枇杷叶三萜酸对慢性支气管炎防治作用的细胞分子机制研究
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摘要
慢性支气管炎(慢支)是严重危害人类健康的常见病、多发病。目前认为,大气污染、吸烟、病原体感染及过敏因素等与慢性支气管炎的发病密切相关,但发病后的机体免疫功能状态直接和(或)间接影响慢性支气管炎的发生和发展。因此,纠正或调节机体免疫功能紊乱可能是防治慢性支气管炎的重要手段之一。
目前对慢性支气管炎的治疗主要着眼于抗炎、镇咳、平喘作用的研究,至今尚无令人十分满意的药物。而对于改善机体免疫功能状态的免疫调节药物,尤其是具有免疫调节作用的中药的研究还没有引起足够的重视。本课题组前期在国家自然科学基金的资助下(NO∶30371766)证实枇杷叶的有效活性部位为三萜酸。枇杷叶三萜酸(Triterpene Acids of Loquat Leaf,TAL)具有明显的抗炎及免疫调节作用,对慢支具有防治作用。
鉴于慢性支气管炎免疫功能紊乱的病理机制和枇杷叶三萜酸(Triterpeneacids of Loquat.Leaf,TAL)高效、低毒的作用特征,基于AM在慢支发病中的重要作用,本实验以肺泡巨噬细胞(AM)为研究靶点,探讨TAL对慢性支气管炎防治作用的细胞分子机制,为将其开发为治疗慢支的新药提供试验依据。前期研究表明TAL灌胃给药可明显降低慢支大鼠肺组织匀浆中TNF-α、IL-8水平,升高IL-10的表达,并对慢支大鼠气道粘膜上皮细胞NF-κB、ICAM-1的蛋白表达具有一定的抑制作用。TAL能明显抑制慢支大鼠AM自由基的产生;抑制炎症介质PGE_2及LTB_4的合成及释放;抑制AM中iNOS的表达及NO的合成;此外通过抑制NF-κB表达及活化,降低AM中TNF-α、IL-1的表达和分泌。TAL既能抑制AM细胞因子(TNF-α、IL-8、IL-1)炎症介质(PGE_2、LTB_4)的表达又明显抑制AM自由基、iNOS的合成。但AM是如何被激活的以及炎性介质的生成与释放机制—即基因的转录和翻译是如何调控的目前还不明了。因此进一步研究AM等细胞激活的分子机制是CB发病机制研究的主要方向。鉴于MAPK信号传导通路在炎症反应中的重要作用,本课题旨在前期研究的基础上,以AM为平台,MAPK信号通路为研究对象,研究慢支大鼠AM MAPK信号传导通路,探讨TAL对其信号传导通路的影响,研究TAL对慢支大鼠AM凋亡的影响,从而进一步阐明TAL对慢性支气管炎防治作用的细胞分子机制,为将其开发为治疗慢支的新药提供试验依据。课题为国家自然科学基金资助项目(NO∶30572355)。主要研究内容包括以下三个方面:
1.慢支模型大鼠肺泡巨噬细胞细胞因子、炎症介质的MAPK信号通路研究
MAPK三条通路的特异性阻制剂均能显著抑制慢支模型大鼠AM异常增加的IL-1、TNF-α活性,而JNK,ERK MAPK通路的特异性阻制剂Curcumin,PD98059能显著抑制慢支模型大鼠AM异常增加的PGE_2活性(P＜0.01)。JNK,ERK MAPK通路的特异性阻制剂可显著抑制CB大鼠AM内COX-2 mRNA及蛋白表达(P＜0.01 or P＜0.05)。p38 MAPK通路的特异性阻制剂SB203580体外给药可显著抑制CB大鼠AM内HO-1mRNA表达而p38,JNK MAPK通路的特异性阻制剂SB203580及Curcumin可显著抑制CB大鼠AM内HO-1蛋白表达(P＜0.01or P＜0.05)。MAPK三条信号传导通路阻制剂体外给药均可显著抑制CB大鼠AM内TNF-αmRNA表达,而JNK,p38 MAPK通路的特异性阻制剂Curcumin,SB203580可显著抑制CB大鼠AM内TNF-α蛋白表达(P＜0.05)。提示慢支大鼠AM中细胞因子、炎症介质(COX-2、TNF-α、HO-1、IL-1、PGE_2)的表达及活性分别由不同的MAPK信号传导通路介导。MAPK信号传导通路可分别从转录水平及转录后水平对其表达进行调节。
2.慢支大鼠肺泡巨噬细胞内MAPK信号传导通路及TAL的作用环节研究
