哮喘大鼠肺组织中血管紧张素Ⅱ受体和β_2肾上腺素能受体表达及缬沙坦的影响
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摘要
研究背景:支气管哮喘是世界范围内患病率和死亡率很高的慢性疾病之一,变态反应、气道炎症、气道高反应性及神经等因素及其相互作用被认为与哮喘的发病关系密切。在受体方面,有关β_2-AR、M受体、糖皮质激素受体的研究很多,这些在哮喘的发病、治疗中起着不同的重要作用。近有研究显示,哮喘患者外周血液中可见AngⅡ升高,AT_1R拮抗剂有降低哮喘模型支气管肺泡灌洗液中细胞数,减轻气道反应性作用,且AT_1R拮抗剂有抑制慢性哮喘气道炎症,减轻气道阻力作用,提示AngⅡ及其受体参与了哮喘的发病。但有关哮喘中肺组织ATR的表达,ATR与其他受体之间的互相影响鲜见有报道。本文拟通过研究AT_1R拮抗剂缬沙坦对哮喘大鼠模型干预后大鼠肺组织中ATR和β_2-AR的表达变化,进一步探讨AngⅡ及其受体在慢性哮喘发病中的作用和机制。
目的:探讨哮喘大鼠肺组织中血管紧张素Ⅱ(AngⅡ)两种受体亚型(AT_1R、AT_2R)和β_2肾上腺素受体(β_2-AR)的表达及缬沙坦对两类受体的影响。
方法:将50只SPF级Wistar大鼠按随机数字法分为5组(n=10),分别为正常对照组(A组)、哮喘组(B组)、缬沙坦15mg/kg组(C_1组)、缬沙坦30mg/kg组(C_2组)、缬沙坦50mg/kg组(C_3组)。用10%鸡卵白蛋白(OVA)致敏和1%OVA激发大鼠建立哮喘模型;分别用逆转录-聚合酶链反应(RT-PCR)和Western blot法检测肺组织中ATR和β_2-AR mRNA和蛋白表达;用原位杂交法检测肺组织中ATR和β_2-AR mRNA的分布情况;用Western blot法各组肺组织中转录活化因子-3(STAT3)基因的表达。结果:①与A纽相比,B组的AT_1R阳性表达率明显增高(P＜0.05)。缬沙坦干预后,C_1、C_2、C_3组的AT_1R阳性表达率均明显下降(P均＜0.05);相关性分析提示AT_1R的表达与缬沙坦剂量呈负相关(r=-0.96)。②A组未见AT_2R表达,B组AT_2R表达明显增加。缬沙坦干预后,C_1组无AT_2R表达,C_2、C_3组AT_2R表达量低于B组(P均＜0.01)。③与A组相比,B组的β_2-AR阳性表达率明显下调(P＜0.01),缬沙坦干预后,C_1、C_2、C_3组的β_2-AR阳性表达率均明显上调(P均＜0.05)。④与A组相比,B组的STAT3阳性表达率明显增高(P＜0.05)。缬沙坦干预后,C_1、C_2、C_3组的STAT3阳性表达率均明显下降(P均＜0.05)。结论大鼠肺组织中存在血管紧张素Ⅱ受体,并在哮喘发作时被活化,可能参与哮喘发病的病理生理过程。ATR与β_2-AR的变化可能存在相关性。哮喘大鼠肺组织中AT_1R和AT_2R表达增加,β_2-AR表达下调。AT_1R拮抗剂缬沙坦能抑制AT_1R表达,上调β_2-AR表达。AngⅠ的可能作用途径之一是通过STAT3信号通路。
Background:Asthma is one of the high morbidity and mortality rate diseases over the world,aeroallergen、airway inflammation、high airway reactive、nervous factors and their interaction are highly related with the progress of asthma.As receptors,they are many research onβ_2-AR、M receptor、glucocorticoid receptor,which play an important part in the morbidity and treat of asthma.Recent research indicate that the incereased AngⅡcan be found in the peripheral blood of asthmatic patients.The antagon of AT_1R have the action of decrease the cell number in bronchoal veolar lavage fluid(BALF)and relieve airway reactive.Moreover,the antagon of AT_1R can improve airway inflammation and relieve airway resistance,which suggests AngⅡand its receptors participate the progress of asthma.However,there is few report about the expression of ATR,how ATR interaction with other receptors in the lung. By intervention on asthmatic rat samples with valsartan,this article is designed to study the expression ATR andβ_2-AR,also the action and mechanism of AngⅡand its receptors in the chronic asthma.
Objective:To investigate the expression of angiotensinⅡreceptor subtypes (AT_1R,AT_2R)andβ_2- adrenergic receptor(AR)in the lungs of asthmatic rats, and the influence of valsartan upon their expression.
Methods:Fifty Wistar rats were randomly divided into 5 groups,group A (control),group B(asthma),group C_1(Valsartan 15mg/kg),group C_2 (Valsartan 30mg/kg),group C_3(Valsartan 50mg/kg),each containing 10 subjects.The rats were sensitized by 10%ovalbumin peritoneal injection and challenged by 1%ovalbumin aerosol inhalation to establish the asthmatic model.The levels of AT_1R,AT_2R andβ_2-AR mRNA and protein in lung tissues were analyzed by reverse transcriptase-polymerase chain reaction(RT-PCR) and Western blot.
