哮喘患儿环磷酸腺苷/环磷酸鸟苷平衡的研究及环磷酸腺苷葡甲胺对其的调节作用
摘要
目的:哮喘(asthma)是由多种细胞如嗜酸性细胞、肥大细胞、T淋巴细胞、中性粒细胞以及气道上皮细胞等和细胞组分共同参与的气道慢性炎症性疾患。这些细胞相互作用,活化并分泌多种细胞因子导致粘膜上皮损伤和气道高反应性。目前,在哮喘发病机制、病情批评及治疗效果研究中,对cAMP与cGMP平衡失调越发关注。支气管平滑肌维持正常的稳定张力状态有赖于细胞膜上受体的正常功能及胞内的2个第二信使—cAMP与cGMP平衡。cAMP起到扩张支气管作用,cGMP引起气道平滑肌收缩,导致肥大细胞(嗜碱性粒细胞)脱颗粒,加速炎症介质的释放而诱发哮喘。故任何减少细胞内cAMP和(或)增加cGMP原因均可诱发支气管平滑肌痉挛和哮喘。由于支气管舒缩效应主要依赖于cAMP和cGMP均衡,单靠某一项判断哮喘发病不够全面,应用cAMP/cGMP比值变化可作为监测和指导哮喘患儿的疗效和评价哮喘药物疗效的较好生化指标,具有一定临床意义。
环磷酸腺苷葡甲胺(MCA,心先安)是cAMP新的衍生物,它通过增强cAMP脂溶性渗透进入细胞,直接增加细胞内cAMP浓度,cAMP可稳定细胞膜,抑制炎性介质的释放及减轻支气管粘膜出血水肿,舒张平滑肌作用。因此,通过对环磷酸腺苷葡甲胺进行一系列研究与临床观察,发现其在哮喘治疗中对cAMP和cGMP平衡具有极其重要调节意义。这将有助于进一步阐明哮喘的病因,并为该病的治疗提供新的理论根据和途径。
方法:①患儿组:依据全国儿童哮喘防治协作组制定标准,选自2006年10月～2007年4月在我院诊治的哮喘急性期患儿41例,男24例,女17例;年龄2岁～6岁。采血前2周内均未曾使用过糖皮质激素及免疫增强或抑制剂药物。入院后立即取血检测血浆cAMP、cGMP水平及cAMP/cGMP比值。其中22例为常规治疗组,经糖皮质激素及支气管扩张剂治疗,临床症状缓解后取晨血复查上述各项检测指标。其余19例哮喘患儿为心先安治疗组,经糖皮质激素、支气管扩张剂治疗及接受环磷酸腺苷葡甲胺静点治疗(每次2.5～5mg/Kg,每日1～2次,连续7天),临床症状缓解后取晨血复查上述各项检测指标。②正常对照组24例,男13例,女11例;年龄2～6岁;为本科门诊健康儿童,无过敏史、寄生虫感染史、喘息病史及慢性呼吸道疾病。③应用放射免疫分析法(radioimmunoasssay,RIA)测定心先安治疗组,常规治疗组及正常对照组患儿外周血浆cAMP、cGMP水平表达情况。心先安治疗组,常规治疗组及正常对照组患儿均于清晨空腹状态下抽取静脉血1ml,注入预冷的含50μl 10%草酸钠(DETA-2Na)的试管中,充分混匀后于4℃下离心20min,吸取血浆后置-20℃冰箱内保存待测cAMP、cGMP。采用上海市第二中医学院同位素研究所提供的放射免疫分析盒,严格按说明书操作;用北京医用离心机厂提供的LDR4-8.4℃低温离心机进行分离;测量仪器采用西安二六二厂生产的EJ-2003型全自动6-免疫计数器。
统计学处理:应用SAS6.0软件包,两样本均数间比较采用t-test程序进行t检验,全部数据以(?)±s表示,两样本间率的比较采用x~2的Fisher精确概率,P＜0.05为差异有统计学意义。
结果:①哮喘患儿急性期外周血浆cGMP水平高于缓解期和正常组(P＜0.05);②哮喘患儿急性期外周血浆cAMP水平低于缓解期和正常组(P＜0.05);③哮喘患儿急性期外周血浆cAMP/cGMP水平低于缓解期和正常组(P＜0.05);④给予环磷酸腺苷葡甲胺治疗的哮喘患儿外周血浆cAMP水平高于常规治疗组(P＜0.05);⑤给予环磷酸腺苷葡甲胺治疗的哮喘患儿外周血浆cGMP水平低于常规治疗组(P＜0.05);⑥给予环磷酸腺苷葡甲胺治疗的哮喘患儿急性期外周血浆cAMP/cGMP水平高于常规治疗组(P＜0.05)。
结论:①哮喘患儿cGMP表达亢进,cAMP表达不足;②哮喘患儿cAMP/cGMP平衡失调,可作为监测和指导哮喘治疗的生化指标;③哮喘患儿给予环磷酸腺苷葡甲胺治疗能够纠正cAMP/cGMP失衡,有较好的治疗效果。
Objective.Asthma is viewed as a chronic inflammatory disease of the airway, which is common in childhood.Many inflammatory cells,such as eosinophil,mast cell,T lymphocyte,neutrophil and their ingredients are involved in it.These cells interact activate and secret various cytokines,thus cause the injury of mucosal epithelium and high bronchial reaction.Nowadays,studies are still undergoing on mechanism,evulation and therapeutic effect of asthma and more attention are paid to the imbalance of cAMP/cGMP system.As is known that to keep the stable strain state depends on the functional receptors of the cellular membrane and two intracellular second messages named cAMP and cGMP.cAMP serves as bronchial expander, while cGMP goes the contrary,with releasing granules of mast cell and inflammatory mediators.So spasm of bronchial smooth muscle and asthma can be induced by the decrease of cAMP or/and elevated level of cGMP.The ratio of cAMP/cGMP is perhaps a desired biochemical target for monitoring and directing administration to children with asthma and evulating therapeutic effects of medication.