分别应用MAPK通路上游信号蛋白(PTK、P13K、Akt、PKC)的特异性阻制剂预处理AM,观察下游蛋白磷酸化水平,以确定转录前调节相关信号蛋白。结果显示:Genistein可以不同程度的抑制PKC、PI3K/Akt、MAPK通路磷酸化的程度;LY294002可以抑制PI3K/Akt磷酸化的水平,同时诱导p-p38、p-JNK的高表达,对PKC/ERK这条经典途径的磷酸化也有一定的激活作用;CalphostinC阻断PKC的磷酸化,对P-ERK水平有较大影响,而对p-p38和p-JNK则影响不大。推出慢支模型大鼠AM中LPS信号转导MAPK通路可能为PTK-----PI3K/Akt------JNK/P38或者PTK-----PI3K-----PKC-----ERK。进一步探讨了TAL对MAPK通路的转录前信号蛋白的作用环节。发现TAL对p-p38,p-JNK,p-ERK,p-PKC,p-Akt皆有一定抑制作用(其中对p38和JNK磷酸化水平的抑滞效应最为显著),而对p-PI3K,其作用不甚明显,同时,TAL对模型组TLR4受体水平的增高也没有明显的降低作用。也就证明TAL对MAPK调控可能发生在PI3K下游某个环节,具体机制还有待研究。
3.TAL对慢支模型大鼠肺泡巨噬细胞凋亡的影响及其可能的作用机制研究
与正常组比较,模型大鼠AM凋亡率明显降低(P＜0.01);与模型组比较,TAL给药组及ERK通路抑制剂PD98059组AM凋亡率显著升高(P＜0.05 orP＜0.01)。而JNK通路抑制剂Curcumin组AM凋亡率显著降低(P＜0.05)。进一步研究显示,模型大鼠AM Bax表达降低而Bel-2表达升高(P＜0.01);TAL给药组可显著升高慢支大鼠AM Bcl-2表达而降低Bax表达(P＜0.05 or P＜0.01)。TAL抑制慢支大鼠AM胞浆内游离钙浓度升高,可使慢支大鼠AM激活数量减少。TAL能明显诱导AM的凋亡,降低AM的活性,使AM的数量减少,活性降低,从而发挥防治慢支的作用。MAPK通路参与细胞凋亡的调节,其中ERK通路可能抑制细胞凋亡而JNK通路发挥促凋亡的作用。TAL对慢支大鼠AM的促凋亡作用可能与其调节AM Bcl-2/Bax的表达,调节慢支大鼠AM游离钙胞内分布及影响AM MAPK通路的活化有关。
Chronic bronchitis(CB) is a common and preventable disease that has implications for global health.It is a complicated pathophysiological process,including calcium overload,free radical production,metabolic abnormalities,and inflammatory reaction,etc.Regulation disorder of neuroendocrine-immuno-function is one of the important techniques for chronic bronchitis therapy.
As a major effector of the innate immune system of the body,alveolar macrophage (AM) interact with other cells in airways and alveoli immediately after birth,resulting in generation of intracellular signaling cascades,leading to various effects or functions that make up the initial immune response in the lungs.Interaction of AM and lipopolysaccharides(LPS) causes a sequential activation production of both proand anti-inflammatory mediator in the lungs.
