罗格列酮对大鼠急性胰腺炎肺损伤的作用及其机制探讨
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摘要
第一部分静脉注射罗格列酮干预大鼠急性胰腺炎量效关系的探讨
目的：探讨罗格列酮(rosiglitazone, ROSI)静脉注射给药,干预大鼠急性胰腺炎(acute pancreatitis, AP)模型的量效关系,为ROSI干预急性胰腺炎肺损伤(acute pancreatitis associated-lung injury, APALI)选择合适的用药剂量提供依据。
方法：雄性Wistar大鼠42只,体重200～250g,随机分为7组(N=6)：正常对照组(control group, CON组)、急性胰腺炎模型组(acute pancreatitis model group,AP组)、罗格列酮0.3mg/kg、3mg/kg、6mg/kg、10mg/kg预处理组(rosiglitazone pretreatment group, ROSI组)和药物对照组(drug control group, Drug-CON组)。实验前大鼠禁食12 h,自由饮水。10%水合氯醛腹腔注射(0.3ml/100g)麻醉,无菌操作下大鼠行上腹正中切口进腹,逆行穿刺胆胰管注射5%牛磺胆酸钠溶液(sodium taurocholate, STC) (0.1ml/100g)制备急性胰腺炎模型；CON组和Drug-CON组操作如上所述,但胆胰管内注射等容量生理盐水。CON组、AP组造模前30min经股静脉注射10%二甲基亚砜(dimethyl sulphoxide, DMSO)溶液(0.2ml/100g)；不同剂量梯度罗格列酮预处理组则注射等量、10%DMSO溶解的ROSI。大鼠术后12 h心脏取血分离血清,全自动生化仪检测各组血清淀粉酶(amylase, AMY)、丙氨酸氨基转移酶(alanine aminotransferase, ALT)水平。HE染色观察各组胰腺组织病理学改变并评分。药物对照组操作同正常对照组,根据干预效果选择最佳剂量的ROSI,术前30min经股静脉注射最佳剂量ROSI取代10% DMSO,术后12h检测其血清AMY、ALT水平变化,观察胰腺组织病理学改变并评分。
结果：0.3mg/kg、3 mg/kg ROSI预处理组血清AMY和血清ALT与AP组比较差异无统计学意义(P>0.05),胰腺组织病理学评分有所改善,差异有统计学意义(P<0.05)；6mg/kg ROSI预处理组血清AMY、血清ALT和胰腺组织病理学评分较AP组降低,差异有统计学意义(P<0.05),10 mg/kg ROSI预处理组血清AMY、胰腺组织病理学评分较AP组降低,差异有统计学意义(P<0.05),但血清ALT与AP组比较差异无统计学意义(P>0.05)。6 mg/kg和10 mg/kg ROSI预处理组间对比,上述指标差异无统计学意义(P>0.05)。药物对照组(6 mg/kg)血清AMY、血清ALT和胰腺组织病理学评分与CON组比较差异无统计学意义(P>0.05)。
结论：罗格列酮干预牛磺胆酸钠诱导的大鼠AP模型时,6 mg/kg静脉注射是安全、有效的剂量。
第二部分罗格列酮对大鼠急性胰腺炎肺损伤的作用
目的：探讨罗格列酮(rosiglitazone, ROSI)静脉给药对大鼠急性胰腺炎肺损伤(acute pancreatitis associated-lung injury, APALI)的作用。
方法：雄性Wistar大鼠54只,体重200～250g,随机分为3组(N=18)：正常对照组(control group, CON组)、急性胰腺炎模型组(acute pancreatitis model group, AP组)和罗格列酮预处理组(rosiglitazone pretreatment group, ROSI组)。实验前大鼠禁食12 h,自由饮水。10%水合氯醛腹腔注射(0.3ml/100g)麻醉,大鼠无菌操作下行上腹正中切口进腹,逆行穿刺胆胰管注射5%牛磺胆酸钠溶液(sodium taurocholate, STC) (0.1ml/100g)制备急性胰腺炎模型；CON组操作如上所述,但胆胰管内注射等容量生理盐水。CON组、AP组造模前30min经股静脉注射10%二甲基亚砜(dimethyl sulphoxide, DMSO)溶液(0.2ml/100g)；ROSI组造模前30min经股静脉注射10%DMSO溶解的ROSI (6 mg/kg)。术后3h、6h、12h分批剖杀大鼠,每个时间点6只。HE染色观察各组胰腺组织和肺脏病理学改变并评分。心脏取血分离血清,全自动生化仪检测各组血清淀粉酶(amylase, AMY)水平。比色法检测肺组织髓过氧化物酶(myeloperoxidase, MPO)活性(间接表示中性粒细胞浸润程度)。左主支气管穿刺插管行支气管肺泡灌洗,收集支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)并检测其蛋白含量(反应肺毛细血管渗透性)。取右肺中叶拭去肺组织表面血迹及水分后称湿重,置于70℃烘箱24h后称干重,计算肺湿干比(W/D)(反应肺脏水肿程度)。