Meglumine adenosine cyclophosphate is a new derivant from cAMP.It translocates into the cell by enhancing fat-soluble infiltration of cAMP,and up-regulates the concentration of intracellular cAMP.cAMP helps to stabilize cellular membrane,inhibit the excretion of inflammatory mediators,reduces the edema and hemorrhage of bronchial mucosa,and relaxes smooth muscles.Therefore,researches and clinical observation on the regulatory significance of meglumine adenosine cyclophosphate for cAMP/cGMP system may contribute to set forth the etiology of asthma and provide new theoretical basis and way for clinical treatment.
Methods.The level of cAMP/cGMP in peripheral plasma of 22 children with asthma,both in acute stage and catabasis is detected by specific radioimmunoassay.Meanwhile 24 sex and age matched healthy children serve as the control.For those 19 children with meglumine adenosine cyclophosphate taken(5～10mg/Kg.d,for continuous 7 days)and 22 control patients receiving required treatment,peripherial plasma is gathered for the measurement of cAMP/cGMP.From all the children,1ml venous blood is extracted in the morning limosis,put into prefrozen tubes containing 50μl EDTA(10%),mixed abubdantly,centrifuged for 20 minutes under 4℃,and plasma is dripped and stroed under 20℃below zero for use.Radio-immunoassay kit from isotope institute of Shanghai second Chinese medical university is adopted and operated according to the instruction.Low-temperature centrifuge of LDR4—8.4℃type from Beijing medical centrifuge factory and EJ-2003 type full-automatic immune arithmometer from Xi'an 262 factroy are also introduced.
Data analysis.All data are expressed as mean±standard deviation(SD). Significant differences between two groups are estimated by student's t-test andχ~2 test(Chi-square test)for categorical variable at specific time points.A P value of less than 0.05 indicates statistical significance.The SAS Version 6.0 program is used for all statistical calculations.
Results- The level of cGMP of peripheral plasma in children with asthma of acute stage is significantly higher than that of the catabasis and the control(both P＜0.05),while the level of plasma cAMP lower(P＜0.05).The ratio of cAMP/cGMP in peripheral plasma of children with asthma of acute stage is statistically different form that of the catabasis and the control(both P＜0.05). With meglumine adenosine cyclophosphate administrated in the acute stage, elevated plasma level of cAMP and the ratio of cAMP/cGMP is detected,and decreased cGMP as well(P＜0.05).
Conclusions.overexpression of plasma cGMP and insufficiency of cAMP consist in children with asthma,and the ratiop of cAMP/cGMP can serve as a biochemical target for monitoring and directing the treatment of asthma.Meglumine adenosine cyclophosphate medication is beneficient for the balance of cAMP/cGMP and the control of asthma.