Traditionally,the leaf of Eriobotrya japonica(Thunb.)Lindl has a long history of medicinal use in South-east Asia in a variety of inflammatory conditions especially CB therapy.According to our previous study,the triterpene acids extracted from Eriobotrya japonica(Thunb.)Lindl Leaf was the effective component and had therapy effect on chronic bronchitis.TAL could suppress the LPS-induced inflammatory response through inhibiting the production of NF-κB,TNF-α,IL-1,iNOS expression increase IL-10 expression from alveolar macrophage in CB rats,affect the oxide and anti-oxide balance so as to protect the lung from oxidative damage,decrease the inflammation media such as PGE_2 and LTB_4 production.The signal transduction of inflammation media in AM of CB remains unclear.
The anti-inflammatory mechanisms of Triterpene Acids of Loquat.Leaf(TAL) in chronic bronchitis were studied by using the method in vivo and in vitro.Owing to the importance of AM in the processor of chronic bronchitis,effects of TAL on AM functions were investigated.Since Mitogen-activated protein kinases(MAPKs) are crucial for maintenance of cells in many signaling pathways operant in a variety of stress responses especially in inflammation process MAPK signal transduction pathway of inflammation media and cytokines production in AM of CB rats was studied.Furthermore the effect of TAL on the pathway was also investigated.The main contents are divided into some sections as follows:
1.MAPK signal transdnction pathway of inflammation media and cytokines production in AM of CB rats
The inhibitors of JNK,p38 or ERK MAPK suppressed IL-1 and TNF-αactivity and mRNA expression while JNK,p38 MAPK inhibitors suppressed TNF-αprotein expression.PGE_2 synthesis from AM of CB rats was suppressed by PD98059 and Curcumin.COX-2 mRNA and protein expression were partially downregulated by the JNK and ERK MAPK inhibitors Curcumin and PD98059.HO-1 mRNA was partially downregulated by the p38 MAPK inhibitor SB203580 while HO-1 protein secretion was notably suppressed by SB203580 and Curcumin.In summary,different MAPK signal transduction(JNK,p38 or ERK MAPK) participated into the inflammation media and cytokines production in AM of CB rats and MAPK signal transduction could modulate inflammation media expression through transduction post-transduction levels.
2.MAPK signal transduction pathway in AM of CB rats and the effect of TAL on MAPK activation.
Special inhibitors of PTK,PI3-K,Akt and PKC were used to detect correlated signal protein of MAPK before transcription in AM of CB rats.PKC,PI3K/Akt, phosphorylation were reduced after treatment with inhibitors of PTK.LY294002,the inhibitor of PI3K suppressed PI3K and Akt phosphorylation but increased p38 and JNK phosphorylation.ERK phosphorylation was decreased by Calphostin C,a inhibitor of PKC,while it had no effect of p38 and JNK phosphorylation.The LPS-induced MAPK signal pathway in AM of CB rats may be PTK-----PI3K/Akt------JNK/p38 or PTK-----PI3K-----PKC-----ERK.Further research investigated that phosphorylation of p38,JNK,ERK,PKC and Akt but not PI3K was decreased by TAL.TLR4 receptor expression in AM of CB rats was highly increased while TAL could not effect on its production.In summary,action of TAL on MAPK in AM may be happened on certain tache backward position of PI3K
3.Effect of TAL on AM apoptosis of CB rats and its probable mechanism
Effect of TAL on alveolar macrophage(AM) apoptosis and activity of chronic bronchitis(CB) rats was investigated.MTT method was used to detect the AM activity and the apoptosis rate of AM was observed by flow cytometry:FITC-Annexin V/PI double staining.To further investigate the underlying mechanism,expressions of Bax and Bcl-2 protein were examined.The number and activity of AM in CB rats was increased than that of normal group(P＜0.01).The apoptotic rate of AM in CB group was much lower than the control group[(13.93±3.34)%vs(5.37±1.38)%](P＜0.01). ERK inhibitor PD98059 induced the apoptosis of cultured AM while JNK inhibitor Curcumin reduced the apoptosis.TAL could decrease activity and increase apoptosis of AM in CB rats witch might be related to its therapy effect of CB.ERK and p38MAPK signal transduction participate in the apoptosis of AM.Further investigation showed that Bcl-2 protein expression and cytosolic calcium concentration was significantly increased while Bax evidently decreased in AM of CB rats.TAL could significantly decrease Bcl-2 expression and increase Bax protein expression,decrease cytosolic calcium concentration in AM of CB rats,which might be mechanism of its effect.