结果：随着时间的延长,AP组血清AMY水平、肺脏MPO活性、肺脏W/D比值、BALF蛋白含量、胰腺和肺组织评分逐渐升高,至12 h达最高值,分别为(5353.0±728.2)U/L、(1.12±0.14)U/g、(3.00±0.14)、(0.438±0.056)g/L、(11.17±0.93)和(8.17±0.75)；上述指标在各时点均高于CON组,差异有统计学意义(P<0.05)。ROSI组上述指标均较AP组有所下降,以6h、12h差异有统计学意义(P<0.05)。
结论：罗格列酮通过减低肺组织MPO活性,降低肺脏水肿程度和肺毛细血管渗透性,对急性胰腺炎肺损伤具有保护作用。
第三部分罗格列酮对大鼠急性胰腺炎肺损伤保护作用的机制探讨
目的：探讨罗格列酮(rosiglitazone, ROSI)静脉给药对大鼠急性胰腺炎肺损伤(acute pancreatitis associated-lung injury, APALI)保护作用的机制。
方法：雄性Wistar大鼠54只,体重200～250g,随机分为3组(N=18)：正常对照组(control group, CON组)、急性胰腺炎模型组(acute pancreatitis model group, AP组)和罗格列酮预处理组(rosiglitazone pretreatment group, ROSI组)。实验前大鼠禁食12 h,自由饮水。10%水合氯醛腹腔注射(0.3ml/100g)麻醉,大鼠无菌操作下行上腹正中切口进腹,逆行穿刺胆胰管注射5%牛磺胆酸钠溶液(sodium taurocholate, STC) (0.1ml/100g)制备急性胰腺炎模型；CON组操作如上所述,但胆胰管内注射等容量生理盐水。CON组、AP组造模前30min经股静脉注射10%二甲基亚砜(dimethyl sulphoxide, DMSO)溶液(0.2ml/100g)；ROSI组造模前30min经股静脉注射10%DMSO溶解的ROSI (6mg/kg)。术后3h、6h、12h分批剖杀大鼠。免疫组化法检测肺组织核因子-κB (nuclear factor-kappa B, NF-κB) p65的表达水平。逆转录聚合酶链反应(reverse transcription-reverse transcription, RT-PCR)检测肺组织肿瘤坏死因子-α(tumor necrosis factor-a, TNF-α)、细胞问粘附分子-1(intercellular adhesion molecule, ICAM-1)、P-选择素(P-selectin) mRNA表达水平。Western blot法检测肺组织ICAM-1、P-selectin蛋白的表达水平。
结果：随着时间的延长,AP组肺脏NF-κB评分、TNF-a mRNA表达、ICAM-1 mRNA表达和P-selectin mRNA表达逐渐升高,均在12h达高峰,分别为(1.04±0.13)、(0.57±0.03)、(1.53±0.08)、(0.51±0.09)；上述指标在各时点均高于CON组,差异有统计学意义(P<0.05)。ROSI组肺脏NF-κB评分和TNF-αmRNA较AP组下降,以6h、12h差异有统计学意义(P<0.05)。ROSI组肺脏ICAM-1、P-selectin mRNA和蛋白表达在12h点较AP组下降,差异有统计学意义(P<0.05)。
结论：罗格列酮通过抑制肺组织NF-κB和TNF-α,减少ICAM-1、P-selectin的表达,对大鼠急性胰腺炎肺损伤具有保护作用。
Part 1. Dose-response relationship of rosiglitazone administered via vein on acute pancreatitis in rats
Objective:The aim of this study is to investigate dose-response relationship of rosiglitazone administered via vein on acute pancreatitis in order to obtain the optimal dose of rosiglitazone for preventing sodium taurocholate-induced acute pancreatitis associated-lung injury.