Results:①Comparing with control(group A),the expression levels of AT_1R in asthmatic subjects(group B)was significantly increased(P＜0.05). Valsartan decreased the level of AT_1R in asthmatic groups(group C_1,C_2 and C_3).A negative correlation between the expression of AT_1R and the dose of valsartan was demonstrated(r=-0.96).②There was no AT_2R expression in control(group A),while in asthmatic subjects(group B)the AT_2R expression increased markably.By the use of valsartan,the elevated level of AT_2R either could not be found(group C_1)or markedly decreased(group C_2 and C_3);③Comparing with control(group A),theβ_2-AR level in asthmatic subjects (group B)was significantly decreased(P＜0.01).By the use of valsartan,the positive expression rate ofβ_2-AR increased in group C_1、C_2 and C_3 compared with group B(P＜0.05,respectively);④Comparing with control(group A),the expression levels of STAT3 in asthmatic subjects(group B)was significantly increased(P＜0.05).Valsartan decreased the level of STAT3 in asthmatic groups(group C_1,C_2 and C_3).
Conclusions:The results suggest that angiotensinⅡreceptors(ATR)are expressed in rat lung tissues.The ATR may be activated and play a role in asthma attack.The expression and the function of ATR in the asthmatic rats lung may be related with the change ofβ_2-AR.The expression of AT_1R and AT_2R in the asthmatic rats lung were increased,whileβ_2-AR decreased. Valsartan can inhibit the expression of AT_1R and restore the expression ofβ_2-AR.One possible pathogenes of AngⅡis by STAT3 pathway.
目的:探讨哮喘大鼠肺组织中血管紧张素Ⅱ(AngⅡ)两种受体亚型(AT_1R、AT_2R)和β_2肾上腺素受体(β_2-AR)的表达及缬沙坦对两类受体的影响。
方法:将50只SPF级Wistar大鼠按随机数字法分为5组(n=10),分别为正常对照组(A组)、哮喘组(B组)、缬沙坦15mg/kg组(C_1组)、缬沙坦30mg/kg组(C_2组)、缬沙坦50mg/kg组(C_3组)。用10%鸡卵白蛋白(OVA)致敏和1%OVA激发大鼠建立哮喘模型;分别用逆转录-聚合酶链反应(RT-PCR)和Western blot法检测肺组织中ATR和β_2-AR mRNA和蛋白表达;用原位杂交法检测肺组织中ATR和β_2-AR mRNA的分布情况;用Western blot法各组肺组织中转录活化因子-3(STAT3)基因的表达。结果:①与A纽相比,B组的AT_1R阳性表达率明显增高(P＜0.05)。缬沙坦干预后,C_1、C_2、C_3组的AT_1R阳性表达率均明显下降(P均＜0.05);相关性分析提示AT_1R的表达与缬沙坦剂量呈负相关(r=-0.96)。②A组未见AT_2R表达,B组AT_2R表达明显增加。缬沙坦干预后,C_1组无AT_2R表达,C_2、C_3组AT_2R表达量低于B组(P均＜0.01)。③与A组相比,B组的β_2-AR阳性表达率明显下调(P＜0.01),缬沙坦干预后,C_1、C_2、C_3组的β_2-AR阳性表达率均明显上调(P均＜0.05)。④与A组相比,B组的STAT3阳性表达率明显增高(P＜0.05)。缬沙坦干预后,C_1、C_2、C_3组的STAT3阳性表达率均明显下降(P均＜0.05)。结论大鼠肺组织中存在血管紧张素Ⅱ受体,并在哮喘发作时被活化,可能参与哮喘发病的病理生理过程。ATR与β_2-AR的变化可能存在相关性。哮喘大鼠肺组织中AT_1R和AT_2R表达增加,β_2-AR表达下调。AT_1R拮抗剂缬沙坦能抑制AT_1R表达,上调β_2-AR表达。AngⅠ的可能作用途径之一是通过STAT3信号通路。
Background:Asthma is one of the high morbidity and mortality rate diseases over the world,aeroallergen、airway inflammation、high airway reactive、nervous factors and their interaction are highly related with the progress of asthma.As receptors,they are many research onβ_2-AR、M receptor、glucocorticoid receptor,which play an important part in the morbidity and treat of asthma.Recent research indicate that the incereased AngⅡcan be found in the peripheral blood of asthmatic patients.The antagon of AT_1R have the action of decrease the cell number in bronchoal veolar lavage fluid(BALF)and relieve airway reactive.Moreover,the antagon of AT_1R can improve airway inflammation and relieve airway resistance,which suggests AngⅡand its receptors participate the progress of asthma.However,there is few report about the expression of ATR,how ATR interaction with other receptors in the lung. By intervention on asthmatic rat samples with valsartan,this article is designed to study the expression ATR andβ_2-AR,also the action and mechanism of AngⅡand its receptors in the chronic asthma.
Objective:To investigate the expression of angiotensinⅡreceptor subtypes (AT_1R,AT_2R)andβ_2- adrenergic receptor(AR)in the lungs of asthmatic rats, and the influence of valsartan upon their expression.
Methods:Fifty Wistar rats were randomly divided into 5 groups,group A (control),group B(asthma),group C_1(Valsartan 15mg/kg),group C_2 (Valsartan 30mg/kg),group C_3(Valsartan 50mg/kg),each containing 10 subjects.The rats were sensitized by 10%ovalbumin peritoneal injection and challenged by 1%ovalbumin aerosol inhalation to establish the asthmatic model.The levels of AT_1R,AT_2R andβ_2-AR mRNA and protein in lung tissues were analyzed by reverse transcriptase-polymerase chain reaction(RT-PCR) and Western blot.
