IL-4、β_2-AR基因多态性及ECP、IgE与维吾尔族支气管哮喘的关系
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摘要
支气管哮喘(哮喘)为Ⅰ型超敏性疾病，具有明显的个体差异，一般只有少数过敏体质的人才会发生。过敏体质与特应性(atopy)相关，亦与遗传有密切关系，有明显的家族聚集性，50％特应性患者的子代都患有特应性疾病，但所表现的症状即使在同一家族中也可不同。随着分子生物学与分子免疫学研究的不断深入，对参与哮喘在内的Ⅰ型超敏反应的IgE抗体、各种炎症细胞以及血小板活化因子(PAF)为代表的化学递质或细胞因子有了更新的理解。许多研究结果提示，哮喘除与上述因素以及自律神经异常、环境因素等有关外，遗传因素在其发病中起着举足轻重的作用。目前公认哮喘是一种具有多基因遗传倾向的疾病。我们在详细询问病史并进行肺功能检查的同时检测了新疆和田地区212例维吾尔族人群血样中的S-ECP、血清总IgE和吸入性变应原的特异性IgE抗体(Phadiatop)水平，以探讨新疆维吾尔族人群血清总IgE、特异性IgE及ECP与支气管哮喘发病的关系。同时，应用多聚酶链式反应—限制性片段长度多态性(PCR-RFLP)及等位基因特异性PCR(ASP)等现代分子生物学方法，对目前已知的可能涉及哮喘发病的β_2-AR16和27位点基因多态性、IL-4启动子区-589(C/T)位点基因多态性进行检测及其与总IgE的关系进行分析，旨在了解β_2-AR和IL-4二者的基因多态性与新疆维吾尔族人群哮喘的关联情况，从分子水平探索遗传因素在新疆维吾尔族人群哮喘发病中的作用。
一、血清总IgE、特异性IgE及ECP水平与维吾尔族人群支气
管哮喘的关系
研究苔景和目的
哮喘是由多种炎症细胞及细胞因子（CKS）共同参与而形成的气
道慢性变态反应性炎症。而嗜酸细胞己被公认是变态反应性疾病的标
志。在变态反应和慢性炎症中起着重要作用。嗜酸细胞亦有免疫调节
功能，在几个方面修饰T、B淋巴细胞、肥大细胞和中性粒细胞等的
活性。此外，它在组织修复、重建和抗原的表达中亦起着重要作用。
在嗜酸细胞释放的颗粒蛋白中，嗜酸细胞阳离于蛋白（ECP）和主要
碱性蛋白（MBP）的毒性作用最强，而其中以ECP 更加明显，ECP
被普遍认为是炎性反应标志，反映了嗜酸细胞的活化程度。测定病人
血清、痰液及支气管肺泡灌洗液（BALF）中的ECP水平，可以判定
哮喘炎症的严重程度及预后，预测疾病的发作，直接监测和指导抗炎
治疗。为此，我们在详细询问病史并进行肺功能检查的同时检测了新
疆和田地区维吾尔族人群血样中的 S干CP、血情总屹E和吸入性变应
原的特异性lgE抗体ohadiatop）水平，以探讨新疆维吾尔族人群血
清总IgE、特异性IgE及ECP与支气管哮喘发病的关系。
方法
作者于 2002年 3月在新疆和田地区共调查了 ZIZ例 18～72岁维
吾尔族人（哮喘患者123例，正常对照89例），详细询问病史，采集
血样并进行肺功能检查。根据临床特点、肺功能（FEVl占预计值％）
和所需药物情况将患者分为间歇发作门 例）、轻度门 例）、中度（3
例）、重度门 例）四个组，平均年龄38．35士9I7 岁。健康成年人
89名，平均年龄3 8．12土8．23岁（18－71岁卜作为正常对照组。均采用
真空S盯管采集和处理血清。血清肛P、皿清总lgE和吸入性变应原
的特异性IgE抗体卯hadiatop）水平测定（血样）均在新疆医科大学
变态反应检验中心（新疆医科大学第一附属医院耳鼻喉科）由固定资深
专业测试人员进行测定，应用Un汇AP 00全自动体外变应原检测系
统（SWEDEN PHARMACIA Un汇AP SystemS）检测，操作按说明进行，
定量测定血清ECP、血清总IgE，同时对吸入性变应原的特异性IgE
— —2一
抗体（PhadiatoP）水平进行定性测定。测定所用试剂均由瑞典法玛西
亚公司（PHARMACIA UniCAP，SWEDEN）提供。
结果
S正CP与哮喘的症状评分k SCOreX总 IgE和肺功能厌EVI
和PEF）高度相关仪＜0乃1卜在哮喘各组之间，SECP都有显著性差异
（均有 P＜0．01卜 最高值出现在重度哮喘患者组（EC叫．ZIfl。12 11
g／LX且血清 ECP水平与病情严重程度呈正相关关系O－0石3，P＜0刀1＼
同时还发现，变态反应的出现也与SICP值增高有关，IgE与SICP
呈高度正相关关系…－o61，P＜0．01X｝＊CP值也都与哮喘发作的自觉
症状和通过检查所得的客观体征具有高度相关性，ECP与PEF之间存
在负相关关系O—0．67，P＜0刀5卜 以上结果表明，SICP和 lgE二者及
其相互关系主要取决于嗜酸粒细胞激活程度和分泌蛋白的能力，它们
能反映哮喘气道炎症的活动情况，并可预示哮喘发作的严重程度。
二、pZ－肾上腺素能受体基因多态性与新瞩锥吾尔族人群支气管
哮喘及其临床表型的关系
研究背景和目的
pZ肾上腺素能受体（pZ－AR）基因与哮喘的关系一直受到广泛
的重视。编码人02叭x的基困定位于染色体sq“”卫区，己有几个多态
性位点被发现，其中编码区第16和27位氨基酸的变异已在体外实验
中被证实其可以改变BZ人R的功能，是近年来国际上研究哮喘易感性
及疾病调节基因的重要候选基因之一。我们以新?
I Association between serum measurements of ECPx T-IgE and S-IgE with bronchial asthma in the Uygur population
Background The accumulating knowledge during recent years has clearly indicated that one important cause of bronchial asthma is a kind of allergic and chronic inflanimation of the airway. In most instances the histopathology of this inflammation is characterized by the presence of an increased number of eosinophilic granulocytes. In particular, this seems to be true in the allergic type of asthma. Other causes of asthma way, in addition, involve