Methods:Forty-two male Wistar rats, weighing 200-250g, were randomly divided into seven groups (N=6):control group (CON group), acute pancreatitis model group(AP group), different dosage(0.3mg/kg,3mg/kg,6mg/kg and 10mg/kg) rosiglitazone pretreatment group (ROSI group) and drug control group (Drug-CON group) (dosage according to the effect of rosiglitazone). Prior to the experiment, rats were deprived of food for 12 hours, while drinking water was available ad libitum. Anaesthesia was conducted by intraperitoneal injection of 10% chloraldurat (0.3ml/ 100g) and rats underwent sterile laparotomy. The bile-pancreatic duct was cannulated through the duodenum and acute pancreatitis model was induced by a standardized pressure-controlled retrograde infusion 5% sodium taurocholate(0.1ml/100g) into the bile-pancreatic duct. The CON group was identical to the AP group except that the saline was injected instead of sodium taurocholate. The CON group and the AP group were received 10% dimethyl sulphoxide (DMSO) (0.2ml/100g) administered via femoral vein 30min prior to the operation. In the ROSI group, different concentration rosiglitazone were injected partes aequales respectivly instead of 10% DMSO. The drug control group was identical to the CON group except that partes aequales rosiglitazone was injected instead of 10% DMSO. Rats were killed at 12 hours after operation. Blood were obtained from the left ventricle of heart. The samples were centrifuged and the serum amylase level, alanine aminotransferase level were detected by automatic biochemistry analyzer. Continuous sections of the paraffin embedded tissue were taken for pathological examination with hematoxylin-eosin (HE) staining. Morphometric documentation for pancreatic and pulmonary sections under light microscope were evaluated.
Results:Compared with the AP group,0.3mg/kg,3mg/kg dosage failed to improve the levels of amylase and alanine aminotransferase (P> 0.05), but attenuated severity of pancreatic injury (P<0.05).6mg/kg dosage had the best effect on improving the levels of amylase, alanine aminotransferase and pathologic score (P<0.05). The dosage of 10mg/kg also improve level of amylase and pathologic score (P<0.05), but failed to improve the level of alanine aminotransferase (P>0.05). There was no statistically significant between 6mg/kg dosage and 10mg/kg dosage of all the indexes. Compared with the CON group, rats of preteatment with rosiglitazone (6mg/kg) in the absence of sodium taurocholate revealed virtually the same serum amylaselevel, alanine aminotransferase level and pathologic score (P>0.05).
Conclusion:Rosiglitazone (6mg/kg) administered intravenously was the safe, effective dosage for attenuating the severity of acute pancreatitis induced by retrograde infusion sodium taurocholate.
Part 2. Effect of rosiglitazone on acute pancreatitis associated lung injury in rats
Objective:The aim of this study is to investigate the effect of rosiglitazone on acute pancreatitis associated lung injury in rats.
Methods:Fifty-four male Wistar rats, weighing 200-250g, were randomly divided into three groups (N=18):control group (CON group), acute pancreatitis model group (AP group) and rosiglitazone pretreatment group (ROSI group). Prior to the experiment, rats were deprived of food for 12 hours, while drinking water was available ad libitum. Anaesthesia was conducted by intraperitoneal injection of 10% chloraldurat(0.3ml/100g) and rats underwent sterile laparotomy. The bile-pancreatic duct was cannulated through the duodenum and acute pancreatitis model was induced by a standardized pressure-controlled retrograde infusion 5% sodium taurocholate (0.1ml/100g) into the bile-pancreatic duct. The CON group was identical to the AP group except that the saline was injected instead of sodium taurocholate. The CON group and the AP group were received 10% dimethyl sulphoxide (DMSO) (0.2ml/ 100g) administered via femoral vein 30min prior to the operation. In the ROSI group, rosiglitazone (6mg/kg) dissolved in 10% DMSO was injected by femoral vein 30 minutes piror to the operation. Rats were killed at 3,6 and 12 hours after operation. Blood were obtained from the left ventricle of heart. The samples were centrifuged and the serum amylase level was detected by automatic biochemistry analyzer. Continuous sections of the paraffin embedded tissue were taken for pathological examination with hematoxylin-eosin (HE) staining. Morphometric documentation for pancreatic and pulmonary sections under light microscope were evaluated. Lung myeloperoxidase (MPO) activity was detceted by chromatometry(reflect neutrophil infiltration). The left main bronchus was instilled with 3 mL saline at appropriate pressure, and bronchoalveolar lavage fluid (BALF) was collected for detecting protein content (reflect pulmonary microvascular permeability). The lung wet/dry ratio (W/D) was determined by calculating from the initial weight of the right lung middle lobe (wet weight) to its weight after desiccation at 70℃for 24 hours (dry weight) (reflect pulmonary edema extent).