环磷酸腺苷葡甲胺(MCA,心先安)是cAMP新的衍生物,它通过增强cAMP脂溶性渗透进入细胞,直接增加细胞内cAMP浓度,cAMP可稳定细胞膜,抑制炎性介质的释放及减轻支气管粘膜出血水肿,舒张平滑肌作用。因此,通过对环磷酸腺苷葡甲胺进行一系列研究与临床观察,发现其在哮喘治疗中对cAMP和cGMP平衡具有极其重要调节意义。这将有助于进一步阐明哮喘的病因,并为该病的治疗提供新的理论根据和途径。
方法:①患儿组:依据全国儿童哮喘防治协作组制定标准,选自2006年10月～2007年4月在我院诊治的哮喘急性期患儿41例,男24例,女17例;年龄2岁～6岁。采血前2周内均未曾使用过糖皮质激素及免疫增强或抑制剂药物。入院后立即取血检测血浆cAMP、cGMP水平及cAMP/cGMP比值。其中22例为常规治疗组,经糖皮质激素及支气管扩张剂治疗,临床症状缓解后取晨血复查上述各项检测指标。其余19例哮喘患儿为心先安治疗组,经糖皮质激素、支气管扩张剂治疗及接受环磷酸腺苷葡甲胺静点治疗(每次2.5～5mg/Kg,每日1～2次,连续7天),临床症状缓解后取晨血复查上述各项检测指标。②正常对照组24例,男13例,女11例;年龄2～6岁;为本科门诊健康儿童,无过敏史、寄生虫感染史、喘息病史及慢性呼吸道疾病。③应用放射免疫分析法(radioimmunoasssay,RIA)测定心先安治疗组,常规治疗组及正常对照组患儿外周血浆cAMP、cGMP水平表达情况。心先安治疗组,常规治疗组及正常对照组患儿均于清晨空腹状态下抽取静脉血1ml,注入预冷的含50μl 10%草酸钠(DETA-2Na)的试管中,充分混匀后于4℃下离心20min,吸取血浆后置-20℃冰箱内保存待测cAMP、cGMP。采用上海市第二中医学院同位素研究所提供的放射免疫分析盒,严格按说明书操作;用北京医用离心机厂提供的LDR4-8.4℃低温离心机进行分离;测量仪器采用西安二六二厂生产的EJ-2003型全自动6-免疫计数器。
统计学处理:应用SAS6.0软件包,两样本均数间比较采用t-test程序进行t检验,全部数据以(?)±s表示,两样本间率的比较采用x~2的Fisher精确概率,P＜0.05为差异有统计学意义。
结果:①哮喘患儿急性期外周血浆cGMP水平高于缓解期和正常组(P＜0.05);②哮喘患儿急性期外周血浆cAMP水平低于缓解期和正常组(P＜0.05);③哮喘患儿急性期外周血浆cAMP/cGMP水平低于缓解期和正常组(P＜0.05);④给予环磷酸腺苷葡甲胺治疗的哮喘患儿外周血浆cAMP水平高于常规治疗组(P＜0.05);⑤给予环磷酸腺苷葡甲胺治疗的哮喘患儿外周血浆cGMP水平低于常规治疗组(P＜0.05);⑥给予环磷酸腺苷葡甲胺治疗的哮喘患儿急性期外周血浆cAMP/cGMP水平高于常规治疗组(P＜0.05)。
结论:①哮喘患儿cGMP表达亢进,cAMP表达不足;②哮喘患儿cAMP/cGMP平衡失调,可作为监测和指导哮喘治疗的生化指标;③哮喘患儿给予环磷酸腺苷葡甲胺治疗能够纠正cAMP/cGMP失衡,有较好的治疗效果。
Objective.Asthma is viewed as a chronic inflammatory disease of the airway, which is common in childhood.Many inflammatory cells,such as eosinophil,mast cell,T lymphocyte,neutrophil and their ingredients are involved in it.These cells interact activate and secret various cytokines,thus cause the injury of mucosal epithelium and high bronchial reaction.Nowadays,studies are still undergoing on mechanism,evulation and therapeutic effect of asthma and more attention are paid to the imbalance of cAMP/cGMP system.As is known that to keep the stable strain state depends on the functional receptors of the cellular membrane and two intracellular second messages named cAMP and cGMP.cAMP serves as bronchial expander, while cGMP goes the contrary,with releasing granules of mast cell and inflammatory mediators.So spasm of bronchial smooth muscle and asthma can be induced by the decrease of cAMP or/and elevated level of cGMP.The ratio of cAMP/cGMP is perhaps a desired biochemical target for monitoring and directing administration to children with asthma and evulating therapeutic effects of medication.
