盐酸戊乙奎醚对急性肺损伤的保护作用及其部分机制的研究
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摘要
成人呼吸窘迫症(Adult respiratory distress syndrome,ARDS)是急救医学中发病率和死亡率都很高的一种并发症。急性肺损伤(Acute lung injury,ALI)系ARDS病程的早期阶段,是指机体遭受严重感染、创伤、休克等打击后,出现以弥漫性肺泡毛细血管膜损伤导致肺水肿和肺不张为病理特征,临床表现为呼吸窘迫,伴有顽固性低氧血症、肺顺应性下降和扩散性炎症浸润,其病死率高达45%-50%。因此,防治本类疾病在急危重领域具有非常重要的意义。
药物干预在ALI防治中具有重要作用。抗胆碱药物已应用于ALI治疗多年,但因传统抗胆碱药物如山莨菪碱等的作用机制不甚明了和副作用大,限制了抗胆碱类药物的临床应用。盐酸戊乙奎醚(pneheydidine hydrochloride,PHCD)是中国原创的新型选择性的抗胆碱药物,该药对M受体亚型有选择性,主要选择作用于亚型M1、M3受体,对M2受体无明显作用或作用较弱,因此对心脏作用弱,对心率变异性、心肌耗氧量均优于山莨菪碱。近来研究表明,盐酸戊乙奎醚能改善微循环、降低毛细血管壁的通透性、细胞保护和减少溶酶体释放等作用,提示盐酸戊乙奎醚可能对急性肺损伤具有治疗作用,因此,本研究从整体和分子水平研究盐酸戊乙奎醚对ALI的保护作用及其机制,旨在为盐酸戊乙奎醚治疗ALI提供理论依据。全文分四部分进行研究:
第一部分盐酸戊乙奎醚对内毒素诱导ALI大鼠的保护作用
盐酸戊乙奎醚(ip 0.03mg/kg,0.10mg/kg,0.30mg/kg)能显著降低LPS诱导ALI大鼠肺含水量、肺湿/干重比值、肺通透性指数、BALF中的蛋白含量及动脉血PaCO_2值(p＜0.05),明显提高ALI大鼠动脉血PaO_2值及PH值(p＜0.05),并显著改善肺部炎症病理改变,减轻ALI大鼠肺泡Ⅱ型上皮细胞损伤。提示PHCD能减轻内毒素诱导ALI的微血管屏障损伤和肺泡Ⅱ型上皮细胞损伤,抑制内毒素诱导ALI的肺部炎症反应和通透性增高,提高肺部气体交换功能。第二部分盐酸戊乙奎醚对内毒素ALI中性拉细胞肺内聚集与氧自由基损伤的抑制作用
盐酸戊乙奎醚(ip 0.03mg/kg,0.10mg/kg,0.30mg/kg)显著降低ALI大鼠BALF中PMN计数比例、肺组织髓过氧化物酶活性、丙二醛含量和血清乳酸脱氢酶活性(p＜0.05),显著提高肺组织和血清中的超氧化物歧化酶活性(p＜0.05);采用TUNEL法检测肺组织细胞凋亡的情况,PHCD明显抑制肺组织细胞凋亡。研究提示PHCD通过抑制内毒素ALI中性粒细胞肺内聚集与氧自由基损伤作用,减轻肺组织细胞凋亡,来改善ALI肺部炎症反应和换气功能,缓解LPS诱导微血管屏障损伤和通透性增高。
第三部分盐酸戊乙奎醚对内毒素急性肺损伤大鼠中性粒细胞凋亡的影响
采用流式细胞仪和EMSA法观察PHCD(0.03、0.3mg/kg)对ALI大鼠外周血中PMN凋亡凋亡率的影响;采用Westernblot法和RT-PCR法观察PHCD(0.03mg/kg,0.10mg/kg,0.30mg/kg)对PMN Mcl/bax蛋白表达和Fas/FasL mRNA表达的影响。结果表明,与模型组PMN凋亡率(16.05%±0.93%)相比,PHCD0.3mg/mg能显著促进PMN的凋亡(6.05%±0.93%)。中、高剂量的PHCD促凋亡机制可能是通过显著增加Fas/FasL mRNA表达,降低抗凋亡基因Mcl—1蛋白表达,增加促凋亡基因bax蛋白表达,降低Mcl-1/bax比值来促进PMN的凋亡,因此,PHCD通过促进PMN凋亡来调节机体的抗炎和促炎反应,以达到促炎与抗炎平衡,起到保护肺损伤的作用。
第四部分盐酸戊乙奎醚对内毒素ALI大鼠肺组织NF-κB活性和表达及炎性细胞因子和一氧化氮合酶(NOS)的影响
采用EMSA法观察PHCD对肺组织NF-κB活性的影响;免疫组化法观察PHCD对NF-κB p65mRAN在肺组织中的表达;RT-PCR法观察PHCD对LPS引起的肺组织中TNF-α和IL-βmRNA表达的影响;ELISA法检测PHCD对肺组织中TNF-α和IL-β细胞因子水平的影响;采用RT-PCR法和Westernblot法观察PHCD对肺组织NOS mRNA表达和蛋白表达的影响,同时检测血浆和肺组织中NOS和NO的含量。结果表明,盐酸戊乙奎醚(ip 0.03mg/kg,0.10mg/kg,0.30mg/kg)三种剂量不仅能显著抑制大鼠肺组织NF-κB活性和表达(p＜0.05),而且降低肺组织中TNF-α和IL-β的mRNA表达及蛋白含量(p＜0.05),同时显著抑制肺组织中NOS mRNA、NOS蛋白表达和肺组织中NOS及NO含量(p＜0.01)。结果提示盐酸戊乙奎醚对内毒素诱导ALI大鼠保护作用可能与抑制内毒素诱导NF-κB活化,减少炎性细胞因子释放,遏制炎症瀑布反应,进而减轻组织的炎性损伤有关;另外,PHCD也可能通过减低LPS诱导的肺组织NOSmRNA和蛋白表达,减少NO释放,起到对肺损伤的保护作用。