other inflammatory cells such as the neutrophil. The role played by the eosinopb.il in the lung of the asthmatic patient is still not entirely clear. Although some data would indicate that these may be seperative in the process of epithelial shedding, either by a cytotoxic mechanism directed against the epithelial cells by the disruption of the structures necessary for the cells together. Other possibilities include a role in bronchoconstriction due to the production of leukotrienes and platelet-activating factor and the induction of glandular hypersecretion by ECP.
Instrument in defining a role of the eosinophil in asthma have been studies employing broncho-alveolar lavage and biopsies of asthmatic subjects. Biopsy studies have shown the presence of activated eosinophils in the asthmatic lung and the disappearance of these cells after successful
treatment of asthma with inhaled corticosteroids. Similarly, lavage studies have shown a correlation between eosinophil numbers and ECP levels in the broncho-alveolar lavage on the one hand and the severity of asthma on the other. In addition, the studies showed a reduction in these variables by successful treatment. It should be emphasized that ECP levels were the only variables measured that, in these studies, consistently change is parallel with clinical improvement.
The clinical management of asthma includes the monitoring of lung function and the anamnestic monitoring of the activity of daily living .It is well agreed that these measures are very often insufficient and do not accurately reflect, the underlying process of asthma, i.e. the extent of the inflammatory process. This is probably of the greatest importance, since it is well established that it may even be dangerous to treat the patients with symptomatic medication exclusively without controlling the underlying inflammayory process. The problem, however, is how to reflect accurately the inflammatory process of the asthmatic lung. Commonly used indicators of inflammatory activity such as blood ESR and acute-phase reactants in plasma are not altered in asthma.
For some years we have been developing and testing the concept that the measurement of specific markers of various inflammatory activity in the body more sensitively than those tests commonly available today, and that such measurement would also provide unique information as to the underlying pathophysiological process of the disease. Until now we have developed assays specifically to reflect neutrophil activity [i.e. myeloperoxidase (MPO) and lactoferrin], eosinophil activity [i.e.ECP, eosinophil protein /eosinophil-derived neurotoxin (EPX/EDN)], eosinophil peroxidase (EPO)], and macrophage activity (i.e. lysozyme). These assays could be supplemented by tryptase specifically to reflect mast cell activity.