Meglumine adenosine cyclophosphate is a new derivant from cAMP.It translocates into the cell by enhancing fat-soluble infiltration of cAMP,and up-regulates the concentration of intracellular cAMP.cAMP helps to stabilize cellular membrane,inhibit the excretion of inflammatory mediators,reduces the edema and hemorrhage of bronchial mucosa,and relaxes smooth muscles.Therefore,researches and clinical observation on the regulatory significance of meglumine adenosine cyclophosphate for cAMP/cGMP system may contribute to set forth the etiology of asthma and provide new theoretical basis and way for clinical treatment.
Methods.The level of cAMP/cGMP in peripheral plasma of 22 children with asthma,both in acute stage and catabasis is detected by specific radioimmunoassay.Meanwhile 24 sex and age matched healthy children serve as the control.For those 19 children with meglumine adenosine cyclophosphate taken(5～10mg/Kg.d,for continuous 7 days)and 22 control patients receiving required treatment,peripherial plasma is gathered for the measurement of cAMP/cGMP.From all the children,1ml venous blood is extracted in the morning limosis,put into prefrozen tubes containing 50μl EDTA(10%),mixed abubdantly,centrifuged for 20 minutes under 4℃,and plasma is dripped and stroed under 20℃below zero for use.Radio-immunoassay kit from isotope institute of Shanghai second Chinese medical university is adopted and operated according to the instruction.Low-temperature centrifuge of LDR4—8.4℃type from Beijing medical centrifuge factory and EJ-2003 type full-automatic immune arithmometer from Xi'an 262 factroy are also introduced.
Data analysis.All data are expressed as mean±standard deviation(SD). Significant differences between two groups are estimated by student's t-test andχ~2 test(Chi-square test)for categorical variable at specific time points.A P value of less than 0.05 indicates statistical significance.The SAS Version 6.0 program is used for all statistical calculations.
Results- The level of cGMP of peripheral plasma in children with asthma of acute stage is significantly higher than that of the catabasis and the control(both P＜0.05),while the level of plasma cAMP lower(P＜0.05).The ratio of cAMP/cGMP in peripheral plasma of children with asthma of acute stage is statistically different form that of the catabasis and the control(both P＜0.05). With meglumine adenosine cyclophosphate administrated in the acute stage, elevated plasma level of cAMP and the ratio of cAMP/cGMP is detected,and decreased cGMP as well(P＜0.05).
Conclusions.overexpression of plasma cGMP and insufficiency of cAMP consist in children with asthma,and the ratiop of cAMP/cGMP can serve as a biochemical target for monitoring and directing the treatment of asthma.Meglumine adenosine cyclophosphate medication is beneficient for the balance of cAMP/cGMP and the control of asthma.
引文
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[1]陈育智.儿童支气管哮喘的诊断及治疗[M].北京:人民卫生出版社,2004:1-2。
[2]吴健,徐军,钟南山.BCG与变应性哮喘Th1/Th2平衡.国外医学,呼吸系统分册,2001,21(3):151-156.
[3]拉杰。 哮喘发病机理及Th1/Th2比例关系[J].天津医科大学学报,2002,8(3):403-406.
[4]KeaneMP,StrieterRM.The importance of balanced proinflammatory and anti-inflammatory mechanism in diffuse lung disease.RespirRes,2002,3(1):5.
[5]Schwede F,Maronde E,Genieser H,etal.Cyclic nucleotide analogs as biochemical tools and prospective drugs[J].Pharmacol Ther,2000,87(2-3):199-226.
[6]Ricciardolo FL.Multiple roles of nitric oxide in the airways.Thorax,2003,58(2):175-182.
[7]LaczaZ,SnipesJA,ZhangJ,etal.Mitochondrial nitric oxide synthase is not eNOS,nNOS or iNOS.FreeRadic BiolMed,2003,35(10),1217-1228.
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