目前对慢性支气管炎的治疗主要着眼于抗炎、镇咳、平喘作用的研究,至今尚无令人十分满意的药物。而对于改善机体免疫功能状态的免疫调节药物,尤其是具有免疫调节作用的中药的研究还没有引起足够的重视。本课题组前期在国家自然科学基金的资助下(NO∶30371766)证实枇杷叶的有效活性部位为三萜酸。枇杷叶三萜酸(Triterpene Acids of Loquat Leaf,TAL)具有明显的抗炎及免疫调节作用,对慢支具有防治作用。
鉴于慢性支气管炎免疫功能紊乱的病理机制和枇杷叶三萜酸(Triterpeneacids of Loquat.Leaf,TAL)高效、低毒的作用特征,基于AM在慢支发病中的重要作用,本实验以肺泡巨噬细胞(AM)为研究靶点,探讨TAL对慢性支气管炎防治作用的细胞分子机制,为将其开发为治疗慢支的新药提供试验依据。前期研究表明TAL灌胃给药可明显降低慢支大鼠肺组织匀浆中TNF-α、IL-8水平,升高IL-10的表达,并对慢支大鼠气道粘膜上皮细胞NF-κB、ICAM-1的蛋白表达具有一定的抑制作用。TAL能明显抑制慢支大鼠AM自由基的产生;抑制炎症介质PGE_2及LTB_4的合成及释放;抑制AM中iNOS的表达及NO的合成;此外通过抑制NF-κB表达及活化,降低AM中TNF-α、IL-1的表达和分泌。TAL既能抑制AM细胞因子(TNF-α、IL-8、IL-1)炎症介质(PGE_2、LTB_4)的表达又明显抑制AM自由基、iNOS的合成。但AM是如何被激活的以及炎性介质的生成与释放机制—即基因的转录和翻译是如何调控的目前还不明了。因此进一步研究AM等细胞激活的分子机制是CB发病机制研究的主要方向。鉴于MAPK信号传导通路在炎症反应中的重要作用,本课题旨在前期研究的基础上,以AM为平台,MAPK信号通路为研究对象,研究慢支大鼠AM MAPK信号传导通路,探讨TAL对其信号传导通路的影响,研究TAL对慢支大鼠AM凋亡的影响,从而进一步阐明TAL对慢性支气管炎防治作用的细胞分子机制,为将其开发为治疗慢支的新药提供试验依据。课题为国家自然科学基金资助项目(NO∶30572355)。主要研究内容包括以下三个方面:
1.慢支模型大鼠肺泡巨噬细胞细胞因子、炎症介质的MAPK信号通路研究
MAPK三条通路的特异性阻制剂均能显著抑制慢支模型大鼠AM异常增加的IL-1、TNF-α活性,而JNK,ERK MAPK通路的特异性阻制剂Curcumin,PD98059能显著抑制慢支模型大鼠AM异常增加的PGE_2活性(P＜0.01)。JNK,ERK MAPK通路的特异性阻制剂可显著抑制CB大鼠AM内COX-2 mRNA及蛋白表达(P＜0.01 or P＜0.05)。p38 MAPK通路的特异性阻制剂SB203580体外给药可显著抑制CB大鼠AM内HO-1mRNA表达而p38,JNK MAPK通路的特异性阻制剂SB203580及Curcumin可显著抑制CB大鼠AM内HO-1蛋白表达(P＜0.01or P＜0.05)。MAPK三条信号传导通路阻制剂体外给药均可显著抑制CB大鼠AM内TNF-αmRNA表达,而JNK,p38 MAPK通路的特异性阻制剂Curcumin,SB203580可显著抑制CB大鼠AM内TNF-α蛋白表达(P＜0.05)。提示慢支大鼠AM中细胞因子、炎症介质(COX-2、TNF-α、HO-1、IL-1、PGE_2)的表达及活性分别由不同的MAPK信号传导通路介导。MAPK信号传导通路可分别从转录水平及转录后水平对其表达进行调节。
2.慢支大鼠肺泡巨噬细胞内MAPK信号传导通路及TAL的作用环节研究
分别应用MAPK通路上游信号蛋白(PTK、P13K、Akt、PKC)的特异性阻制剂预处理AM,观察下游蛋白磷酸化水平,以确定转录前调节相关信号蛋白。结果显示:Genistein可以不同程度的抑制PKC、PI3K/Akt、MAPK通路磷酸化的程度;LY294002可以抑制PI3K/Akt磷酸化的水平,同时诱导p-p38、p-JNK的高表达,对PKC/ERK这条经典途径的磷酸化也有一定的激活作用;CalphostinC阻断PKC的磷酸化,对P-ERK水平有较大影响,而对p-p38和p-JNK则影响不大。推出慢支模型大鼠AM中LPS信号转导MAPK通路可能为PTK-----PI3K/Akt------JNK/P38或者PTK-----PI3K-----PKC-----ERK。进一步探讨了TAL对MAPK通路的转录前信号蛋白的作用环节。发现TAL对p-p38,p-JNK,p-ERK,p-PKC,p-Akt皆有一定抑制作用(其中对p38和JNK磷酸化水平的抑滞效应最为显著),而对p-PI3K,其作用不甚明显,同时,TAL对模型组TLR4受体水平的增高也没有明显的降低作用。也就证明TAL对MAPK调控可能发生在PI3K下游某个环节,具体机制还有待研究。