Results In the AP group, serum amylase level, lung MPO activity, W/D ratio, protein content of BALF, pancreatic and pulmonary pathologic score reached the peak level at 12 hours after operation(5353.0±728.2 U/L,1.12±0.14 U/g,3.00±0.14, 0.438±0.056,11.17±0.93 and 8.17±0.75 respectively). All the indexes were increased significantly at each time point in the AP group than in the CON group (P< 0.05). Compared with the AP group, pretreatment with rosiglitazone reduced serum amylase level, lung MPO activity, W/D weight ratio, protein content of BALF, pancreatic and pulmonary pathologic score at 6h and 12h(P<0.05).
Conclusions:Rosiglitazone exerts the protective effect against acute pancreatitis associated lung injury by inhibition of lung MPO activity, reducing pulmonary edema and pulmonary microvascular permeability.
Part 3. Effect mechanism of rosiglitazone on acute pancreatitis associated lung injury in rats
Objective:The aim of this study is to investigate the effect of rosiglitazone on adhesion molecules expression in acute pancreatitis associated lung injury in rats.
Methods:Fifty-four male Wistar rats, weighing 200-250g, were randomly divided into three groups (N=18):control group (CON group), acute pancreatitis model group(AP group)and rosiglitazone pretreatment group(ROSI group). Prior to the experiment, rats were deprived of food for 12 hours, while drinking water was available ad libitum. Anaesthesia was conducted by intraperitoneal injection of 10% chloraldurat(0.3ml/100g) and rats underwent sterile laparotomy. The bile-pancreatic duct was cannulated through the duodenum and acute pancreatitis model was induced by a standardized pressure-controlled retrograde infusion 5% sodium taurocholate (0.1ml/100g) into the bile-pancreatic duct. The CON group was identical to the AP group except that the saline was injected instead of sodium taurocholate. The CON group and the AP group were received 10% dimethyl sulphoxide (DMSO) (0.2ml/ 100g) administered via femoral vein 30min prior to the operation. In the ROSI group, rosiglitazone (6mg/kg) dissolved in 10% DMSO was injected by femoral vein 30 minutes piror to the operation. Rats were killed at 3,6 and 12 hours after operation. In pulmonary tissue, nuclear factor-kappa B (NF-κB) p65 expression was assayed by immuno-histochemistry. Tumor necrosis factor-α(TNF-α), intercellular adhesion molecule-1 (ICAM-1) and P-selectin mRNA expression were detected by reverse transcriptase polymerase chain reaction (RT-PCR). ICAM-1 and P-selectin protein expression were studied using Western blot analysis.
Results In the AP group, the peak of NF-κB score, TNF-a mRNA expression ICAM-1 mRNA expression, P-selectin mRNA expression of the lung tissue were at 12 hours (1.04±0.13, 0.57±0.03,1.53±0.08,0.51±0.09). All the indexes were increased significantly at each time point in the AP group than in the CON group (P< 0.05). Compared with the AP group, pretreatment with rosiglitazone decreased the NF-κB score and the expression of TNF-a mRNA at 6h and 12h(P< 0.05), down-regulation the expression of ICAM-1, P-selectin mRNA and protein at 12 hours (P<0.05).
Conclusions:Rosiglitazone exerts the protective effect against acute pancreatitis associated lung injury by inhibition of NF-κB and TNF-α, down-regulation the expression of ICAM-1 and P-selectin.
