胰腺组织病理损伤较ANP组明显减轻。
结论罗格列酮预可能是激活PPARγ后通过诱导胰腺HSP‐70mRNA的表达,抑制胰腺NF‐κB的活化,减少TNF‐α、IL‐6的产生从而改善ANP病情,提示早期应用罗格列酮进行干预对急性坏死性胰腺炎可能具有一定的保护作用。
第二部分罗格列酮对急性坏死性胰腺炎肺损伤保护作用的实验研究
目的探讨罗格列酮对急性坏死性胰腺炎肺损伤的保护作用及其作用机制。
方法72只健康SD大鼠随机分为3组:假手术组(SO组)、ANP组及罗格列酮处理组。采用经十二指肠胰胆管逆行注射5%牛磺胆酸钠诱导大鼠ANP模型,于模型制作前30分钟腹腔内注射罗格列酮(10mg/kg)进行预处理。各组于术后3h、6h和12h分批处死动物,观测各组各时点大鼠动脉血氧分压(PaO2)、肺组织髓过氧化物酶(MPO)及肺湿/干比值的变化,采用免疫组化法检测肺组织NF‐κB的表达,采用半定量逆转录聚合酶链反应(RT‐PCR)检测肺组织中TNF‐αmRNA及ICAM‐1 mRNA的表达,光镜下观察肺组织病理变化。
结果(1)ANP组各时间点动脉PaO2较SO组明显降低(P<0.05),肺组织MPO均较SO组明显升高(P<0.05),6h、12h肺湿/干比值较SO组明显升高(P<0.01),肺组织NF‐κB的表达较SO组显著增加(P<0.01),肺组织TNF‐αmRNA、ICAM‐1 mRNA表达水平较SO组显著增加(P<0.01),3h、6h、12h肺组织病理损伤呈进行性加重。(2)罗格列酮处理组6h、12h动脉PaO2较ANP组明显升高(P<0.05),各时间点肺组织MPO均较ANP组显著降低(P<0.05),6h、12h肺湿/干比值较ANP组明显降低(P<0.05),各时间点肺组织NF‐κB表达均较ANP组显著降低(P<0.05),各时间点肺组织TNF‐αmRNA、ICAM‐1 mRNA表达水平均较ANP组显著降低(P<0.05),各时间点肺组织病理损伤较ANP组明显减轻。
结论罗格列酮可能通过抑制肺组织NF‐κB的活性,减少肺组织TNF‐α、ICAM‐1的产生从而改善急性坏死性胰腺炎肺组织损伤,早期应用罗格列酮进行干预对急性坏死性胰腺炎肺损伤具有一定的保护作用。
第三部分重症急性胰腺炎并发ALI/ARDS危险因素的临床研究
目的研究重症急性胰腺炎(SAP)并发急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)的危险因素。
方法回顾性分析2007年7月至2010年7月收治的73例SAP患者,按SAP是否合并ALI/ARDS分为两组,合并ALI/ARDS组和未合并ALI/ARDS组,入院时立即检测血清淀粉酶、血白细胞、血糖、血清甘油三酯、血清钙离子、动脉血氧分压,24小时进行APACHEⅡ评分及CT评分,并观察患者住院期间是否合并感染,比较两组患者在性别、年龄、发病原因以及上述观察指标的差异,采用非条件Logistic回归分析ALI/ARDS发生的危险因素。
结果1.两组在年龄、血白细胞、血糖、动脉血氧分压、APACHE评分、CT评分以及合并感染方面差异有显著性﹙P<0.05﹚,两组在病因方面比较差异均无显著性﹙P>0.05﹚。2.年龄、血白细胞、血糖、APACHE评分、CT评分以及合并感染是SAP并发ALI/ARDS的独立危险因素﹙P<0.05﹚。
结论年龄、血白细胞、血糖、APACHE评分、CT评分以及合并感染是SAP并发ALI/ARDS的独立危险因素,早期监测上述相关因素有利于预测ALI/ARDS的发生。
Part one Experimental study of the protective effects of rosiglitazone on
acute necrotic pancreatitis
Objective To investigate the protective effects and mechanisms of Rosiglitazone on acute necrotic pancreatitis (ANP).