Acute lung injury(ALI) is a cause of acute respiratory failure that develops in patients of all ages from a variety of clinical disorders,including sepsis(pulmonary and nonpulmonary),pneumonia(bacterial,viral,and fungal),aspiration of gastric and oropharyngeal contents,major trauma,and several other clinical disorders including severe acute pancreatitis,drug overdose,and blood products.ALI is characterized by neutrophil accumulation in the lungs,loss of epithelial integrity,widening of the alveolar-arterial O_2 gradient,and the development of interstitial pulmonary edema and remains a significant cause of morbidity and mortality in critically ill patients.
Penehyclidine hydrochloride(PHCD) a new anticholinerigic drug,which invented by the institute of Pharmacology and Toxicology,Academy of Military Medical Sciences in the People's Republic of China,is different from anisodamine with long duration and slight effection on M_2 receptor.It is noteworthy that PHCD can decrease significantly the nasal mucosa capillary permeability.Thus,PHCD is potentially beneficial for treatment of ALI.
In this study we aimed to investigate whether PHCD has in vivo protective effect on ALI induced by LPS and to explore the mechanisms for the inhibitory effects of PHCD on ALI.The principal contents were divided into some sections as follows:
1.Effects of Penehyclidine hydrochloride on ALI induced by LPS
PHCD(0.03,0.1,0.3mg/kg,ig) significantly increased the partial pressure of oxygen and decreased partial pressure of carbondioxide of arterial blood.Furthermore, PHCD markedly reduced lung water content,wet-to-dry weight ratio of lung,the lung permeability index and the bronchoalveolar lavage protein concentration.Lung histopathological and electron microscopy examination showed PHCD could also ameliorate lung injury and alveolar type cell injury induced by LPS.All data showed that PHCD had significant protective effects in ALl induced by LPS.
2.Effects of PHCD on the neutrophil accumulation and production of oxygen free radical in lung induced by LPS
PHCD(0.03,0.1,0.3mg/kg,ig) significnatly reduced MDA level in lung and serum and increased SOD level in lung and serum in LPS-induced ALI rats.PHCD also decreased activities of MPO in lung and activities of LDH in BALF.PHCD also significantly decreased the apoptosis of lung cell with method of TUNEL.All this showed that PHCD attenuates LPS-induced acute lung responses through inhibition massive accumulation of neutrophils in the lungs and the production of reactive oxygen species and apotosis of lung cell.
