水飞蓟素对急性胰腺炎大鼠急性肺损伤及MAPK/NF-κB信号通路的影响
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摘要
目的探究水飞蓟素对急性胰腺炎大鼠急性肺损伤的保护作用,以及与丝裂原活化蛋白激酶(MAPK)/核因子κB(NF-κB)信号通路的关系。方法将SD大鼠分为假手术组、模型组、水飞蓟素低、中、高剂量组(50、100、200 mg·kg~(-1))、地塞米松组(2 mg·kg~(-1)),酶联免疫法测定炎症指标;苏木精-伊红染色法(HE)观察胰腺、肺部组织病理学变化;免疫印迹法检测MAPK/NF-κB通路蛋白表达。结果建模后,模型组PaO_2、OI降低,PaCO_2、胰腺、肺组织病理评分、淀粉酶活性、TNF-α和IL-1β水平均升高,与假手术组相比差异有显著性(P<0.05);给药后,水飞蓟素各组、阳性组的PaO_2、OI升高,PaCO_2、胰腺、肺组织病理评分、淀粉酶活性、TNF-α、IL-1β水平、胰腺、肺组织W/D、PMN降低,p-JNK、p-p38、p-ERK1/2、p-IκBα蛋白表达降低,呈剂量依赖性,与模型组相比差异有显著性(P<0.05)。结论水飞蓟素可能通过抑制MAPK/NF-κB通路,发挥对重症急性胰腺炎大鼠急性肺损伤的保护作用。
Aim To explore the protective effect of silymarin on acute lung injury in rats with severe acute pancreatitis and its relationship with mitogen activated protein kinase(MAPK)/nuclear factor κB(NF-κB) signaling pathway. Methods SD rats were divided into sham operation group, model group, silymarin low, medium and high dose group(50, 100, 200 mg·kg~(-1)), and dexamethasone group(2 mg·kg~(-1)). Enzyme-linked immunosorbent assay was used to detect inflammatory markers. Hematoxylin eosin staining(HE) was used to observe the histopathological changes of pancreas and lung. Western blot was used to detect the protein expression of MAPK/NF-κB pathway. Results After modeling, PaO_2 and OI decreased, PaCO_2, pancreas, lung histopathological score, amylase activity, TNF-α, IL-1β levels all increased in model group, compared with sham operation group, the differences were significant(P<0.05). After administration of silymarin, PaO_2 and OI increased, PaCO_2, pancreas, lung histopathological score, amylase activity, TNF-α, IL-1β levels, W/D and PMN in pancreas, lung tissues decreased, p-JNK, p-p38, p-ERK1/2, p-IκBα protein expression decreased in a dose-dependent manner, which was significantly different from those of model group(P<0.05). Conclusions Silymarin may play a protective role in acute lung injury in rats with severe acute pancreatitis by inhibiting MAPK/NF-κB pathway.
Aim To explore the protective effect of silymarin on acute lung injury in rats with severe acute pancreatitis and its relationship with mitogen activated protein kinase(MAPK)/nuclear factor κB(NF-κB) signaling pathway. Methods SD rats were divided into sham operation group, model group, silymarin low, medium and high dose group(50, 100, 200 mg·kg~(-1)), and dexamethasone group(2 mg·kg~(-1)). Enzyme-linked immunosorbent assay was used to detect inflammatory markers. Hematoxylin eosin staining(HE) was used to observe the histopathological changes of pancreas and lung. Western blot was used to detect the protein expression of MAPK/NF-κB pathway. Results After modeling, PaO_2 and OI decreased, PaCO_2, pancreas, lung histopathological score, amylase activity, TNF-α, IL-1β levels all increased in model group, compared with sham operation group, the differences were significant(P<0.05). After administration of silymarin, PaO_2 and OI increased, PaCO_2, pancreas, lung histopathological score, amylase activity, TNF-α, IL-1β levels, W/D and PMN in pancreas, lung tissues decreased, p-JNK, p-p38, p-ERK1/2, p-IκBα protein expression decreased in a dose-dependent manner, which was significantly different from those of model group(P<0.05). Conclusions Silymarin may play a protective role in acute lung injury in rats with severe acute pancreatitis by inhibiting MAPK/NF-κB pathway.
引文
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[5] 张珂, 张琬啉, 李洪图. 水飞蓟素对大鼠肺缺血/再灌注损伤的保护作用[J]. 中华实验外科杂志, 2016, 33(8):1935-7. Zhang K, Zhang W L, Li H T. Protective effect of silymarin on lung ischemia-reperfusion injury[J]. Chin J Exp Surg, 2016, 33(8):1935-7.