目的：探讨罗格列酮(rosiglitazone, ROSI)静脉注射给药,干预大鼠急性胰腺炎(acute pancreatitis, AP)模型的量效关系,为ROSI干预急性胰腺炎肺损伤(acute pancreatitis associated-lung injury, APALI)选择合适的用药剂量提供依据。
方法：雄性Wistar大鼠42只,体重200～250g,随机分为7组(N=6)：正常对照组(control group, CON组)、急性胰腺炎模型组(acute pancreatitis model group,AP组)、罗格列酮0.3mg/kg、3mg/kg、6mg/kg、10mg/kg预处理组(rosiglitazone pretreatment group, ROSI组)和药物对照组(drug control group, Drug-CON组)。实验前大鼠禁食12 h,自由饮水。10%水合氯醛腹腔注射(0.3ml/100g)麻醉,无菌操作下大鼠行上腹正中切口进腹,逆行穿刺胆胰管注射5%牛磺胆酸钠溶液(sodium taurocholate, STC) (0.1ml/100g)制备急性胰腺炎模型；CON组和Drug-CON组操作如上所述,但胆胰管内注射等容量生理盐水。CON组、AP组造模前30min经股静脉注射10%二甲基亚砜(dimethyl sulphoxide, DMSO)溶液(0.2ml/100g)；不同剂量梯度罗格列酮预处理组则注射等量、10%DMSO溶解的ROSI。大鼠术后12 h心脏取血分离血清,全自动生化仪检测各组血清淀粉酶(amylase, AMY)、丙氨酸氨基转移酶(alanine aminotransferase, ALT)水平。HE染色观察各组胰腺组织病理学改变并评分。药物对照组操作同正常对照组,根据干预效果选择最佳剂量的ROSI,术前30min经股静脉注射最佳剂量ROSI取代10% DMSO,术后12h检测其血清AMY、ALT水平变化,观察胰腺组织病理学改变并评分。
结果：0.3mg/kg、3 mg/kg ROSI预处理组血清AMY和血清ALT与AP组比较差异无统计学意义(P>0.05),胰腺组织病理学评分有所改善,差异有统计学意义(P<0.05)；6mg/kg ROSI预处理组血清AMY、血清ALT和胰腺组织病理学评分较AP组降低,差异有统计学意义(P<0.05),10 mg/kg ROSI预处理组血清AMY、胰腺组织病理学评分较AP组降低,差异有统计学意义(P<0.05),但血清ALT与AP组比较差异无统计学意义(P>0.05)。6 mg/kg和10 mg/kg ROSI预处理组间对比,上述指标差异无统计学意义(P>0.05)。药物对照组(6 mg/kg)血清AMY、血清ALT和胰腺组织病理学评分与CON组比较差异无统计学意义(P>0.05)。
结论：罗格列酮干预牛磺胆酸钠诱导的大鼠AP模型时,6 mg/kg静脉注射是安全、有效的剂量。
第二部分罗格列酮对大鼠急性胰腺炎肺损伤的作用
目的：探讨罗格列酮(rosiglitazone, ROSI)静脉给药对大鼠急性胰腺炎肺损伤(acute pancreatitis associated-lung injury, APALI)的作用。
方法：雄性Wistar大鼠54只,体重200～250g,随机分为3组(N=18)：正常对照组(control group, CON组)、急性胰腺炎模型组(acute pancreatitis model group, AP组)和罗格列酮预处理组(rosiglitazone pretreatment group, ROSI组)。实验前大鼠禁食12 h,自由饮水。10%水合氯醛腹腔注射(0.3ml/100g)麻醉,大鼠无菌操作下行上腹正中切口进腹,逆行穿刺胆胰管注射5%牛磺胆酸钠溶液(sodium taurocholate, STC) (0.1ml/100g)制备急性胰腺炎模型；CON组操作如上所述,但胆胰管内注射等容量生理盐水。CON组、AP组造模前30min经股静脉注射10%二甲基亚砜(dimethyl sulphoxide, DMSO)溶液(0.2ml/100g)；ROSI组造模前30min经股静脉注射10%DMSO溶解的ROSI (6 mg/kg)。术后3h、6h、12h分批剖杀大鼠,每个时间点6只。HE染色观察各组胰腺组织和肺脏病理学改变并评分。心脏取血分离血清,全自动生化仪检测各组血清淀粉酶(amylase, AMY)水平。比色法检测肺组织髓过氧化物酶(myeloperoxidase, MPO)活性(间接表示中性粒细胞浸润程度)。左主支气管穿刺插管行支气管肺泡灌洗,收集支气管肺泡灌洗液(bronchoalveolar lavage fluid, BALF)并检测其蛋白含量(反应肺毛细血管渗透性)。取右肺中叶拭去肺组织表面血迹及水分后称湿重,置于70℃烘箱24h后称干重,计算肺湿干比(W/D)(反应肺脏水肿程度)。