Objective To explore serum ECP, T-IgE and S-IgE levels of Xinjiang
-10-
Uygur population, to study the correalation and their clinical significance in asthmatic patients in different degrees, and to elucidate the role of ECP and IgE in the pathogenesis of bronchial asthma.
Methods 123 Uyger asthmatics and 89 normal healthy controls with the same ethnic nearby Xinjiang Hetian region were investigated. The serum ECP and total IgE and specific aeroallergen were detected using a pharmacia UniCAP 100 type instrument, pulmonary ventilatory function assessed by FEV_(1) and PEF.
Results The positive rate of specific IgE antibody in asthmatics was 17.89%(22/123). The inc
一、血清总IgE、特异性IgE及ECP水平与维吾尔族人群支气
管哮喘的关系
研究苔景和目的
哮喘是由多种炎症细胞及细胞因子（CKS）共同参与而形成的气
道慢性变态反应性炎症。而嗜酸细胞己被公认是变态反应性疾病的标
志。在变态反应和慢性炎症中起着重要作用。嗜酸细胞亦有免疫调节
功能，在几个方面修饰T、B淋巴细胞、肥大细胞和中性粒细胞等的
活性。此外，它在组织修复、重建和抗原的表达中亦起着重要作用。
在嗜酸细胞释放的颗粒蛋白中，嗜酸细胞阳离于蛋白（ECP）和主要
碱性蛋白（MBP）的毒性作用最强，而其中以ECP 更加明显，ECP
被普遍认为是炎性反应标志，反映了嗜酸细胞的活化程度。测定病人
血清、痰液及支气管肺泡灌洗液（BALF）中的ECP水平，可以判定
哮喘炎症的严重程度及预后，预测疾病的发作，直接监测和指导抗炎
治疗。为此，我们在详细询问病史并进行肺功能检查的同时检测了新
疆和田地区维吾尔族人群血样中的 S干CP、血情总屹E和吸入性变应
原的特异性lgE抗体ohadiatop）水平，以探讨新疆维吾尔族人群血
清总IgE、特异性IgE及ECP与支气管哮喘发病的关系。
方法
作者于 2002年 3月在新疆和田地区共调查了 ZIZ例 18～72岁维
吾尔族人（哮喘患者123例，正常对照89例），详细询问病史，采集
血样并进行肺功能检查。根据临床特点、肺功能（FEVl占预计值％）
和所需药物情况将患者分为间歇发作门 例）、轻度门 例）、中度（3
例）、重度门 例）四个组，平均年龄38．35士9I7 岁。健康成年人
89名，平均年龄3 8．12土8．23岁（18－71岁卜作为正常对照组。均采用
真空S盯管采集和处理血清。血清肛P、皿清总lgE和吸入性变应原
的特异性IgE抗体卯hadiatop）水平测定（血样）均在新疆医科大学
变态反应检验中心（新疆医科大学第一附属医院耳鼻喉科）由固定资深
专业测试人员进行测定，应用Un汇AP 00全自动体外变应原检测系
统（SWEDEN PHARMACIA Un汇AP SystemS）检测，操作按说明进行，
定量测定血清ECP、血清总IgE，同时对吸入性变应原的特异性IgE
— —2一
抗体（PhadiatoP）水平进行定性测定。测定所用试剂均由瑞典法玛西
亚公司（PHARMACIA UniCAP，SWEDEN）提供。
结果
S正CP与哮喘的症状评分k SCOreX总 IgE和肺功能厌EVI
和PEF）高度相关仪＜0乃1卜在哮喘各组之间，SECP都有显著性差异
（均有 P＜0．01卜 最高值出现在重度哮喘患者组（EC叫．ZIfl。12 11
g／LX且血清 ECP水平与病情严重程度呈正相关关系O－0石3，P＜0刀1＼
同时还发现，变态反应的出现也与SICP值增高有关，IgE与SICP
呈高度正相关关系…－o61，P＜0．01X｝＊CP值也都与哮喘发作的自觉
症状和通过检查所得的客观体征具有高度相关性，ECP与PEF之间存
在负相关关系O—0．67，P＜0刀5卜 以上结果表明，SICP和 lgE二者及
其相互关系主要取决于嗜酸粒细胞激活程度和分泌蛋白的能力，它们
能反映哮喘气道炎症的活动情况，并可预示哮喘发作的严重程度。
二、pZ－肾上腺素能受体基因多态性与新瞩锥吾尔族人群支气管
哮喘及其临床表型的关系
研究背景和目的
pZ肾上腺素能受体（pZ－AR）基因与哮喘的关系一直受到广泛
的重视。编码人02叭x的基困定位于染色体sq“”卫区，己有几个多态
性位点被发现，其中编码区第16和27位氨基酸的变异已在体外实验
中被证实其可以改变BZ人R的功能，是近年来国际上研究哮喘易感性
及疾病调节基因的重要候选基因之一。我们以新?