Results:①Comparing with control(group A),the expression levels of AT_1R in asthmatic subjects(group B)was significantly increased(P＜0.05). Valsartan decreased the level of AT_1R in asthmatic groups(group C_1,C_2 and C_3).A negative correlation between the expression of AT_1R and the dose of valsartan was demonstrated(r=-0.96).②There was no AT_2R expression in control(group A),while in asthmatic subjects(group B)the AT_2R expression increased markably.By the use of valsartan,the elevated level of AT_2R either could not be found(group C_1)or markedly decreased(group C_2 and C_3);③Comparing with control(group A),theβ_2-AR level in asthmatic subjects (group B)was significantly decreased(P＜0.01).By the use of valsartan,the positive expression rate ofβ_2-AR increased in group C_1、C_2 and C_3 compared with group B(P＜0.05,respectively);④Comparing with control(group A),the expression levels of STAT3 in asthmatic subjects(group B)was significantly increased(P＜0.05).Valsartan decreased the level of STAT3 in asthmatic groups(group C_1,C_2 and C_3).
Conclusions:The results suggest that angiotensinⅡreceptors(ATR)are expressed in rat lung tissues.The ATR may be activated and play a role in asthma attack.The expression and the function of ATR in the asthmatic rats lung may be related with the change ofβ_2-AR.The expression of AT_1R and AT_2R in the asthmatic rats lung were increased,whileβ_2-AR decreased. Valsartan can inhibit the expression of AT_1R and restore the expression ofβ_2-AR.One possible pathogenes of AngⅡis by STAT3 pathway.
引文
1.Millar EA,Angus RM,Hulks G,et al.Activity of the renin-angiotensin system in acute severe asthma and the effect ofangiotensin Ⅱ on lung function[J].Thorax,1994,49:492-495
2.刘扣英,王彤,张希龙,等.缬沙坦对哮喘大鼠气道炎症及气道反应性的影响[J].2006,26:1021-1024
3.Kaschina E,Unger T.Angiotmsin AT1/AT2 receptors:regulation and function[J].Blood Press,2003,12(2):70-88
4.Ming M,Wu J,Lachance S,et al.Beta-adrenergic receptors and angiotensinogen gene expression in mouse hepatoma cells in vitro[J].Hypertension.1995 Jan;25(1):105-9
5.Henegar JR,Schwartz DD,Janicki JS.ANG Ⅱ-related myocardial damage:role of cardiac sympathetic catecholamines and beta-receptor regulation[J].Am J Physiol,1998,275:534-541
6.马秀琴,黄茂,卞涛,等.地塞米松对哮喘大鼠肺组织NF-KB和MMP-9及TIMP-1表达的影响[J].南京医科大学学报,2005,25:255-261
7.Matsusaka T,Ichikawa I.Biological functions of angiotensin and its receptors[J].Annu Rev Physiol,1997,59:395-412
8.Bumier M.Angiotensin Ⅱ type 1 receptor blockers[J].Circulation.2001,103:904-912
9.Weir TD,Mallek N,Sandford AJ,et al.β2-Adrenergic receptor haplotypes in mild,moderate and fatal/near fatal asthma[J].Am J Respir Crit Care Med,1998,158:787-791
10.高海鹏,薛全福,林友华,等.支气管哮喘发病中β2AR mRNA水平变化的初步探讨[J].中国病理生理杂志,1999,15:525-527
11.李艳芳,张利,郑秋甫.心脏血管紧张素Ⅱ受体与β肾上腺素受体相关的调节特点[J].中国循环杂志,1999,14:252
12.Shinichi Okuda,Masafumi Yano,Masahiro Doi,et al.Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure[J].Circulation,2004;109;911-919
13.Makino T,Hattori Y,Matsuda N,et al.Effects of angiotensin-converting enzyme inhibition and angiotensin Ⅱ type 1 receptor blockade on β-adrenoceptor signaling in heart failure produced by myocardial Infarction in rabbits:reversal of altered expression of β-adrenoceptor kinase and G_(ia)[J].J PharmacoI Exp Ther,2003,304:370-379
14.Myou S,Fujimura M,Kurashima K,et al.Type 1 Angiotensin Ⅱ Receptor Antagonism Reduces Antigen-induced Airway Reactions[J].Am J Respir Crit Care Med,2000,162:45-49
15.Barki-Harrington L,Luttrell LM,Rockman HA.Dual Inhibition of β-Adrenergic and Angiotensin Ⅱ Receptors by a Single Antagonist:A Functional Role for Receptor-Receptor Interaction In Vivo[J].Circulation,2003,108:1611-1618
16.Goodfriend TL,Elliott ME,catt KJ,et al.Angiotensin receptors and Their antagonists[J]. N Engl J Med, 1996, 334:1649-1654
17. Levy BI, Benessiano J, Henrion D, et al. Chronic Blockade of AT2-subtype Receptors Prevents the Effect of Angiotensin II on the Rat Vascular Structure [J]. The J Clin Invest, 1996, 98:418-425.