Methods seventy‐two SD rats were randomized into three groups: sham operation (SO)group, ANP group and rosiglitazone‐pretreated group. The model of ANP was induced by retrograde injection of 5% sodium taurocholate into the bili‐pancreatic duct in SD rats, rosiglitazone‐pretreated group were given 10mg/kg rosiglitazone intraperitoneally 30 min before inducing ANP. Rats in the three groups were killed at 3,6,12 hours after induction of the model. The levels of amylase in plasm, the myeloperoxidase(MPO) in the pancreas were measured. The levels of plasm TNF‐α,IL‐6 were detected by enzyme linked immunosorbent assay(ELISA).The expressions of NF‐κB in pancreatic tissue were assayed by immunohistochemistry,the expressions of PPARγmRNA and HSP‐70mRNA in pancreatic tissue was detected by reverse transcript PCR(RT‐PCR).The histopathological changes and the histologic scores of pancreatic tissue were evaluated.
Results (1)Compared with SO group, the levels of plasm amylase,TNF‐α,IL‐6, and the intrapancreatic MPO significantly increased in ANP group(P<0.05), the expression of NF‐κB in pancreatic tissue significantly increased in ANP group(P<0.01), the histologic scores of pancreatic tissue significantly increased in ANP group(P<0.01),the pancreas injury were aggravated gradually. (2)Compared with ANP group, the levels of plasm amylase,TNF‐α, IL‐6 ,intrapancreatic MPO, and the expression of NF‐κB in pancreatic tissue significantly decreased in rosiglitazone‐pretreated group(P<0.05), the expressions of PPARγmRNA and HSP‐70mRNA in pancreatic tissue significantly increased in rosiglitazone‐pretreated group ( P<0.05 ) , the pancreatic histopathologic scores significantly decreased in rosiglitazone‐pretreated group at 6h,12h(P<0.05), the severity of pancreas injury also significantly decreased in rosiglitazone‐pretreated group.
Conclusions rosiglitazone might have protective effects on ANP by activing PPARγ, inducing HSP‐70 and inhibiting NF‐κB in the pancreas, and decreasing the production of TNF‐α,IL‐6.
Part tow Experimental study of the protective effects of rosiglitazone on
acute necrotic pancreatitis‐associated lung injury
Objective To investigate the protective effects and mechanisms of rosiglitazone on acute necrotic pancreatitis‐associated lung injury
Methods seventy‐two SD rats were randomized into three groups: sham operation (SO)group, ANP group and rosiglitazone‐pretreated group. The model of ANP was induced by retrograde injection of 5% sodium taurocholate into the bili‐pancreatic duct in SD rats, rosiglitazone‐pretreated group were given 10mg/kg rosiglitazone intraperitoneally 30 min before inducing ANP. Rats in the three groups were killed at 3,6,12 hours after induction of the model. The levels of PaO2, the intrapulmonary MPO , and the wet /dry ratio of lung were measured. The expressions of NF‐κB in pulmonary tissue were assayed by immunohistochemistry, the expressions of TNF‐αmRNA and ICAM‐1 mRNA in pulmonary tissue was detected by reverse transcript PCR(RT‐PCR). The histopathological changes of pulmonary tissue were evaluated.
Results (1)Compared with SO group, the levels of PaO2 decreased in ANP group(P<0.05), the intrapulmonary MPO significantly increased in ANP group(P<0.05), the expression of NF‐κB , TNF‐αmRNA and ICAM‐1 mRNA in the lung significantly increased in ANP group(P<0.01), and the wet /dry ratio of lung also significantly increased in ANP group at 6h,12h(P<0.01), the lung injury were aggravated gradually. (2)Compared with ANP group, the levels of PaO2 increased in rosiglitazone‐pretreated group(P<0.05),the levels of intrapulmonary MPO, the expression of TNF‐αmRNA and ICAM‐1 mRNA in the lung significantly decreased in rosiglitazone‐pretreated group (P<0.05), the expression of NF‐κB in pulmonary tissue significantly decreased in rosiglitazone‐pretreated group(P<0.05), the wet /dry ratio of lung significantly decreased in rosiglitazone‐pretreated group at 6h,12h(P<0.05), the severity of lung injury also significantly decreased in rosiglitazone‐pretreated group.
Conclusions Rosiglitazone might have protective effects on lung injury associated with ANP by inhibiting NF‐κB and decreasing the production of TNF‐α,ICAM‐1.
Part three Clinical study of risk factors for severe acute pancreatitis
complicated with acute lung injury/acute respiratory distress syndrome
Objective To analysis of risk factors for severe acute pancreatitis(SAP) complicated with acute lung injury/acute respiratory distress syndrome.