3.Effect of PHCD on the apoptosis of activated PMN
Flow cytometry was used to analyze the apoptosis rate of PMN obtained from blood.The protein expressions of Mcl-1 and bax of PMN were measured by Western-blot.Fas/FasL mRNA expression of PMN was analyzed by semi-quantitative RT-PCR.The result showed that the apoptosis rate(16.05±0.93%) of PMN with PHCD(0.3mg/mg) treatment was significantly decreased,when compared with that (1.85%±0.31%) in the model group(P＜0.05).Moreover the expression of Mcl-1/bax was down-regulated and Fas/FasL mRNA expression was up-regulated after PHCD(0.1, 0.3mg/mg) treatment respectivily.But,pretreatment with PHCD(0.03mg/mg) could not decrease the apoptosis rate of PMN.
4.Effects of PHCD on the expression of NF-κB p65 and NF-κB activation,expression of proinflammatory cytokines and NOS in lung tissue
NF-κB is an essential transcription factor that regulates the gene expression of various cytokines,chemokines,growth factors,and cell-adhesion molecules.The expression of NF-κB p65 and NF-κB activation in lung measurd by Immunohistochemical staining and EMSA.The mRNA and levels of TNF-αand IL-1βin lung tissue were measured by semi-quantitative RT-PCR and ELISA methods respectively.The NOS mRNA and protein expressions were measured by semi-quantitative RT-PCR and Western-blot methods respectively and the levels of NO in lung and serum were also measured.
The results showed that PHCD could significantly inhibite the LPS-induced the induction of NF-κB activation and reduced TNF-αand IL-1βexpression.Furthermore, PHCD also substantially reduced the LPS-induced NOS mRNA and protein expression in lung tissue,dcreased activity of NOS and levels of NO in lung and serum.These results suggest that PHCD attenuates LPS-induced acute lung responses through inhibition of LPS-induced NF-κB DNA binding activity,down- regulation gene expression of IL-1βand TNF-a cytokines in lung tissue.In addition,the level of NO might contribute to the lung injury by LPS.NF-κB activation appears to be an important mechanism mediating LPS-induced TNF-αand IL-1βproduction,NO production,which resulting neutrophil recruitment associated with acute lung inflammation and injury.
In summary.,PHCD could possess obvious protective effect on ALI induced by LPS in our experiment without does-dependently in vivo.Its mechanisms of protective effect might be reletive to(1)antioxidation,(2) increase apoptosis rate of PMN, mechanisms of which might be associated with its down-regulation protein expression rato of Mcl-1/bax and up-regulation Fas/FasL mRNA expression,(3) inhibition NF-κB activativity,which might mediate LPS-induced TNF-αand IL-1βproduction,NO production.