结果：随着时间的延长,AP组血清AMY水平、肺脏MPO活性、肺脏W/D比值、BALF蛋白含量、胰腺和肺组织评分逐渐升高,至12 h达最高值,分别为(5353.0±728.2)U/L、(1.12±0.14)U/g、(3.00±0.14)、(0.438±0.056)g/L、(11.17±0.93)和(8.17±0.75)；上述指标在各时点均高于CON组,差异有统计学意义(P<0.05)。ROSI组上述指标均较AP组有所下降,以6h、12h差异有统计学意义(P<0.05)。
结论：罗格列酮通过减低肺组织MPO活性,降低肺脏水肿程度和肺毛细血管渗透性,对急性胰腺炎肺损伤具有保护作用。
第三部分罗格列酮对大鼠急性胰腺炎肺损伤保护作用的机制探讨
目的：探讨罗格列酮(rosiglitazone, ROSI)静脉给药对大鼠急性胰腺炎肺损伤(acute pancreatitis associated-lung injury, APALI)保护作用的机制。
方法：雄性Wistar大鼠54只,体重200～250g,随机分为3组(N=18)：正常对照组(control group, CON组)、急性胰腺炎模型组(acute pancreatitis model group, AP组)和罗格列酮预处理组(rosiglitazone pretreatment group, ROSI组)。实验前大鼠禁食12 h,自由饮水。10%水合氯醛腹腔注射(0.3ml/100g)麻醉,大鼠无菌操作下行上腹正中切口进腹,逆行穿刺胆胰管注射5%牛磺胆酸钠溶液(sodium taurocholate, STC) (0.1ml/100g)制备急性胰腺炎模型；CON组操作如上所述,但胆胰管内注射等容量生理盐水。CON组、AP组造模前30min经股静脉注射10%二甲基亚砜(dimethyl sulphoxide, DMSO)溶液(0.2ml/100g)；ROSI组造模前30min经股静脉注射10%DMSO溶解的ROSI (6mg/kg)。术后3h、6h、12h分批剖杀大鼠。免疫组化法检测肺组织核因子-κB (nuclear factor-kappa B, NF-κB) p65的表达水平。逆转录聚合酶链反应(reverse transcription-reverse transcription, RT-PCR)检测肺组织肿瘤坏死因子-α(tumor necrosis factor-a, TNF-α)、细胞问粘附分子-1(intercellular adhesion molecule, ICAM-1)、P-选择素(P-selectin) mRNA表达水平。Western blot法检测肺组织ICAM-1、P-selectin蛋白的表达水平。
结果：随着时间的延长,AP组肺脏NF-κB评分、TNF-a mRNA表达、ICAM-1 mRNA表达和P-selectin mRNA表达逐渐升高,均在12h达高峰,分别为(1.04±0.13)、(0.57±0.03)、(1.53±0.08)、(0.51±0.09)；上述指标在各时点均高于CON组,差异有统计学意义(P<0.05)。ROSI组肺脏NF-κB评分和TNF-αmRNA较AP组下降,以6h、12h差异有统计学意义(P<0.05)。ROSI组肺脏ICAM-1、P-selectin mRNA和蛋白表达在12h点较AP组下降,差异有统计学意义(P<0.05)。
结论：罗格列酮通过抑制肺组织NF-κB和TNF-α,减少ICAM-1、P-selectin的表达,对大鼠急性胰腺炎肺损伤具有保护作用。
Part 1. Dose-response relationship of rosiglitazone administered via vein on acute pancreatitis in rats
Objective:The aim of this study is to investigate dose-response relationship of rosiglitazone administered via vein on acute pancreatitis in order to obtain the optimal dose of rosiglitazone for preventing sodium taurocholate-induced acute pancreatitis associated-lung injury.