I Association between serum measurements of ECPx T-IgE and S-IgE with bronchial asthma in the Uygur population
Background The accumulating knowledge during recent years has clearly indicated that one important cause of bronchial asthma is a kind of allergic and chronic inflanimation of the airway. In most instances the histopathology of this inflammation is characterized by the presence of an increased number of eosinophilic granulocytes. In particular, this seems to be true in the allergic type of asthma. Other causes of asthma way, in addition, involve other inflammatory cells such as the neutrophil. The role played by the eosinopb.il in the lung of the asthmatic patient is still not entirely clear. Although some data would indicate that these may be seperative in the process of epithelial shedding, either by a cytotoxic mechanism directed against the epithelial cells by the disruption of the structures necessary for the cells together. Other possibilities include a role in bronchoconstriction due to the production of leukotrienes and platelet-activating factor and the induction of glandular hypersecretion by ECP.
Instrument in defining a role of the eosinophil in asthma have been studies employing broncho-alveolar lavage and biopsies of asthmatic subjects. Biopsy studies have shown the presence of activated eosinophils in the asthmatic lung and the disappearance of these cells after successful
treatment of asthma with inhaled corticosteroids. Similarly, lavage studies have shown a correlation between eosinophil numbers and ECP levels in the broncho-alveolar lavage on the one hand and the severity of asthma on the other. In addition, the studies showed a reduction in these variables by successful treatment. It should be emphasized that ECP levels were the only variables measured that, in these studies, consistently change is parallel with clinical improvement.
The clinical management of asthma includes the monitoring of lung function and the anamnestic monitoring of the activity of daily living .It is well agreed that these measures are very often insufficient and do not accurately reflect, the underlying process of asthma, i.e. the extent of the inflammatory process. This is probably of the greatest importance, since it is well established that it may even be dangerous to treat the patients with symptomatic medication exclusively without controlling the underlying inflammayory process. The problem, however, is how to reflect accurately the inflammatory process of the asthmatic lung. Commonly used indicators of inflammatory activity such as blood ESR and acute-phase reactants in plasma are not altered in asthma.
For some years we have been developing and testing the concept that the measurement of specific markers of various inflammatory activity in the body more sensitively than those tests commonly available today, and that such measurement would also provide unique information as to the underlying pathophysiological process of the disease. Until now we have developed assays specifically to reflect neutrophil activity [i.e. myeloperoxidase (MPO) and lactoferrin], eosinophil activity [i.e.ECP, eosinophil protein /eosinophil-derived neurotoxin (EPX/EDN)], eosinophil peroxidase (EPO)], and macrophage activity (i.e. lysozyme). These assays could be supplemented by tryptase specifically to reflect mast cell activity.
Objective To explore serum ECP, T-IgE and S-IgE levels of Xinjiang
-10-
Uygur population, to study the correalation and their clinical significance in asthmatic patients in different degrees, and to elucidate the role of ECP and IgE in the pathogenesis of bronchial asthma.
Methods 123 Uyger asthmatics and 89 normal healthy controls with the same ethnic nearby Xinjiang Hetian region were investigated. The serum ECP and total IgE and specific aeroallergen were detected using a pharmacia UniCAP 100 type instrument, pulmonary ventilatory function assessed by FEV_(1) and PEF.
Results The positive rate of specific IgE antibody in asthmatics was 17.89%(22/123). The inc
引文
[1] Global Initiative for Asthma. Global strategy for asthma management and prevention. National Institutes of Health National Heart, Lung, and Blood Institute(NHLBI/WHO) workshop report. NIH Publication, Revised 2002.
[2] 叶任高，内科学，第五版．北京：人民卫生出版社，2000，32．
[3] 张恩森．哮喘发病机制的研究新进展．医学综述，2001，7(12)：744
[4] 戴爱国，张平．嗜酸性粒细胞凋亡与哮喘呼吸道炎症．中华结核与呼吸杂志，1998，21(4)：243-244．
[5] 黄宏，徐军，钟南山．哮喘患者外周血嗜酸性粒细胞抗体的表达及临床意义．中华结核与呼吸杂志，1998，21(10)：612-614．
[6] 叶世泰，主编．变态反应学．科学出版社，1998，325．
[7] 张丹，杨振峰．哮喘的呼吸道重塑和嗜酸细胞性炎症．医学综述，2001，7(5)：301-303．
[8] Oettgen HC, Geha RS. IgE in asthma and atopy: celluar and molecular connections. J Clin Invest 1999, 104:829-835.