18. AbdAlla S, Lother H, Abdel-tawab AM, et al. The Angiotensin II AT2 Receptor is an AT1 Receptor Antagonist [J]. J Biol Chem,2001,276: 39721-39726
19. BrombergJF,Wrzeszczynska MH,Devan G,etal. Stat3 as an oncogene [J] .Cell,1999,98 (3) : 295-303
20. Darnell JE.STATs and gene regulation [J] .Science, 1997,277 (5332) : 1630-1635
21. David M, Petricoin E,Benjamin C, etal. Requirement for MAP Kinase (ERK2) activity in interferon alpha and interferon beta stimulated gene expression through STAT proteins [J]. Science, 1995, 269:1721-1723
22. Seebach F A, Walte T, Fu X Y, etal. Differential activation of The STAT pathway by angiotensin II via angiotensin type 1 and type 2 receptors in cultured human fetal mesangial cells[J].Exp MolPathol, 2001, 70:265-273
23. Nishiyama A, Yoshizumi M, Rahman M, etal. Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats [J]. Kidney Int, 2004, 65:972-981
24. Zhou L, Hershenson MB. Mitogenic signaling pathways in airway smooth muscle. Respir Physiol Neurobiol. 2003;137(2-3):295-308
1.Millar EA,Angus RM,Hulks G,et al.Activity of the renin-angiotensin system in acute severe asthma and the effect of angiotensin Ⅱ on lung function[J].Thorax,1994,49:492-495.
2.刘扣英,王彤,张希龙,等.缬沙坦对哮喘大鼠气道炎症及气道反应性的影响[J].2006,26:1021-1024.
3.马秀琴,黄茂,卞涛,等.地塞米松对哮喘大鼠肺组织NF-KB和MMP-9及TIMP-1表达的影响[J].南京医科大学学报,2005,25:255-261.
4.Matsusaka T,Ichikawa I.Biological functions of angiotensin and its receptors[J].Annu Rev Physiol,1997,59:395-412.
5.Burnier M.Angiotensin Ⅱ type 1 receptor blockers[J].Circulation.2001,103:904-912.
6.Weir TD,Mallek N,Sandford AJ,et al.β2-Adrenergic receptor haplotypes in mild,moderate and fatal/near fatal asthma[J].Am J Respir Crit Care Med,1998,158:787-791.
7.高海鹏,薛全福,林友华,等.支气管哮喘发病中β2AR mRNA水平变化的初步探讨[J].中国病理生理杂志,1999,15:525-527.
8.李艳芳,张利,郑秋甫.心脏血管紧张素Ⅱ受体与β肾上腺素受体相关的调节特点[J].中国循环杂志,1999,14:252.
9.Shinichi Okuda,Masafumi Yano,Masahiro Doi,et al.Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure[J].CirCulation,2004; 109; 911-919.
10. Makino T, Hattori Y, Matsuda N,et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on β-adrenoceptor signaling in heart failure produced by myocardial Infarction in rabbits: reversal of altered expression of β-adrenoceptor kinase and G_(ia)[J]. J Pharmacol Exp Ther, 2003, 304:370-379.
11. Myou S, Fujimura M, Kurashima K, et al. Type 1 Angiotensin II Receptor Antagonism Reduces Antigen-induced Airway Reactions [J]. Am J Respir Crit Care Med, 2000, 162:45-49.
12. Barki-Harrington L, Luttrell LM, Rockman HA. Dual Inhibition of β-Adrenergic and Angiotensin II Receptors by a Single Antagonist: A Functional Role for Receptor-Receptor Interaction In Vivo [J]. Circulation, 2003,108: 1611-1618.
13. Goodfriend TL,Elliott ME, catt KJ, et al. Angiotensin receptors and Their antagonists[J]. N Engl J Med, 1996, 334:1649-1654.
14. Levy BI, Benessiano J, Henrion D, et al. Chronic Blockade of AT2-subtype Receptors Prevents the Effect of Angiotensin II on the Rat Vascular Structure [J]. The J Clin Invest, 1996,98:418-425.
15. AbdAlla S, Lother H, Abdel-tawab AM, et al. The Angiotensin II AT2 Receptor is an AT1 Receptor Antagonist [J]. J Biol Chem, 2001, 276: 39721-39726.
1. Dvir H, Harel M, Bon S, et al. The synaptic acetyl cholinesterase tetramer assembles around a polyproline II helix. EMBO Journal,2004;23:4394-4405.
2. Radhika Kajekar, Bradley J.Undem, Allen C.Myers. Role of cyclooxygenase active-tion and prostaglandins in antigen-induced excitability changes of bronchial pa-rasympathetic ganglia neurons. Am J Physiol Lung Cell Mol Physiol,2003;284: 581-587.
3. Shenoy SK, McDonald PH, Kohout TA, et al. Regulation of receptor fate by ubiquitination of activatedβ2-adrenergic receptor and β-arrestin. Science, 2001;294:1307-1313.
4. Benovic JL. Novel β_2-adrenergic receptor signaling pathways. J Allergy Clin Immunol,2002;110: 229-235.
5. McGraw DW, Almoosa KF, Paul RJ, et al. Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airwayβ-agonist paradox. J Clin Invest,2003;112:619-626.
6. Bartel S, Karczewski P, Krause EG. Protein phosphorylation and cardiac function:cholinergic-adrenergic interaction. Cardiovasc Res, 1993;27:1948-1953.
7. Pepe S, Xiao RP, Hohl C, et al. Cross talk between opioid peptide and adrenergic receptor signaling in isolated rat heart. Circulation, 1997;95:2122-2129.
8. Small KM, McGraw DW, Liggett SB. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol,2003;43:381-411.
9. Von Reitzenstein C, Kopitz J, Schuhmann V, et aL Differential functional relevance of a plasma membrane ganglioside sialidase in cholinergic and adrenergic neuroblastoma cell lines. Eur J Biochem ,2001;268, 326-333.
10.Ashe JH, Yarosh CA. Differential and selective antagonism of the slow inhi-bitory postsynaptic potential and slow-excitatory postsynaptic potential by gall-amine and pirenzepine in the superior cervical ganglion of the rabbit. Neurophar-macology,1984;23:1321-1329.