Methods 73 case with severe acute pancreatitis were retrospective analysised from july 2007 to july 2010.they were divive into SAP complicated with acute lung injury/acute respiratory distress syndrome group(ALI/ARDS)and SAP without acute lung injury/acute respiratory distress syndrome group(ALI/ARDS). The level of serum amylase, white blood cell, blood glucose, triglyceride, calciumion,and arterial partial pressure of oxygen were measured in all pantients when they were admitted to hospital firstly. APACHEⅡscore and CT score were carried out in 24h after admission. The patients combined with infection or not were observed during admission. The difference in the all above indexes and the cause,age, gender were compared in two group.
Results Compared with SAP complicated with ALI/ARDS group and SAP without ALI/ARDS group, the difference were significant in age, serum white blood cell, glucose, arterial partial pressure of oxygen ,APACHEⅡscore, CT score and infection,but there was no difference in cause. Age, serum white blood cell, blood glucose, APACHEⅡscore, CT score and infection were independent risk factors of SAP complicated with ALI/ARDS.
Conclusions Age, serum white blood cell, blood glucose, APACHEⅡscore, CT score and infection were independent risk factors of SAP complicated with ALI/ARDS.
目的探讨罗格列酮对急性坏死性胰腺炎(ANP)的保护作用及其作用机制。
方法72只健康SD大鼠随机分为3组:假手术组(SO组)、ANP组及罗格列酮处理组。采用经十二指肠胰胆管逆行注射5%牛磺胆酸钠诱导大鼠ANP模型,于模型制作前30分钟腹腔内注射罗格列酮(10mg/kg)进行预处理。各组于术后3h、6h和12h分批处死动物,观测各组各时点大鼠血浆淀粉酶、胰腺组织髓过氧化物酶(MPO)的变化,采用酶联免疫吸附试验(ELISA)检测血浆TNF‐α、IL‐6水平,免疫组化法检测胰腺组织NF‐κB的表达,采用半定量逆转录聚合酶链反应(RT‐PCR)胰腺组织中PPARγmRNA、HSP‐70mRNA的表达,光镜下观察胰腺组织病理变化,根据Schmidt的评分标准对胰腺组织进行病理学评分。
结果(1)ANP组各时间点血浆淀粉酶、TNF‐α、IL‐6、胰腺组织MPO均较SO组明显升高(P<0.05),胰腺组织NF‐κB的表达较SO组显著增加(P<0.01),3h、6h、12h胰腺组织病理损伤呈进行性加重,各时间点胰腺组织病理评分均显著高于SO组(P<0.01)(2)罗格列酮处理组各时间点血浆淀粉酶、TNF‐α、IL‐6、胰腺组织MPO水平均较ANP组显著降低(P<0.05),各时间点胰腺组织NF‐κB表达均较ANP组显著降低(P<0.05),罗格列酮处理组各时点PPARγmRNA和HSP‐70mRNA表达水平均较ANP组增强,6h、12h胰腺组织病理评分均显著低于ANP组(P<0.05),各时间点胰腺组织病理损伤较ANP组明显减轻。
结论罗格列酮预可能是激活PPARγ后通过诱导胰腺HSP‐70mRNA的表达,抑制胰腺NF‐κB的活化,减少TNF‐α、IL‐6的产生从而改善ANP病情,提示早期应用罗格列酮进行干预对急性坏死性胰腺炎可能具有一定的保护作用。
第二部分罗格列酮对急性坏死性胰腺炎肺损伤保护作用的实验研究
目的探讨罗格列酮对急性坏死性胰腺炎肺损伤的保护作用及其作用机制。
方法72只健康SD大鼠随机分为3组:假手术组(SO组)、ANP组及罗格列酮处理组。采用经十二指肠胰胆管逆行注射5%牛磺胆酸钠诱导大鼠ANP模型,于模型制作前30分钟腹腔内注射罗格列酮(10mg/kg)进行预处理。各组于术后3h、6h和12h分批处死动物,观测各组各时点大鼠动脉血氧分压(PaO2)、肺组织髓过氧化物酶(MPO)及肺湿/干比值的变化,采用免疫组化法检测肺组织NF‐κB的表达,采用半定量逆转录聚合酶链反应(RT‐PCR)检测肺组织中TNF‐αmRNA及ICAM‐1 mRNA的表达,光镜下观察肺组织病理变化。
结果(1)ANP组各时间点动脉PaO2较SO组明显降低(P<0.05),肺组织MPO均较SO组明显升高(P<0.05),6h、12h肺湿/干比值较SO组明显升高(P<0.01),肺组织NF‐κB的表达较SO组显著增加(P<0.01),肺组织TNF‐αmRNA、ICAM‐1 mRNA表达水平较SO组显著增加(P<0.01),3h、6h、12h肺组织病理损伤呈进行性加重。(2)罗格列酮处理组6h、12h动脉PaO2较ANP组明显升高(P<0.05),各时间点肺组织MPO均较ANP组显著降低(P<0.05),6h、12h肺湿/干比值较ANP组明显降低(P<0.05),各时间点肺组织NF‐κB表达均较ANP组显著降低(P<0.05),各时间点肺组织TNF‐αmRNA、ICAM‐1 mRNA表达水平均较ANP组显著降低(P<0.05),各时间点肺组织病理损伤较ANP组明显减轻。