[6] 李涛, 刘源, 李冉,等. 氯膦酸二钠脂质体对大鼠重症急性胰腺炎肺损伤的影响及与Akt、MAPK(ERK1/2)通路的关系[J]. 中国普通外科杂志, 2016, 25(3):350-6. Li T, Liu Y, Li R, et al. Alleviative effect of liposomal clodronate against lung injury in rats with severe acute pancreatitis and its relations with Akt and MAPK (ERK1/2) pathways[J]. Chin J Gen Surg, 2016, 25(3):350-6.
[7] Kaplan M, Yazgan Y, Tanoglu A,et al. Effectiveness of interleukin-1 receptor antagonist (Anakinra) on cerulein-induced experimental acute pancreatitis in rats[J]. Scand J Gastroenterol, 2014,49(9):1124-30.
[8] Bukowczan J,Warzecha Z,Ceranowicz P, et al. Pretreatment with obestatin reduces the severity of ischemia/reperfusion-induced acute pancreatitis in rats.[J]. Eur J Pharmacol, 2015,760(5):113-21.
[9] 郭婉薇, 王伟福, 陈晓武,等. 重症急性胰腺炎大鼠肝内胆管组织病理学变化及胆管细胞凋亡情况[J]. 广东医学, 2016, 37(23):3502-6. Guo W W, Wang W F, Chen X W, et al. Pathological changes of intrahepatic bile duct tissue and apoptosis of bile duct cells in rats with severe acute pancreatitis[J]. Guangdong Med J, 2016, 37(23):3502-6.
[10] 雷传江, 焦艳, 王关嵩,等. 受体相互作用蛋白140在脓毒症急性肺损伤大鼠肺泡巨噬细胞中的表达及其作用[J]. 第三军医大学学报, 2015, 37(9):851-7. Lei C J, Jiao Y, Wang G S, et al. Expression and function of RIP140 in alveolar macrophages of rats with septic acute lung injury[J]. J Third Mil Med Univ, 2015, 37(9):851-7.
[11] Takahara M, Aoyama-Ishikawa M, Shuno K, et al. Role of endogenous IL-18 in the lung during endotoxin-induced systemic inflammation[J]. Acute Med Surg, 2014, 1(1):23-30.
[12] Yang C M, Luo S F, Hsieh H L, et al. Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: involvement of ERK, JNK, AP-1, and NF-kappaB[J]. J Cell Physiol, 2010, 224(2):516-26.
[13] 肖雪飞, 杨明施, 孙圣华. 姜黄素对脓毒症急性肺损伤的炎症反应及NF-κB信号通路的影响[J]. 中国现代医学杂志, 2013, 23(30):19-22. Xiao X F, Yang M S, Sun S H, et al. Effect of curcumin on inflammation and NF-κB signaling pathway in septic acute lung injury rats[J]. Chin J Mod Med, 2013, 23(30):19-22.
[14] 唐春林,丁宁,程傲冰. EGFR-p38 MAPK信号通路参与机械通气肺损伤大鼠肺组织HMGB1的表达[J]. 中国病理生理杂志, 2013, 29(6):1029-33. Tang C L, Ding N, Cheng A B. EGFR-p38 MAPK signaling pathway is involved in expression of HMGB1 in pulmonary tissues of rats with ventilator-induced lung injury[J]. Chin J Pathophysiol, 2013, 29(6):1029-33.
[15] 张利鹏, 赵焱, 刘国娟,等. 乌司他丁通过干预p38MAPK/ERK信号通路减轻脓毒症性肺损伤[J]. 中国药理学通报, 2016, 32(9):1311-6. Zhang L P, Zhao Y, Liu G J, et al. Ulinastatin attenuates lipopolysaccharide-induced acute lung injury by intervening p38 MAPK/ERK signaling pathway[J]. Chin Pharmacol Bull, 2016, 32(9):1311-6.
[2] 程石, 杨彬, 闫文貌,等. 抗TNF-α治疗对重症急性胰腺炎肺损伤NF-κB信号通路的影响[J]. 中国普通外科杂志, 2008, 17(3):219-23. Cheng S, Yang B, Yan W M, et al. The effect of anti-tumor necrosis factor α treatment on NF-κB signaling in lung injury in severe acute pancreatitis in rats[J]. Chin J Gen Surg, 2008, 17(3):219-23.
[3] 武丽娜, 余剑波, 刘大全,等. p38MAPK信号通路在内毒素性休克诱发急性肺损伤大鼠肺组织HO-1表达上调中的作用[J]. 中华麻醉学杂志, 2012, 32(6):727-31. Wu L N, Yu J B, Liu D Q, et al. Role of p38MAPK signaling pathway in up-regulation of heme oxygenase-1 expression in lung tissues in rats with acute lung injury induced by endotoxic shock[J]. Chin J Anesthesiol, 2012, 32(6):727-31.