11.Li DP, Chen SR, Pan YZ, et al. Role of presynaptic muscarinic and GABA_B receptors in spinal glutamate release and cholinergic analgesia in rats. Journal of Physiology,2002;543.3: 807-818.
12.Wrzos HF, Tandon T, Ouyang A. Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats. World J Gastroenterol,2004;10:3292-3298.
13. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype stratified, randomised, placebo controlled cross-over trial. Lancet,2004;364:1505-1512.
14.Ehlert FJ. Pharmacological analysis of the contractile role of M2 and M3 muscarinic receptors in smooth muscle. Receptors Channels,2003;9:261 -277.
15. Walker JK, Gainetdinov RR, Feldman DS, et al. G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation. Am J Physiol Lung Cell Mol Physiol,2004;286:312-319.
16.BiHmgton CK, Penn RB. Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res,2003;4:2.
17.Coulson FR, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther,2003;98:59-69.
18.Rogers DF. Motor control of airway goblet cells and glands. Respir Physiol, 2001;125:129-144.
19. Clarke DL, Giembycz MA, Patel HJ, et al.E-ring 8-isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea-pig trachea through agonism of prostanoid receptors of the EP3 -subtype. British Journal of Pharmacology,2004; 141: 600-609.
20.Callaerts-Vegh Z, Evans KL, Dudekula N, et al. Effects of acute and chronic administration ofβ-adrenoceptor ligands on airway function in a murine model of asthma. Proc Natl Acad Sci USA,2004; 101:4948-4953.
21.De Haas JR, Terpstra JS, van der Zwaaq M, et al. Facilitatory beta2-adrenoceptors on cholinergic and adrenergic nerve endings of the guinea pig trachea. Am J Physiol, 1999;276:420-425.
22.Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med,2000;162:75-80.
23.Gobel I, Trendelenburg AU, Cox SL, et al. Electrically evoked release of [(3)H]noradrenaline from mouse cultured sympathetic neurons: release modulating heteroreceptors. JNeurochem 2000;75:2087-2094.
24.Johnson M, Rennard S. Alternative mechanisms for long-acting beta(2) adrenergic agonists in COPD. Chest,2001;120:258-270.
25.Wessler I, Kilbinger H, Bittinger F, et al. The nonneuronal cholinergic system in humans: expression, function and pathophysiology.Life Sci,2003;72:2055-2061.
26.Lagente V, Naline E, Guenon I, et al. A nitric oxide-releasing salbutamol elicits potent relaxant and anti- inflammatory activities. J Pharmacol Exp Ther,2004;310:367-375.
27.Jeffery PK, Venge P, Gizycki MJ, et al. Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study. Eur Respir J 2002;20:1378-1385.
28.Reid DW, Ward C, Wang N, et al. Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma in vivo. Eur Respir J,2003;21:994-999.
29.Fryer AD, Lein PJ, Howard AS, et al. Mechanisms of organophosphate insecticide-induced airway hyper reactivity. Am J Physiol Lung Cell Mol Physiol,2004;286:963-969.
30.Lein PJ, Fryer AD. Organophosphorus insecticides induce airway hyperreactivity by decreasing neuronal M2 muscarinic receptor function independent of acetylchol-inesterase inhibition. Toxicol Sci,2005;83:166- 176.
31.Lee AM, Fryer AD, van Rooijen N, et al. Role of macrophages in virus-induced airway hyperresponsiveness and neuronal M2 muscarinic receptor dysfunction. Am J Physiol Lung Cell Mol Physiol,2004,286:L1255-L1259.
32.Bowerfmd WM, Fryer AD, Jacoby DB. Double-stranded RNA causes airway hyperreactivity and neuronal M2 muscarinic receptor dysfunction. J Appl Physiol, 2002;92:1417-1422.
33.On LS, Boonyongsunchai P, Webb S, et al. Function of pulmonary neuronal M(2) muscarinic receptors in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med,2001; 163:1320-1325.
1.季颖群,张卓莉,陆慰萱.结缔组织相关肺动脉高压的临床分析.中华内科杂志,2006,45(6):467-471.
2.郑捷,潘萌,丁晓毅,等.应用一氧化碳弥散功能检测结缔组织病患者肺间质病变的意义.中华结核和呼吸杂志,2002,25(7):396-398.
3.沈敏,王玉,许文兵,等.系统性红斑狼疮肺部受累的临床表现.中华医学杂志,2005,85(48):3392-3395.
4.郭强,顾越英,黄文群,等.系统性红斑狼疮患者525例肺部病变的调查.中华风湿病学杂志,2004,8(6):363-366.
5.Mukerjee D,Yap LB,Ong V,et al.The myth of pulmonary Raynaud's phenomenon:the contribution of pulmonary arterial vasospasm in patients with systemic sclerosis related pulmonary arterial hypertension.Ann Rheum Dis,2004,63(12):1627-1631.
1.Castro M,Krowka MJ.Hepatopulmonary syndrome.A pulmonary vascular complication of liver disease[J].Clin Chest Med.1996;17:35-48.
2.苏少慧、吕晓萍、杨晶等。肝肺综合征16例临床分析[J]。中华结核和呼吸杂志,2002,25:251。
3.张伟华,陆慰萱。肝肺综合征23例临床分析[J]。中华结核和呼吸杂志,2006,29:821-823。
4.牛娜,陈黎波,龙明清等。~(99)TC~m-MAA显像肺外多脏器显影一例[J]。中华核医学杂志,2007,27:99。
5.Andrew J Peacock主编。肺动脉高压治疗学(第二版)[M]。张石江等主 译。江苏:江苏科学技术出版社。2007:561-569。
6.Palma DT,Fallon MB.The hepatopulmonary syndrome[J].J Hepatol,2006,45:617-625.