结论罗格列酮可能通过抑制肺组织NF‐κB的活性,减少肺组织TNF‐α、ICAM‐1的产生从而改善急性坏死性胰腺炎肺组织损伤,早期应用罗格列酮进行干预对急性坏死性胰腺炎肺损伤具有一定的保护作用。
第三部分重症急性胰腺炎并发ALI/ARDS危险因素的临床研究
目的研究重症急性胰腺炎(SAP)并发急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)的危险因素。
方法回顾性分析2007年7月至2010年7月收治的73例SAP患者,按SAP是否合并ALI/ARDS分为两组,合并ALI/ARDS组和未合并ALI/ARDS组,入院时立即检测血清淀粉酶、血白细胞、血糖、血清甘油三酯、血清钙离子、动脉血氧分压,24小时进行APACHEⅡ评分及CT评分,并观察患者住院期间是否合并感染,比较两组患者在性别、年龄、发病原因以及上述观察指标的差异,采用非条件Logistic回归分析ALI/ARDS发生的危险因素。
结果1.两组在年龄、血白细胞、血糖、动脉血氧分压、APACHE评分、CT评分以及合并感染方面差异有显著性﹙P<0.05﹚,两组在病因方面比较差异均无显著性﹙P>0.05﹚。2.年龄、血白细胞、血糖、APACHE评分、CT评分以及合并感染是SAP并发ALI/ARDS的独立危险因素﹙P<0.05﹚。
结论年龄、血白细胞、血糖、APACHE评分、CT评分以及合并感染是SAP并发ALI/ARDS的独立危险因素,早期监测上述相关因素有利于预测ALI/ARDS的发生。
Part one Experimental study of the protective effects of rosiglitazone on
acute necrotic pancreatitis
Objective To investigate the protective effects and mechanisms of Rosiglitazone on acute necrotic pancreatitis (ANP).
Methods seventy‐two SD rats were randomized into three groups: sham operation (SO)group, ANP group and rosiglitazone‐pretreated group. The model of ANP was induced by retrograde injection of 5% sodium taurocholate into the bili‐pancreatic duct in SD rats, rosiglitazone‐pretreated group were given 10mg/kg rosiglitazone intraperitoneally 30 min before inducing ANP. Rats in the three groups were killed at 3,6,12 hours after induction of the model. The levels of amylase in plasm, the myeloperoxidase(MPO) in the pancreas were measured. The levels of plasm TNF‐α,IL‐6 were detected by enzyme linked immunosorbent assay(ELISA).The expressions of NF‐κB in pancreatic tissue were assayed by immunohistochemistry,the expressions of PPARγmRNA and HSP‐70mRNA in pancreatic tissue was detected by reverse transcript PCR(RT‐PCR).The histopathological changes and the histologic scores of pancreatic tissue were evaluated.
Results (1)Compared with SO group, the levels of plasm amylase,TNF‐α,IL‐6, and the intrapancreatic MPO significantly increased in ANP group(P<0.05), the expression of NF‐κB in pancreatic tissue significantly increased in ANP group(P<0.01), the histologic scores of pancreatic tissue significantly increased in ANP group(P<0.01),the pancreas injury were aggravated gradually. (2)Compared with ANP group, the levels of plasm amylase,TNF‐α, IL‐6 ,intrapancreatic MPO, and the expression of NF‐κB in pancreatic tissue significantly decreased in rosiglitazone‐pretreated group(P<0.05), the expressions of PPARγmRNA and HSP‐70mRNA in pancreatic tissue significantly increased in rosiglitazone‐pretreated group ( P<0.05 ) , the pancreatic histopathologic scores significantly decreased in rosiglitazone‐pretreated group at 6h,12h(P<0.05), the severity of pancreas injury also significantly decreased in rosiglitazone‐pretreated group.