[9] Chang TW. The pharmacological basis of anti-IgE therapy. Nat Biotechnol, 2000, 18:157-162.
[10] Venge Per. The monitoring of inflammation by specific cellular markers. Scand J Clin Lab Invest 1994, Suppl 219: 47-54.
[11] Ahlstedt S, Peterson CGB, Enander I. Update in allergy testing in childhood asthma: how do you know whether you are successfully controlling the patient's inflammation? Pediatr Pulmonol. 1995, Suppl 11:32-33.
[12] Venge Per. Role of Eosinophils in childhood asthma inflammation. Pediatr Pulmonol. 1995, Suppl 11:34-35.
[13] Woolley KL, Adelroth E, Woolley MJ, et al. Effects of allergen challenge on eosinophil cationic protein, and granulocyte-macrophage colony-stimulating factor in mild asthma. Am J Respir Crit
Care Med, 1995, 151:1915-1924.
[14] Sporik R, Ingram JM, Price W, et al. Association of asthma with serum IgE and skin test reactivity to allergens among children living at high altitude. Am J Respir Crit Care Med, 1995, 151:1388-1392.
[15] 郭晓明，赖克方，王长征等．哮喘豚鼠嗜酸性粒细胞凋亡及凋亡相关基因表达的研究．中华结核与呼吸杂志，1998，21(12)：708．
[16] 严永东，盛锦云，郁晰等．哮喘患儿血清嗜酸细胞阳离子蛋白、总IgE及外周血嗜酸细胞水平的变化及临床意义．中国实用儿科杂志，2000,8：325．
[17] 杨铁生，樊春红．发作期哮喘患者激素治疗前后血清ECP水平的变化及意义．上海医学检验杂志，2000，6：219．
[18] Sunyer J, Anto JM, Sabria J, et al. Relationship between serum IgE and airway responsiveness in adult; with asthma. J Allergy Clin Immunol, 1995,95:699-706.
[19] Squillace SP, Spoirk RB, Rakes G, et al. Sensitization to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia: multiple regression analysis of a population-based study. Am J Respir Crit Care Med, 1997, 156: 1760-1764.
[20] Lau S, Illi S, Sommerfeld C, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet, 2000, 356:1392-1397.
[21] 张景波，杨建华，倪玉美等．支气管哮喘患者血清嗜酸细胞阳离子蛋白的变化．细胞与分子免疫学杂志，2000，1：37-39．
[22] 徐辉，王建东，罗炎杰等．哮喘患者诱导痰嗜酸细胞阳离子蛋白、白细胞介素5水平的改变及其意义．急诊医学，2000，3：121．
[23] 邓念强，王琦筠，万德胜等．无症状气道高反应性与血清特异性IgE及血清嗜酸细胞阳离子蛋白的相关性研究．中华结核与呼吸杂志，2000，6：213．
[24] 孙宝清，黄海鹭，王远照等．支气管哮喘患者血清特异性IgE与
ECP的关系．广州医学院学报，1998,4：175．
[25] 王莲芸，王怀云，赵嘉惠等．支气管哮喘患者sVCAM-1和ECP的分析．上海免疫学杂志，2000，5：235．
[26] 王翔．IL-5和ECP在支气管哮喘病因中的作用．四川医学，2000，12：654．
[26] Wang W, Halmurat U. Association between serum measurements of eosinophil cationic protein、total IgE and specific IgE with bronchial asthma in Uygur population. 2003,3.
[27] Newman-Taylor A. Environmental determinants of asthma. Lancet, 1995, 345:296-299.
[28] Becklake MR, Ernst P. Environmental factors. Lancet, 1997, 350: 10-13.
[29] 况少青，张宇舟，陈苎．基因组扫描—遗传病相关基因定位的有力工具．中华医学遗传学杂志，1997，14：99-103．
[30] 罗慰慈主编．现代呼吸病学．第一版，北京：人民军医出版社，1997，271．
[31] 周斌，刘宏，殷明．哮喘药物的基因组学研究进展．中国临床药理学杂志，2003，19(1)：63-66．
[32] Pearlman DS. Pathophysiology of the inflammatory response. J Allergy Clin Immunol, 1999, 104: S132-S137.