Methods:Forty-two male Wistar rats, weighing 200-250g, were randomly divided into seven groups (N=6):control group (CON group), acute pancreatitis model group(AP group), different dosage(0.3mg/kg,3mg/kg,6mg/kg and 10mg/kg) rosiglitazone pretreatment group (ROSI group) and drug control group (Drug-CON group) (dosage according to the effect of rosiglitazone). Prior to the experiment, rats were deprived of food for 12 hours, while drinking water was available ad libitum. Anaesthesia was conducted by intraperitoneal injection of 10% chloraldurat (0.3ml/ 100g) and rats underwent sterile laparotomy. The bile-pancreatic duct was cannulated through the duodenum and acute pancreatitis model was induced by a standardized pressure-controlled retrograde infusion 5% sodium taurocholate(0.1ml/100g) into the bile-pancreatic duct. The CON group was identical to the AP group except that the saline was injected instead of sodium taurocholate. The CON group and the AP group were received 10% dimethyl sulphoxide (DMSO) (0.2ml/100g) administered via femoral vein 30min prior to the operation. In the ROSI group, different concentration rosiglitazone were injected partes aequales respectivly instead of 10% DMSO. The drug control group was identical to the CON group except that partes aequales rosiglitazone was injected instead of 10% DMSO. Rats were killed at 12 hours after operation. Blood were obtained from the left ventricle of heart. The samples were centrifuged and the serum amylase level, alanine aminotransferase level were detected by automatic biochemistry analyzer. Continuous sections of the paraffin embedded tissue were taken for pathological examination with hematoxylin-eosin (HE) staining. Morphometric documentation for pancreatic and pulmonary sections under light microscope were evaluated.
Results:Compared with the AP group,0.3mg/kg,3mg/kg dosage failed to improve the levels of amylase and alanine aminotransferase (P> 0.05), but attenuated severity of pancreatic injury (P<0.05).6mg/kg dosage had the best effect on improving the levels of amylase, alanine aminotransferase and pathologic score (P<0.05). The dosage of 10mg/kg also improve level of amylase and pathologic score (P<0.05), but failed to improve the level of alanine aminotransferase (P>0.05). There was no statistically significant between 6mg/kg dosage and 10mg/kg dosage of all the indexes. Compared with the CON group, rats of preteatment with rosiglitazone (6mg/kg) in the absence of sodium taurocholate revealed virtually the same serum amylaselevel, alanine aminotransferase level and pathologic score (P>0.05).
Conclusion:Rosiglitazone (6mg/kg) administered intravenously was the safe, effective dosage for attenuating the severity of acute pancreatitis induced by retrograde infusion sodium taurocholate.
Part 2. Effect of rosiglitazone on acute pancreatitis associated lung injury in rats
Objective:The aim of this study is to investigate the effect of rosiglitazone on acute pancreatitis associated lung injury in rats.
Methods:Fifty-four male Wistar rats, weighing 200-250g, were randomly divided into three groups (N=18):control group (CON group), acute pancreatitis model group (AP group) and rosiglitazone pretreatment group (ROSI group). Prior to the experiment, rats were deprived of food for 12 hours, while drinking water was available ad libitum. Anaesthesia was conducted by intraperitoneal injection of 10% chloraldurat(0.3ml/100g) and rats underwent sterile laparotomy. The bile-pancreatic duct was cannulated through the duodenum and acute pancreatitis model was induced by a standardized pressure-controlled retrograde infusion 5% sodium taurocholate (0.1ml/100g) into the bile-pancreatic duct. The CON group was identical to the AP group except that the saline was injected instead of sodium taurocholate. The CON group and the AP group were received 10% dimethyl sulphoxide (DMSO) (0.2ml/ 100g) administered via femoral vein 30min prior to the operation. In the ROSI group, rosiglitazone (6mg/kg) dissolved in 10% DMSO was injected by femoral vein 30 minutes piror to the operation. Rats were killed at 3,6 and 12 hours after operation. Blood were obtained from the left ventricle of heart. The samples were centrifuged and the serum amylase level was detected by automatic biochemistry analyzer. Continuous sections of the paraffin embedded tissue were taken for pathological examination with hematoxylin-eosin (HE) staining. Morphometric documentation for pancreatic and pulmonary sections under light microscope were evaluated. Lung myeloperoxidase (MPO) activity was detceted by chromatometry(reflect neutrophil infiltration). The left main bronchus was instilled with 3 mL saline at appropriate pressure, and bronchoalveolar lavage fluid (BALF) was collected for detecting protein content (reflect pulmonary microvascular permeability). The lung wet/dry ratio (W/D) was determined by calculating from the initial weight of the right lung middle lobe (wet weight) to its weight after desiccation at 70℃for 24 hours (dry weight) (reflect pulmonary edema extent).