3.TAL对慢支模型大鼠肺泡巨噬细胞凋亡的影响及其可能的作用机制研究
与正常组比较,模型大鼠AM凋亡率明显降低(P＜0.01);与模型组比较,TAL给药组及ERK通路抑制剂PD98059组AM凋亡率显著升高(P＜0.05 orP＜0.01)。而JNK通路抑制剂Curcumin组AM凋亡率显著降低(P＜0.05)。进一步研究显示,模型大鼠AM Bax表达降低而Bel-2表达升高(P＜0.01);TAL给药组可显著升高慢支大鼠AM Bcl-2表达而降低Bax表达(P＜0.05 or P＜0.01)。TAL抑制慢支大鼠AM胞浆内游离钙浓度升高,可使慢支大鼠AM激活数量减少。TAL能明显诱导AM的凋亡,降低AM的活性,使AM的数量减少,活性降低,从而发挥防治慢支的作用。MAPK通路参与细胞凋亡的调节,其中ERK通路可能抑制细胞凋亡而JNK通路发挥促凋亡的作用。TAL对慢支大鼠AM的促凋亡作用可能与其调节AM Bcl-2/Bax的表达,调节慢支大鼠AM游离钙胞内分布及影响AM MAPK通路的活化有关。
Chronic bronchitis(CB) is a common and preventable disease that has implications for global health.It is a complicated pathophysiological process,including calcium overload,free radical production,metabolic abnormalities,and inflammatory reaction,etc.Regulation disorder of neuroendocrine-immuno-function is one of the important techniques for chronic bronchitis therapy.
As a major effector of the innate immune system of the body,alveolar macrophage (AM) interact with other cells in airways and alveoli immediately after birth,resulting in generation of intracellular signaling cascades,leading to various effects or functions that make up the initial immune response in the lungs.Interaction of AM and lipopolysaccharides(LPS) causes a sequential activation production of both proand anti-inflammatory mediator in the lungs.
Traditionally,the leaf of Eriobotrya japonica(Thunb.)Lindl has a long history of medicinal use in South-east Asia in a variety of inflammatory conditions especially CB therapy.According to our previous study,the triterpene acids extracted from Eriobotrya japonica(Thunb.)Lindl Leaf was the effective component and had therapy effect on chronic bronchitis.TAL could suppress the LPS-induced inflammatory response through inhibiting the production of NF-κB,TNF-α,IL-1,iNOS expression increase IL-10 expression from alveolar macrophage in CB rats,affect the oxide and anti-oxide balance so as to protect the lung from oxidative damage,decrease the inflammation media such as PGE_2 and LTB_4 production.The signal transduction of inflammation media in AM of CB remains unclear.