7.Abrams GA,Fallon MB.Treatment of hepatopulmonary syndrome with Allium sativum L.(garlic):a pilot trial[J].J Clin Gastroenterol,1998,27:232-235.
8.Auzinger G;Wendon JA.Hepatopulmonary Syndrome and Portopulmonary Hypertension[J].Crit Care Med,2005,33:470-471.
2.刘扣英,王彤,张希龙,等.缬沙坦对哮喘大鼠气道炎症及气道反应性的影响[J].2006,26:1021-1024
3.Kaschina E,Unger T.Angiotmsin AT1/AT2 receptors:regulation and function[J].Blood Press,2003,12(2):70-88
4.Ming M,Wu J,Lachance S,et al.Beta-adrenergic receptors and angiotensinogen gene expression in mouse hepatoma cells in vitro[J].Hypertension.1995 Jan;25(1):105-9
5.Henegar JR,Schwartz DD,Janicki JS.ANG Ⅱ-related myocardial damage:role of cardiac sympathetic catecholamines and beta-receptor regulation[J].Am J Physiol,1998,275:534-541
6.马秀琴,黄茂,卞涛,等.地塞米松对哮喘大鼠肺组织NF-KB和MMP-9及TIMP-1表达的影响[J].南京医科大学学报,2005,25:255-261
7.Matsusaka T,Ichikawa I.Biological functions of angiotensin and its receptors[J].Annu Rev Physiol,1997,59:395-412
8.Bumier M.Angiotensin Ⅱ type 1 receptor blockers[J].Circulation.2001,103:904-912
9.Weir TD,Mallek N,Sandford AJ,et al.β2-Adrenergic receptor haplotypes in mild,moderate and fatal/near fatal asthma[J].Am J Respir Crit Care Med,1998,158:787-791
10.高海鹏,薛全福,林友华,等.支气管哮喘发病中β2AR mRNA水平变化的初步探讨[J].中国病理生理杂志,1999,15:525-527
11.李艳芳,张利,郑秋甫.心脏血管紧张素Ⅱ受体与β肾上腺素受体相关的调节特点[J].中国循环杂志,1999,14:252
12.Shinichi Okuda,Masafumi Yano,Masahiro Doi,et al.Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure[J].Circulation,2004;109;911-919
13.Makino T,Hattori Y,Matsuda N,et al.Effects of angiotensin-converting enzyme inhibition and angiotensin Ⅱ type 1 receptor blockade on β-adrenoceptor signaling in heart failure produced by myocardial Infarction in rabbits:reversal of altered expression of β-adrenoceptor kinase and G_(ia)[J].J PharmacoI Exp Ther,2003,304:370-379
14.Myou S,Fujimura M,Kurashima K,et al.Type 1 Angiotensin Ⅱ Receptor Antagonism Reduces Antigen-induced Airway Reactions[J].Am J Respir Crit Care Med,2000,162:45-49
15.Barki-Harrington L,Luttrell LM,Rockman HA.Dual Inhibition of β-Adrenergic and Angiotensin Ⅱ Receptors by a Single Antagonist:A Functional Role for Receptor-Receptor Interaction In Vivo[J].Circulation,2003,108:1611-1618
16.Goodfriend TL,Elliott ME,catt KJ,et al.Angiotensin receptors and Their antagonists[J]. N Engl J Med, 1996, 334:1649-1654
17. Levy BI, Benessiano J, Henrion D, et al. Chronic Blockade of AT2-subtype Receptors Prevents the Effect of Angiotensin II on the Rat Vascular Structure [J]. The J Clin Invest, 1996, 98:418-425.
18. AbdAlla S, Lother H, Abdel-tawab AM, et al. The Angiotensin II AT2 Receptor is an AT1 Receptor Antagonist [J]. J Biol Chem,2001,276: 39721-39726
19. BrombergJF,Wrzeszczynska MH,Devan G,etal. Stat3 as an oncogene [J] .Cell,1999,98 (3) : 295-303
20. Darnell JE.STATs and gene regulation [J] .Science, 1997,277 (5332) : 1630-1635
21. David M, Petricoin E,Benjamin C, etal. Requirement for MAP Kinase (ERK2) activity in interferon alpha and interferon beta stimulated gene expression through STAT proteins [J]. Science, 1995, 269:1721-1723
22. Seebach F A, Walte T, Fu X Y, etal. Differential activation of The STAT pathway by angiotensin II via angiotensin type 1 and type 2 receptors in cultured human fetal mesangial cells[J].Exp MolPathol, 2001, 70:265-273
23. Nishiyama A, Yoshizumi M, Rahman M, etal. Effects of AT1 receptor blockade on renal injury and mitogen-activated protein activity in Dahl salt-sensitive rats [J]. Kidney Int, 2004, 65:972-981
24. Zhou L, Hershenson MB. Mitogenic signaling pathways in airway smooth muscle. Respir Physiol Neurobiol. 2003;137(2-3):295-308
1.Millar EA,Angus RM,Hulks G,et al.Activity of the renin-angiotensin system in acute severe asthma and the effect of angiotensin Ⅱ on lung function[J].Thorax,1994,49:492-495.
2.刘扣英,王彤,张希龙,等.缬沙坦对哮喘大鼠气道炎症及气道反应性的影响[J].2006,26:1021-1024.