[33] Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodeling in asthma. Curr Opin Pulm Med, 2000, 6:15-20.
[34] Sandford A, Weir T, Pare P.The genetics of asthma. Am J Respir Crit Care Mod ,1996,153:1749-1765.
[35] Weiss ST. Gene by environment interaction and asthma. Clin Exp Allergy, 1999, 29 Suppl 2:96-9.
[36] 赵华，杜晓娟，林丽渊等．中国人哮喘易感性与染色体5q~(31-33)区连锁关系的初步研究．中华儿科杂志，1998，36(12)：713-716．
[37] Postma DS, Bleecker ER, Amelung PJ, et al. Genetic susceptibility to asthma-bronchial hyperresponsiveness coinherited with a major
gene for atopy. N Engl J Med, 1995,333:894-900.
[38]Daniels SE, Bhattacharrya S, James A, et al. A genome-wide search for quantitative trait loci underlying asthma. Nature, 1996, 383:247-250.
[39]Thomas NS, Wilkinson J, Holgate ST. The candidate region approach to the genetics of asthma and allergy. Am J Respir Crit Care Med, 1997, 156:S144-151.
[40]Thomas NS, Holgate ST. Candidate locus approach for studying the genetics of asthma and atopy. Monaldi Arch Chest Dis, 1997, 52: 296-302.
[41] 刘春涛，谢敏，王曾礼．几种新发现的与哮喘有关的细胞因子．国外医学内科学分册，2000，3：165．
[42]Demoly P, Bousquet J. Genetics of asthma and atopy. J Soc Biol, 2000, 194(1): 39-42.
[43] 姜丽敏，朱惠如，章晓冬，支气管哮喘遗传相关基因的研究．现代康复，2001，5：217．
[44] 徐军．支气管哮喘(一)哮喘的基因治疗．实用医学杂志，2001，6：372．
[45]Williams CM, Galli SJ. The diverse potential effector and immuneoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol, 2000, 105:847-859.
[46]Young RP, Sharp PA, Lynch JR, et al. Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J Med Genet, 1992,29:236-238.
[47]Suzuki I, Hizawa N, Yamaguchi E, et al. Association between a C+33T polymorphism in the IL-4 promoter region and total serum IgE levels. Clin Exp Allergy. 2000; 30(12): 1746-9.
[48]Meyers DA, Postma DS, Panhuysen CI, et al. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics, 1994, 23:464-470.
[49] Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL-4 and other chromosome 5q~(31.1) markers and total serum immunoglobulin E concentrations. Science, 1994,264:1152-1156.
[50] Hijazi Z, Haider MZ. Interleukin-4 gene promoter polymorphism [C590-T] and asthma in Kuwaiti Arabs.Int Arch Allergy. Immunol, 2000, 122(3): 190.
[51] Chouchane IL, Sfar R, Bousaffara A, et al. A repeat polymorphism in interleukin-4 gene is highly associated' with specific clinical phenotypes of asthma, Int Arch Allergy Immunol, 1999, 120:50-55.
[52] 高光凯，王士雯，张进川．中国北方汉族人群支气管哮喘患者β_2肾上腺素能受体基因多态性研究．中华结核和呼吸杂志，2000，23(2)：93-97．
[53] 伏瑾，陈虹，胡良平等．β_2-肾上腺素能受体基因的多态性与哮喘及其临床表型的关系．中华医学遗传学杂志，2002，19(1)：41-45．
[54] 戴路明，王曾礼，张亚平等．β_2受体遗传多态性与支气管哮喘患者肺功能关系研究．中华结核和呼吸杂志，2002，25(9)：554-555．
[55] 高金明，林耀广，邱长春等．β_2-肾上腺素能受体基因多态性和支气管哮喘的关系，中国医学科学院学报，2002，24(6)：626-631．
[56] 邱玉英，殷凯生．β_2肾上腺素受体遗传多态性与血清总IgE关系的研究．中华结核和呼吸杂志，2002，1：37．
[57] Liggett S B. Polymorphisms of the β_2-adrenergic receptor and asthma. Am J Respir Crit Care Med, 1997,156:156-162.
[58] Liggett S B. Molecular and genetic basis of β_2-adrenergic receptor function. J Allergy Clin Immunol, 1999, 103:42-46.