药物干预在ALI防治中具有重要作用。抗胆碱药物已应用于ALI治疗多年,但因传统抗胆碱药物如山莨菪碱等的作用机制不甚明了和副作用大,限制了抗胆碱类药物的临床应用。盐酸戊乙奎醚(pneheydidine hydrochloride,PHCD)是中国原创的新型选择性的抗胆碱药物,该药对M受体亚型有选择性,主要选择作用于亚型M1、M3受体,对M2受体无明显作用或作用较弱,因此对心脏作用弱,对心率变异性、心肌耗氧量均优于山莨菪碱。近来研究表明,盐酸戊乙奎醚能改善微循环、降低毛细血管壁的通透性、细胞保护和减少溶酶体释放等作用,提示盐酸戊乙奎醚可能对急性肺损伤具有治疗作用,因此,本研究从整体和分子水平研究盐酸戊乙奎醚对ALI的保护作用及其机制,旨在为盐酸戊乙奎醚治疗ALI提供理论依据。全文分四部分进行研究:
第一部分盐酸戊乙奎醚对内毒素诱导ALI大鼠的保护作用
盐酸戊乙奎醚(ip 0.03mg/kg,0.10mg/kg,0.30mg/kg)能显著降低LPS诱导ALI大鼠肺含水量、肺湿/干重比值、肺通透性指数、BALF中的蛋白含量及动脉血PaCO_2值(p＜0.05),明显提高ALI大鼠动脉血PaO_2值及PH值(p＜0.05),并显著改善肺部炎症病理改变,减轻ALI大鼠肺泡Ⅱ型上皮细胞损伤。提示PHCD能减轻内毒素诱导ALI的微血管屏障损伤和肺泡Ⅱ型上皮细胞损伤,抑制内毒素诱导ALI的肺部炎症反应和通透性增高,提高肺部气体交换功能。第二部分盐酸戊乙奎醚对内毒素ALI中性拉细胞肺内聚集与氧自由基损伤的抑制作用
盐酸戊乙奎醚(ip 0.03mg/kg,0.10mg/kg,0.30mg/kg)显著降低ALI大鼠BALF中PMN计数比例、肺组织髓过氧化物酶活性、丙二醛含量和血清乳酸脱氢酶活性(p＜0.05),显著提高肺组织和血清中的超氧化物歧化酶活性(p＜0.05);采用TUNEL法检测肺组织细胞凋亡的情况,PHCD明显抑制肺组织细胞凋亡。研究提示PHCD通过抑制内毒素ALI中性粒细胞肺内聚集与氧自由基损伤作用,减轻肺组织细胞凋亡,来改善ALI肺部炎症反应和换气功能,缓解LPS诱导微血管屏障损伤和通透性增高。
第三部分盐酸戊乙奎醚对内毒素急性肺损伤大鼠中性粒细胞凋亡的影响
采用流式细胞仪和EMSA法观察PHCD(0.03、0.3mg/kg)对ALI大鼠外周血中PMN凋亡凋亡率的影响;采用Westernblot法和RT-PCR法观察PHCD(0.03mg/kg,0.10mg/kg,0.30mg/kg)对PMN Mcl/bax蛋白表达和Fas/FasL mRNA表达的影响。结果表明,与模型组PMN凋亡率(16.05%±0.93%)相比,PHCD0.3mg/mg能显著促进PMN的凋亡(6.05%±0.93%)。中、高剂量的PHCD促凋亡机制可能是通过显著增加Fas/FasL mRNA表达,降低抗凋亡基因Mcl—1蛋白表达,增加促凋亡基因bax蛋白表达,降低Mcl-1/bax比值来促进PMN的凋亡,因此,PHCD通过促进PMN凋亡来调节机体的抗炎和促炎反应,以达到促炎与抗炎平衡,起到保护肺损伤的作用。
第四部分盐酸戊乙奎醚对内毒素ALI大鼠肺组织NF-κB活性和表达及炎性细胞因子和一氧化氮合酶(NOS)的影响
采用EMSA法观察PHCD对肺组织NF-κB活性的影响;免疫组化法观察PHCD对NF-κB p65mRAN在肺组织中的表达;RT-PCR法观察PHCD对LPS引起的肺组织中TNF-α和IL-βmRNA表达的影响;ELISA法检测PHCD对肺组织中TNF-α和IL-β细胞因子水平的影响;采用RT-PCR法和Westernblot法观察PHCD对肺组织NOS mRNA表达和蛋白表达的影响,同时检测血浆和肺组织中NOS和NO的含量。结果表明,盐酸戊乙奎醚(ip 0.03mg/kg,0.10mg/kg,0.30mg/kg)三种剂量不仅能显著抑制大鼠肺组织NF-κB活性和表达(p＜0.05),而且降低肺组织中TNF-α和IL-β的mRNA表达及蛋白含量(p＜0.05),同时显著抑制肺组织中NOS mRNA、NOS蛋白表达和肺组织中NOS及NO含量(p＜0.01)。结果提示盐酸戊乙奎醚对内毒素诱导ALI大鼠保护作用可能与抑制内毒素诱导NF-κB活化,减少炎性细胞因子释放,遏制炎症瀑布反应,进而减轻组织的炎性损伤有关;另外,PHCD也可能通过减低LPS诱导的肺组织NOSmRNA和蛋白表达,减少NO释放,起到对肺损伤的保护作用。
Acute lung injury(ALI) is a cause of acute respiratory failure that develops in patients of all ages from a variety of clinical disorders,including sepsis(pulmonary and nonpulmonary),pneumonia(bacterial,viral,and fungal),aspiration of gastric and oropharyngeal contents,major trauma,and several other clinical disorders including severe acute pancreatitis,drug overdose,and blood products.ALI is characterized by neutrophil accumulation in the lungs,loss of epithelial integrity,widening of the alveolar-arterial O_2 gradient,and the development of interstitial pulmonary edema and remains a significant cause of morbidity and mortality in critically ill patients.