Conclusions rosiglitazone might have protective effects on ANP by activing PPARγ, inducing HSP‐70 and inhibiting NF‐κB in the pancreas, and decreasing the production of TNF‐α,IL‐6.
Part tow Experimental study of the protective effects of rosiglitazone on
acute necrotic pancreatitis‐associated lung injury
Objective To investigate the protective effects and mechanisms of rosiglitazone on acute necrotic pancreatitis‐associated lung injury
Methods seventy‐two SD rats were randomized into three groups: sham operation (SO)group, ANP group and rosiglitazone‐pretreated group. The model of ANP was induced by retrograde injection of 5% sodium taurocholate into the bili‐pancreatic duct in SD rats, rosiglitazone‐pretreated group were given 10mg/kg rosiglitazone intraperitoneally 30 min before inducing ANP. Rats in the three groups were killed at 3,6,12 hours after induction of the model. The levels of PaO2, the intrapulmonary MPO , and the wet /dry ratio of lung were measured. The expressions of NF‐κB in pulmonary tissue were assayed by immunohistochemistry, the expressions of TNF‐αmRNA and ICAM‐1 mRNA in pulmonary tissue was detected by reverse transcript PCR(RT‐PCR). The histopathological changes of pulmonary tissue were evaluated.
Results (1)Compared with SO group, the levels of PaO2 decreased in ANP group(P<0.05), the intrapulmonary MPO significantly increased in ANP group(P<0.05), the expression of NF‐κB , TNF‐αmRNA and ICAM‐1 mRNA in the lung significantly increased in ANP group(P<0.01), and the wet /dry ratio of lung also significantly increased in ANP group at 6h,12h(P<0.01), the lung injury were aggravated gradually. (2)Compared with ANP group, the levels of PaO2 increased in rosiglitazone‐pretreated group(P<0.05),the levels of intrapulmonary MPO, the expression of TNF‐αmRNA and ICAM‐1 mRNA in the lung significantly decreased in rosiglitazone‐pretreated group (P<0.05), the expression of NF‐κB in pulmonary tissue significantly decreased in rosiglitazone‐pretreated group(P<0.05), the wet /dry ratio of lung significantly decreased in rosiglitazone‐pretreated group at 6h,12h(P<0.05), the severity of lung injury also significantly decreased in rosiglitazone‐pretreated group.
Conclusions Rosiglitazone might have protective effects on lung injury associated with ANP by inhibiting NF‐κB and decreasing the production of TNF‐α,ICAM‐1.
Part three Clinical study of risk factors for severe acute pancreatitis
complicated with acute lung injury/acute respiratory distress syndrome
Objective To analysis of risk factors for severe acute pancreatitis(SAP) complicated with acute lung injury/acute respiratory distress syndrome.
Methods 73 case with severe acute pancreatitis were retrospective analysised from july 2007 to july 2010.they were divive into SAP complicated with acute lung injury/acute respiratory distress syndrome group(ALI/ARDS)and SAP without acute lung injury/acute respiratory distress syndrome group(ALI/ARDS). The level of serum amylase, white blood cell, blood glucose, triglyceride, calciumion,and arterial partial pressure of oxygen were measured in all pantients when they were admitted to hospital firstly. APACHEⅡscore and CT score were carried out in 24h after admission. The patients combined with infection or not were observed during admission. The difference in the all above indexes and the cause,age, gender were compared in two group.
Results Compared with SAP complicated with ALI/ARDS group and SAP without ALI/ARDS group, the difference were significant in age, serum white blood cell, glucose, arterial partial pressure of oxygen ,APACHEⅡscore, CT score and infection,but there was no difference in cause. Age, serum white blood cell, blood glucose, APACHEⅡscore, CT score and infection were independent risk factors of SAP complicated with ALI/ARDS.
Conclusions Age, serum white blood cell, blood glucose, APACHEⅡscore, CT score and infection were independent risk factors of SAP complicated with ALI/ARDS.
引文
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15.代晓明,万献尧。重症急性胰腺炎并发急性呼吸窘迫综合征危险因素的分析[J]。医学与哲学(临床决策论坛版),2009,30(1):34‐35。
16. Cuzzocrea S,Pisano B,Dugo L,et a1.Rosiglitazone,a ligand of the peroxisome proliferator‐activated receptor‐gamma, reduces acute pancreatitis induced by cemlein[J].Intensive Care Med,2004,30(5):951‐956.
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