The anti-inflammatory mechanisms of Triterpene Acids of Loquat.Leaf(TAL) in chronic bronchitis were studied by using the method in vivo and in vitro.Owing to the importance of AM in the processor of chronic bronchitis,effects of TAL on AM functions were investigated.Since Mitogen-activated protein kinases(MAPKs) are crucial for maintenance of cells in many signaling pathways operant in a variety of stress responses especially in inflammation process MAPK signal transduction pathway of inflammation media and cytokines production in AM of CB rats was studied.Furthermore the effect of TAL on the pathway was also investigated.The main contents are divided into some sections as follows:
1.MAPK signal transdnction pathway of inflammation media and cytokines production in AM of CB rats
The inhibitors of JNK,p38 or ERK MAPK suppressed IL-1 and TNF-αactivity and mRNA expression while JNK,p38 MAPK inhibitors suppressed TNF-αprotein expression.PGE_2 synthesis from AM of CB rats was suppressed by PD98059 and Curcumin.COX-2 mRNA and protein expression were partially downregulated by the JNK and ERK MAPK inhibitors Curcumin and PD98059.HO-1 mRNA was partially downregulated by the p38 MAPK inhibitor SB203580 while HO-1 protein secretion was notably suppressed by SB203580 and Curcumin.In summary,different MAPK signal transduction(JNK,p38 or ERK MAPK) participated into the inflammation media and cytokines production in AM of CB rats and MAPK signal transduction could modulate inflammation media expression through transduction post-transduction levels.
2.MAPK signal transduction pathway in AM of CB rats and the effect of TAL on MAPK activation.
Special inhibitors of PTK,PI3-K,Akt and PKC were used to detect correlated signal protein of MAPK before transcription in AM of CB rats.PKC,PI3K/Akt, phosphorylation were reduced after treatment with inhibitors of PTK.LY294002,the inhibitor of PI3K suppressed PI3K and Akt phosphorylation but increased p38 and JNK phosphorylation.ERK phosphorylation was decreased by Calphostin C,a inhibitor of PKC,while it had no effect of p38 and JNK phosphorylation.The LPS-induced MAPK signal pathway in AM of CB rats may be PTK-----PI3K/Akt------JNK/p38 or PTK-----PI3K-----PKC-----ERK.Further research investigated that phosphorylation of p38,JNK,ERK,PKC and Akt but not PI3K was decreased by TAL.TLR4 receptor expression in AM of CB rats was highly increased while TAL could not effect on its production.In summary,action of TAL on MAPK in AM may be happened on certain tache backward position of PI3K
3.Effect of TAL on AM apoptosis of CB rats and its probable mechanism
Effect of TAL on alveolar macrophage(AM) apoptosis and activity of chronic bronchitis(CB) rats was investigated.MTT method was used to detect the AM activity and the apoptosis rate of AM was observed by flow cytometry:FITC-Annexin V/PI double staining.To further investigate the underlying mechanism,expressions of Bax and Bcl-2 protein were examined.The number and activity of AM in CB rats was increased than that of normal group(P＜0.01).The apoptotic rate of AM in CB group was much lower than the control group[(13.93±3.34)%vs(5.37±1.38)%](P＜0.01). ERK inhibitor PD98059 induced the apoptosis of cultured AM while JNK inhibitor Curcumin reduced the apoptosis.TAL could decrease activity and increase apoptosis of AM in CB rats witch might be related to its therapy effect of CB.ERK and p38MAPK signal transduction participate in the apoptosis of AM.Further investigation showed that Bcl-2 protein expression and cytosolic calcium concentration was significantly increased while Bax evidently decreased in AM of CB rats.TAL could significantly decrease Bcl-2 expression and increase Bax protein expression,decrease cytosolic calcium concentration in AM of CB rats,which might be mechanism of its effect.
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