Penehyclidine hydrochloride(PHCD) a new anticholinerigic drug,which invented by the institute of Pharmacology and Toxicology,Academy of Military Medical Sciences in the People's Republic of China,is different from anisodamine with long duration and slight effection on M_2 receptor.It is noteworthy that PHCD can decrease significantly the nasal mucosa capillary permeability.Thus,PHCD is potentially beneficial for treatment of ALI.
In this study we aimed to investigate whether PHCD has in vivo protective effect on ALI induced by LPS and to explore the mechanisms for the inhibitory effects of PHCD on ALI.The principal contents were divided into some sections as follows:
1.Effects of Penehyclidine hydrochloride on ALI induced by LPS
PHCD(0.03,0.1,0.3mg/kg,ig) significantly increased the partial pressure of oxygen and decreased partial pressure of carbondioxide of arterial blood.Furthermore, PHCD markedly reduced lung water content,wet-to-dry weight ratio of lung,the lung permeability index and the bronchoalveolar lavage protein concentration.Lung histopathological and electron microscopy examination showed PHCD could also ameliorate lung injury and alveolar type cell injury induced by LPS.All data showed that PHCD had significant protective effects in ALl induced by LPS.
2.Effects of PHCD on the neutrophil accumulation and production of oxygen free radical in lung induced by LPS
PHCD(0.03,0.1,0.3mg/kg,ig) significnatly reduced MDA level in lung and serum and increased SOD level in lung and serum in LPS-induced ALI rats.PHCD also decreased activities of MPO in lung and activities of LDH in BALF.PHCD also significantly decreased the apoptosis of lung cell with method of TUNEL.All this showed that PHCD attenuates LPS-induced acute lung responses through inhibition massive accumulation of neutrophils in the lungs and the production of reactive oxygen species and apotosis of lung cell.
3.Effect of PHCD on the apoptosis of activated PMN
Flow cytometry was used to analyze the apoptosis rate of PMN obtained from blood.The protein expressions of Mcl-1 and bax of PMN were measured by Western-blot.Fas/FasL mRNA expression of PMN was analyzed by semi-quantitative RT-PCR.The result showed that the apoptosis rate(16.05±0.93%) of PMN with PHCD(0.3mg/mg) treatment was significantly decreased,when compared with that (1.85%±0.31%) in the model group(P＜0.05).Moreover the expression of Mcl-1/bax was down-regulated and Fas/FasL mRNA expression was up-regulated after PHCD(0.1, 0.3mg/mg) treatment respectivily.But,pretreatment with PHCD(0.03mg/mg) could not decrease the apoptosis rate of PMN.
4.Effects of PHCD on the expression of NF-κB p65 and NF-κB activation,expression of proinflammatory cytokines and NOS in lung tissue
NF-κB is an essential transcription factor that regulates the gene expression of various cytokines,chemokines,growth factors,and cell-adhesion molecules.The expression of NF-κB p65 and NF-κB activation in lung measurd by Immunohistochemical staining and EMSA.The mRNA and levels of TNF-αand IL-1βin lung tissue were measured by semi-quantitative RT-PCR and ELISA methods respectively.The NOS mRNA and protein expressions were measured by semi-quantitative RT-PCR and Western-blot methods respectively and the levels of NO in lung and serum were also measured.
The results showed that PHCD could significantly inhibite the LPS-induced the induction of NF-κB activation and reduced TNF-αand IL-1βexpression.Furthermore, PHCD also substantially reduced the LPS-induced NOS mRNA and protein expression in lung tissue,dcreased activity of NOS and levels of NO in lung and serum.These results suggest that PHCD attenuates LPS-induced acute lung responses through inhibition of LPS-induced NF-κB DNA binding activity,down- regulation gene expression of IL-1βand TNF-a cytokines in lung tissue.In addition,the level of NO might contribute to the lung injury by LPS.NF-κB activation appears to be an important mechanism mediating LPS-induced TNF-αand IL-1βproduction,NO production,which resulting neutrophil recruitment associated with acute lung inflammation and injury.
In summary.,PHCD could possess obvious protective effect on ALI induced by LPS in our experiment without does-dependently in vivo.Its mechanisms of protective effect might be reletive to(1)antioxidation,(2) increase apoptosis rate of PMN, mechanisms of which might be associated with its down-regulation protein expression rato of Mcl-1/bax and up-regulation Fas/FasL mRNA expression,(3) inhibition NF-κB activativity,which might mediate LPS-induced TNF-αand IL-1βproduction,NO production.
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