3.马秀琴,黄茂,卞涛,等.地塞米松对哮喘大鼠肺组织NF-KB和MMP-9及TIMP-1表达的影响[J].南京医科大学学报,2005,25:255-261.
4.Matsusaka T,Ichikawa I.Biological functions of angiotensin and its receptors[J].Annu Rev Physiol,1997,59:395-412.
5.Burnier M.Angiotensin Ⅱ type 1 receptor blockers[J].Circulation.2001,103:904-912.
6.Weir TD,Mallek N,Sandford AJ,et al.β2-Adrenergic receptor haplotypes in mild,moderate and fatal/near fatal asthma[J].Am J Respir Crit Care Med,1998,158:787-791.
7.高海鹏,薛全福,林友华,等.支气管哮喘发病中β2AR mRNA水平变化的初步探讨[J].中国病理生理杂志,1999,15:525-527.
8.李艳芳,张利,郑秋甫.心脏血管紧张素Ⅱ受体与β肾上腺素受体相关的调节特点[J].中国循环杂志,1999,14:252.
9.Shinichi Okuda,Masafumi Yano,Masahiro Doi,et al.Valsartan Restores Sarcoplasmic Reticulum Function With No Appreciable Effect on Resting Cardiac Function in Pacing-Induced Heart Failure[J].CirCulation,2004; 109; 911-919.
10. Makino T, Hattori Y, Matsuda N,et al. Effects of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on β-adrenoceptor signaling in heart failure produced by myocardial Infarction in rabbits: reversal of altered expression of β-adrenoceptor kinase and G_(ia)[J]. J Pharmacol Exp Ther, 2003, 304:370-379.
11. Myou S, Fujimura M, Kurashima K, et al. Type 1 Angiotensin II Receptor Antagonism Reduces Antigen-induced Airway Reactions [J]. Am J Respir Crit Care Med, 2000, 162:45-49.
12. Barki-Harrington L, Luttrell LM, Rockman HA. Dual Inhibition of β-Adrenergic and Angiotensin II Receptors by a Single Antagonist: A Functional Role for Receptor-Receptor Interaction In Vivo [J]. Circulation, 2003,108: 1611-1618.
13. Goodfriend TL,Elliott ME, catt KJ, et al. Angiotensin receptors and Their antagonists[J]. N Engl J Med, 1996, 334:1649-1654.
14. Levy BI, Benessiano J, Henrion D, et al. Chronic Blockade of AT2-subtype Receptors Prevents the Effect of Angiotensin II on the Rat Vascular Structure [J]. The J Clin Invest, 1996,98:418-425.
15. AbdAlla S, Lother H, Abdel-tawab AM, et al. The Angiotensin II AT2 Receptor is an AT1 Receptor Antagonist [J]. J Biol Chem, 2001, 276: 39721-39726.
1. Dvir H, Harel M, Bon S, et al. The synaptic acetyl cholinesterase tetramer assembles around a polyproline II helix. EMBO Journal,2004;23:4394-4405.
2. Radhika Kajekar, Bradley J.Undem, Allen C.Myers. Role of cyclooxygenase active-tion and prostaglandins in antigen-induced excitability changes of bronchial pa-rasympathetic ganglia neurons. Am J Physiol Lung Cell Mol Physiol,2003;284: 581-587.
3. Shenoy SK, McDonald PH, Kohout TA, et al. Regulation of receptor fate by ubiquitination of activatedβ2-adrenergic receptor and β-arrestin. Science, 2001;294:1307-1313.
4. Benovic JL. Novel β_2-adrenergic receptor signaling pathways. J Allergy Clin Immunol,2002;110: 229-235.
5. McGraw DW, Almoosa KF, Paul RJ, et al. Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airwayβ-agonist paradox. J Clin Invest,2003;112:619-626.
6. Bartel S, Karczewski P, Krause EG. Protein phosphorylation and cardiac function:cholinergic-adrenergic interaction. Cardiovasc Res, 1993;27:1948-1953.
7. Pepe S, Xiao RP, Hohl C, et al. Cross talk between opioid peptide and adrenergic receptor signaling in isolated rat heart. Circulation, 1997;95:2122-2129.
8. Small KM, McGraw DW, Liggett SB. Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol,2003;43:381-411.
9. Von Reitzenstein C, Kopitz J, Schuhmann V, et aL Differential functional relevance of a plasma membrane ganglioside sialidase in cholinergic and adrenergic neuroblastoma cell lines. Eur J Biochem ,2001;268, 326-333.
10.Ashe JH, Yarosh CA. Differential and selective antagonism of the slow inhi-bitory postsynaptic potential and slow-excitatory postsynaptic potential by gall-amine and pirenzepine in the superior cervical ganglion of the rabbit. Neurophar-macology,1984;23:1321-1329.
11.Li DP, Chen SR, Pan YZ, et al. Role of presynaptic muscarinic and GABA_B receptors in spinal glutamate release and cholinergic analgesia in rats. Journal of Physiology,2002;543.3: 807-818.
12.Wrzos HF, Tandon T, Ouyang A. Mechanisms mediating cholinergic antral circular smooth muscle contraction in rats. World J Gastroenterol,2004;10:3292-3298.
13. Israel E, Chinchilli VM, Ford JG, et al. Use of regularly scheduled albuterol treatment in asthma: genotype stratified, randomised, placebo controlled cross-over trial. Lancet,2004;364:1505-1512.
14.Ehlert FJ. Pharmacological analysis of the contractile role of M2 and M3 muscarinic receptors in smooth muscle. Receptors Channels,2003;9:261 -277.