[59] Green SA, Turki J, Innis M, et al. Aminoterminal polymorphisms of the human β_2-adrenergic receptor impart distinct agonistpromoted regulatory properties. Biochemistry, 1994, 33:9414-9419.
[60] Green SA, Turki J, Bejarano P, et al. Influence of β_2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol, 1995,13:25-33.
[61] 苄如濂．β肾上腺素受体激动剂．见：周汉良，陈季强主编．呼吸药理学与治疗学．第一版．北京：人民卫生出版社，1999，258-259．
[62] Kobilka BK, Frielle HG, Dohlman MA, et al. Delineation of theintronless naturee of the genes for the human and hamster β_2-adrenergic receptor and their promoter regions. J Biol Chem. 1996,262:7321-7327.
[63] Aziz I, Hall IP, Mcfarlane LC, et al. Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol, 1998,101:337-341.
[64] Mcgraw DW, Liggett SB. Coding block and 5 leader cistron polymorphisms of the beta2-adrenergic receptor. Clin Exp Allergy, 1999, 4(Suppl):43-45.
[65] Lipworth BJ, Hall IP, Aziz I, et al. Beta2-adrenoceptor polymorphism and brochoprotective sensitivity with regular short and long acting beta2-agonist therapy. Clin Sci (Colch),1999,96:253-259.
[66] Green SA, Cole M, Jacinto M, et al. A polymorphism of the human Beta 2 adrenoceptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. Biol Chem, 1993,268(19): 23116-23121.
[67] Moore PE, Laporte JD, Abraham JH, et al. Polymorphism of the β_2-adrenergic receptor gene and desensitization in human airway smooth muscle. Am J Respir Crit Care Med. 2000, 162:2117-2124.
[68] Fenech A, Hall IP. Pharmacogenetics of asthma. Br J Clin Pharmacol, 2002,53: 3-15.
[69] Hurley DM, Acclli D, Stratakis CA, et al. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest, 1991, 87: 680-686.
[70] Panarelli M, Holloway CD, Fraser R, et al. Glucocorticoid receptor polymorphism, skin vasoconstriction and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab, 1998, 83:1846-1852.
[71] Xie HG, Stein CM, Kim RB, et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacogenomics, 1999,9:511-516.
[72] Scott MGH, Swan C, Wheatley AP, et al. Identification of novel polymorphisms within the promoter region of the human beta(2) adrenergic receptor gene. Br J Pharmacol, 1999, 126: 841-844.
[73] Lima JJ, Thomason DB, Mohamed MHN, et al. Impact of genetic polymorphisms of the β_2-adrenergic receptor on albuterol hronchodilator pharmacodynamics. Clin Pharmacol Ther, 1999, 65: 519-525.
[74] Lima JJ, Mohamed MH, Self TH, et al. Importance of beta(2)-adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics. Pulm Pharmacol Ther, 2000, 13: 127-134.
[75] Lipworth BJ, Dempsey OJ, Aziz I, et al. Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype. Am J Med, 2000, 109, 114-121.
[76] Ward GM Jr, Woodfolk JA, Hayden ML, et al. Treatment of late-onset asthma with fluconazole. J Allergy Clin Immunol, 1999, 104(3Pt 1): 541-546.
[77] Tan S, Hall IP, Dewar J, et al. Association between β_2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitization in moderately severe stable asthmatics. Lancet, 1997. 350: 995-999.
[78] Lipworth BJ, Dempsey OJ, Aziz I. Functional antagonism with
formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism. Chest, 2000, 118:321-328.
[79]Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med, 2000, 162: 75-80.
[80]Taylor DR, Drazen JM, Herbison GP, et al. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax, 2000, 55: 762-767.
[81]支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗、疗效判断标准及教育和管理方案)．中华结核和呼吸杂志，1997，20(5)：261-267．
[82]Burney PGJ, Laitinen LA, Perdrizet S. et al. Validity and repeatability of the IUATLD (1984) Bronchial Symptoms Questionnaire: an international comparison. Eur Respir J, 1989,2:940-945.