[4] 刘志刚, 李雪玲, 翁立冬,等. 水飞蓟素药理作用研究进展[J]. 辽宁中医药大学学报, 2012,14(10):91-3. Liu Z G, Li X L, Weng L D, et al. Research progress on the pharmacological action of silymarin[J]. J Liaoning Univ Tradit Chin Med, 2012,14(10):91-3.
[5] 张珂, 张琬啉, 李洪图. 水飞蓟素对大鼠肺缺血/再灌注损伤的保护作用[J]. 中华实验外科杂志, 2016, 33(8):1935-7. Zhang K, Zhang W L, Li H T. Protective effect of silymarin on lung ischemia-reperfusion injury[J]. Chin J Exp Surg, 2016, 33(8):1935-7.
[6] 李涛, 刘源, 李冉,等. 氯膦酸二钠脂质体对大鼠重症急性胰腺炎肺损伤的影响及与Akt、MAPK(ERK1/2)通路的关系[J]. 中国普通外科杂志, 2016, 25(3):350-6. Li T, Liu Y, Li R, et al. Alleviative effect of liposomal clodronate against lung injury in rats with severe acute pancreatitis and its relations with Akt and MAPK (ERK1/2) pathways[J]. Chin J Gen Surg, 2016, 25(3):350-6.
[7] Kaplan M, Yazgan Y, Tanoglu A,et al. Effectiveness of interleukin-1 receptor antagonist (Anakinra) on cerulein-induced experimental acute pancreatitis in rats[J]. Scand J Gastroenterol, 2014,49(9):1124-30.
[8] Bukowczan J,Warzecha Z,Ceranowicz P, et al. Pretreatment with obestatin reduces the severity of ischemia/reperfusion-induced acute pancreatitis in rats.[J]. Eur J Pharmacol, 2015,760(5):113-21.
[9] 郭婉薇, 王伟福, 陈晓武,等. 重症急性胰腺炎大鼠肝内胆管组织病理学变化及胆管细胞凋亡情况[J]. 广东医学, 2016, 37(23):3502-6. Guo W W, Wang W F, Chen X W, et al. Pathological changes of intrahepatic bile duct tissue and apoptosis of bile duct cells in rats with severe acute pancreatitis[J]. Guangdong Med J, 2016, 37(23):3502-6.
[10] 雷传江, 焦艳, 王关嵩,等. 受体相互作用蛋白140在脓毒症急性肺损伤大鼠肺泡巨噬细胞中的表达及其作用[J]. 第三军医大学学报, 2015, 37(9):851-7. Lei C J, Jiao Y, Wang G S, et al. Expression and function of RIP140 in alveolar macrophages of rats with septic acute lung injury[J]. J Third Mil Med Univ, 2015, 37(9):851-7.
[11] Takahara M, Aoyama-Ishikawa M, Shuno K, et al. Role of endogenous IL-18 in the lung during endotoxin-induced systemic inflammation[J]. Acute Med Surg, 2014, 1(1):23-30.
[12] Yang C M, Luo S F, Hsieh H L, et al. Interleukin-1beta induces ICAM-1 expression enhancing leukocyte adhesion in human rheumatoid arthritis synovial fibroblasts: involvement of ERK, JNK, AP-1, and NF-kappaB[J]. J Cell Physiol, 2010, 224(2):516-26.
[13] 肖雪飞, 杨明施, 孙圣华. 姜黄素对脓毒症急性肺损伤的炎症反应及NF-κB信号通路的影响[J]. 中国现代医学杂志, 2013, 23(30):19-22. Xiao X F, Yang M S, Sun S H, et al. Effect of curcumin on inflammation and NF-κB signaling pathway in septic acute lung injury rats[J]. Chin J Mod Med, 2013, 23(30):19-22.
[14] 唐春林,丁宁,程傲冰. EGFR-p38 MAPK信号通路参与机械通气肺损伤大鼠肺组织HMGB1的表达[J]. 中国病理生理杂志, 2013, 29(6):1029-33. Tang C L, Ding N, Cheng A B. EGFR-p38 MAPK signaling pathway is involved in expression of HMGB1 in pulmonary tissues of rats with ventilator-induced lung injury[J]. Chin J Pathophysiol, 2013, 29(6):1029-33.
[15] 张利鹏, 赵焱, 刘国娟,等. 乌司他丁通过干预p38MAPK/ERK信号通路减轻脓毒症性肺损伤[J]. 中国药理学通报, 2016, 32(9):1311-6. Zhang L P, Zhao Y, Liu G J, et al. Ulinastatin attenuates lipopolysaccharide-induced acute lung injury by intervening p38 MAPK/ERK signaling pathway[J]. Chin Pharmacol Bull, 2016, 32(9):1311-6.