Results In the AP group, serum amylase level, lung MPO activity, W/D ratio, protein content of BALF, pancreatic and pulmonary pathologic score reached the peak level at 12 hours after operation(5353.0±728.2 U/L,1.12±0.14 U/g,3.00±0.14, 0.438±0.056,11.17±0.93 and 8.17±0.75 respectively). All the indexes were increased significantly at each time point in the AP group than in the CON group (P< 0.05). Compared with the AP group, pretreatment with rosiglitazone reduced serum amylase level, lung MPO activity, W/D weight ratio, protein content of BALF, pancreatic and pulmonary pathologic score at 6h and 12h(P<0.05).
Conclusions:Rosiglitazone exerts the protective effect against acute pancreatitis associated lung injury by inhibition of lung MPO activity, reducing pulmonary edema and pulmonary microvascular permeability.
Part 3. Effect mechanism of rosiglitazone on acute pancreatitis associated lung injury in rats
Objective:The aim of this study is to investigate the effect of rosiglitazone on adhesion molecules expression in acute pancreatitis associated lung injury in rats.
Methods:Fifty-four male Wistar rats, weighing 200-250g, were randomly divided into three groups (N=18):control group (CON group), acute pancreatitis model group(AP group)and rosiglitazone pretreatment group(ROSI group). Prior to the experiment, rats were deprived of food for 12 hours, while drinking water was available ad libitum. Anaesthesia was conducted by intraperitoneal injection of 10% chloraldurat(0.3ml/100g) and rats underwent sterile laparotomy. The bile-pancreatic duct was cannulated through the duodenum and acute pancreatitis model was induced by a standardized pressure-controlled retrograde infusion 5% sodium taurocholate (0.1ml/100g) into the bile-pancreatic duct. The CON group was identical to the AP group except that the saline was injected instead of sodium taurocholate. The CON group and the AP group were received 10% dimethyl sulphoxide (DMSO) (0.2ml/ 100g) administered via femoral vein 30min prior to the operation. In the ROSI group, rosiglitazone (6mg/kg) dissolved in 10% DMSO was injected by femoral vein 30 minutes piror to the operation. Rats were killed at 3,6 and 12 hours after operation. In pulmonary tissue, nuclear factor-kappa B (NF-κB) p65 expression was assayed by immuno-histochemistry. Tumor necrosis factor-α(TNF-α), intercellular adhesion molecule-1 (ICAM-1) and P-selectin mRNA expression were detected by reverse transcriptase polymerase chain reaction (RT-PCR). ICAM-1 and P-selectin protein expression were studied using Western blot analysis.
Results In the AP group, the peak of NF-κB score, TNF-a mRNA expression ICAM-1 mRNA expression, P-selectin mRNA expression of the lung tissue were at 12 hours (1.04±0.13, 0.57±0.03,1.53±0.08,0.51±0.09). All the indexes were increased significantly at each time point in the AP group than in the CON group (P< 0.05). Compared with the AP group, pretreatment with rosiglitazone decreased the NF-κB score and the expression of TNF-a mRNA at 6h and 12h(P< 0.05), down-regulation the expression of ICAM-1, P-selectin mRNA and protein at 12 hours (P<0.05).
Conclusions:Rosiglitazone exerts the protective effect against acute pancreatitis associated lung injury by inhibition of NF-κB and TNF-α, down-regulation the expression of ICAM-1 and P-selectin.
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