15. Walker JK, Gainetdinov RR, Feldman DS, et al. G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation. Am J Physiol Lung Cell Mol Physiol,2004;286:312-319.
16.BiHmgton CK, Penn RB. Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res,2003;4:2.
17.Coulson FR, Fryer AD. Muscarinic acetylcholine receptors and airway diseases. Pharmacol Ther,2003;98:59-69.
18.Rogers DF. Motor control of airway goblet cells and glands. Respir Physiol, 2001;125:129-144.
19. Clarke DL, Giembycz MA, Patel HJ, et al.E-ring 8-isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea-pig trachea through agonism of prostanoid receptors of the EP3 -subtype. British Journal of Pharmacology,2004; 141: 600-609.
20.Callaerts-Vegh Z, Evans KL, Dudekula N, et al. Effects of acute and chronic administration ofβ-adrenoceptor ligands on airway function in a murine model of asthma. Proc Natl Acad Sci USA,2004; 101:4948-4953.
21.De Haas JR, Terpstra JS, van der Zwaaq M, et al. Facilitatory beta2-adrenoceptors on cholinergic and adrenergic nerve endings of the guinea pig trachea. Am J Physiol, 1999;276:420-425.
22.Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med,2000;162:75-80.
23.Gobel I, Trendelenburg AU, Cox SL, et al. Electrically evoked release of [(3)H]noradrenaline from mouse cultured sympathetic neurons: release modulating heteroreceptors. JNeurochem 2000;75:2087-2094.
24.Johnson M, Rennard S. Alternative mechanisms for long-acting beta(2) adrenergic agonists in COPD. Chest,2001;120:258-270.
25.Wessler I, Kilbinger H, Bittinger F, et al. The nonneuronal cholinergic system in humans: expression, function and pathophysiology.Life Sci,2003;72:2055-2061.
26.Lagente V, Naline E, Guenon I, et al. A nitric oxide-releasing salbutamol elicits potent relaxant and anti- inflammatory activities. J Pharmacol Exp Ther,2004;310:367-375.
27.Jeffery PK, Venge P, Gizycki MJ, et al. Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study. Eur Respir J 2002;20:1378-1385.
28.Reid DW, Ward C, Wang N, et al. Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthma in vivo. Eur Respir J,2003;21:994-999.
29.Fryer AD, Lein PJ, Howard AS, et al. Mechanisms of organophosphate insecticide-induced airway hyper reactivity. Am J Physiol Lung Cell Mol Physiol,2004;286:963-969.
30.Lein PJ, Fryer AD. Organophosphorus insecticides induce airway hyperreactivity by decreasing neuronal M2 muscarinic receptor function independent of acetylchol-inesterase inhibition. Toxicol Sci,2005;83:166- 176.
31.Lee AM, Fryer AD, van Rooijen N, et al. Role of macrophages in virus-induced airway hyperresponsiveness and neuronal M2 muscarinic receptor dysfunction. Am J Physiol Lung Cell Mol Physiol,2004,286:L1255-L1259.
32.Bowerfmd WM, Fryer AD, Jacoby DB. Double-stranded RNA causes airway hyperreactivity and neuronal M2 muscarinic receptor dysfunction. J Appl Physiol, 2002;92:1417-1422.
33.On LS, Boonyongsunchai P, Webb S, et al. Function of pulmonary neuronal M(2) muscarinic receptors in stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med,2001; 163:1320-1325.
1.季颖群,张卓莉,陆慰萱.结缔组织相关肺动脉高压的临床分析.中华内科杂志,2006,45(6):467-471.
2.郑捷,潘萌,丁晓毅,等.应用一氧化碳弥散功能检测结缔组织病患者肺间质病变的意义.中华结核和呼吸杂志,2002,25(7):396-398.
3.沈敏,王玉,许文兵,等.系统性红斑狼疮肺部受累的临床表现.中华医学杂志,2005,85(48):3392-3395.
4.郭强,顾越英,黄文群,等.系统性红斑狼疮患者525例肺部病变的调查.中华风湿病学杂志,2004,8(6):363-366.
5.Mukerjee D,Yap LB,Ong V,et al.The myth of pulmonary Raynaud's phenomenon:the contribution of pulmonary arterial vasospasm in patients with systemic sclerosis related pulmonary arterial hypertension.Ann Rheum Dis,2004,63(12):1627-1631.
1.Castro M,Krowka MJ.Hepatopulmonary syndrome.A pulmonary vascular complication of liver disease[J].Clin Chest Med.1996;17:35-48.
2.苏少慧、吕晓萍、杨晶等。肝肺综合征16例临床分析[J]。中华结核和呼吸杂志,2002,25:251。
3.张伟华,陆慰萱。肝肺综合征23例临床分析[J]。中华结核和呼吸杂志,2006,29:821-823。
4.牛娜,陈黎波,龙明清等。~(99)TC~m-MAA显像肺外多脏器显影一例[J]。中华核医学杂志,2007,27:99。
5.Andrew J Peacock主编。肺动脉高压治疗学(第二版)[M]。张石江等主 译。江苏:江苏科学技术出版社。2007:561-569。
6.Palma DT,Fallon MB.The hepatopulmonary syndrome[J].J Hepatol,2006,45:617-625.
7.Abrams GA,Fallon MB.Treatment of hepatopulmonary syndrome with Allium sativum L.(garlic):a pilot trial[J].J Clin Gastroenterol,1998,27:232-235.
8.Auzinger G;Wendon JA.Hepatopulmonary Syndrome and Portopulmonary Hypertension[J].Crit Care Med,2005,33:470-471.