[83]李秋根，刘江红，雷建平等．血清和诱导痰嗜酸细胞阳离子蛋白在检测布地奈德治疗支气管哮喘气道炎症中的作用．治疗哮喘药物临床应用有奖征文论文汇编．中华结核和呼吸杂志编委会，2002，11：61-62．
[84]UniCAP体外检测临床应用指南．南京美瑞制药有限公司诊断试剂部2002，10．
[85]钟南山，黄海鹭．正常人群血清嗜酸细胞阳离子蛋白(ECP)水平的测定．嗜酸细胞阳离子蛋白(ECP)临床应用文集，南京美瑞制药有限公司诊断试剂部2002，10．
[86]Kowalski ML, Woszczek G, Borowiec M. Distribution of theβ_2-adrenoceptor polymorphisms in atopic and non-atopic patients. J Allergy Clin Immunol, 1997,100:338.
[87]Nijkamp F, Engels P, Henricks P, et al. Mechanisms of β-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev, 1992,72:323-367.
[88]Hancox RJ, Sears MR, Taylor DR. Polymorphism of the β_2-adrenoceptor and the response to long-term β_2-agonist therapy in asthma. Eur Respir J. 1998,11:589-593.
[89]Holroyd KJ, Levitt RC, Dragwa DC, et al. Evidence for β_2 adrenergic receptor(ADRB2) polymorphism at amino acid 16 as a risk factor for bronchial hyperresponsiveness(BHR). Am J Respir Crit Care Med, 1995,151:673.
[90]Bleecker ER, Postma DS, Meyers DA, et al. Evidence of multiple genetic susceptibility loci for asthma. Am J Respir Crit Care Med, 1997,156:113-116.
[91]Wang ZX, Chen CZ, Niu TH, et al. Association of asthma with β_2-adrenergic receptor gene polymorphism and cigarette smoking. Am J Respir Crit Care Med, 2001,163:1404-1409.
[92]Ulbrecht M, Hergeth MT, Wist M, et al. Association of beta (2)-adrenoreceptor variants with bronchial hyperresponsiveness. Am J Respir Crit Care Med, 2000,161(2 pt 1): 469-74.
[93]J.萨姆布鲁克，D.W.拉塞尔主编．分子克隆实验指南(第三版)北京：科学出版社，2002：302-532．
[94]Burrows B, Sears MR, Flannery GP, et al. Relations of bronchial responsiveness to allergy skin test reactivity, lung function, respiratory symptoms, and diagnoses in thirteen-year-old New Zealand children. J Allergy Clin Immunol, 1995,95:548-556.
[95]Ying S, Durham SR, Corrigan CJ, et al. Phenotype of cells expressing mRNA for Th2-type(interleukin-4 and interleukin-5) and Th1-type(interleukin-2 and interferon-gamma) cytokines in bronchialveolar lavage and bronchial biopsyes from atopic asthmatics and normal control subjects. Am J Respir Cell Mol Biol. 1995, 12:477-487.
[96]Kenyon NJ, Kelly EA, Jarjour NN. Enhanced cytokine generation by peripheral blood mononuclear cells in allergic and asthma subjects.
Ann Allergy Asthma Immunol, 2000,85(2): 115.
[97]Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma:a phase Ⅰ/Ⅱ randomized placebocontrolled trial. Am J Respir Crit Care Med, 1999, 160:1816-1823.
[98]阳显慧．白细胞介素—5在哮喘发病机制中的作用．医学综述，2001,7(4): 195-197.
[99]Ackerman V, Marini M, Vittori E, et al. Detection of cytokines and their cell sources in bronchial specimens from asthmatic patients. Relationship to atopic status, symptoms, and level of airway hyperresponsiveness. Chest. 1994,105(3):687-696.
[100]Teramoto T, Fukao T, Tashita H, et al. Serum IgE level is negatively correlated with the ability of peripheral mononuclear cells to produce interferon gamma(IFNgamma):Evidence of reduced expression of IFN gamma mRNA in atopic patients. Clin Exp Allergy, 1998, 28(1):74.
[101]Gosset P, Tillie-Leblond I, Janin A, et al. Expression of E-selectin, ICAM-1 and VCAM-1 on bronchial biopasies from allergic and nonallergic asthmatic patients. Int Arch Allergy Immunol, 1995, 106(1):67-69.
[102]钱小顺．哮喘嗜酸粒细胞凋亡的调控．国外医学呼吸系统分册，2000，20(1)：6-9．
[103]Humbert M, Durham SR, Ying S, et al. IL-5 m RNA and protein in bronchial biopsies from Atopic and non-atopic asthmatics: Evidence against "intrinsic" asthma being a distinct immunopathological entity. Am J Respir Crit Care Med. 1996, 154: 1497-1504.
[104]Hansen G, Berry G, Dekruyff RH, et al. Allergen-specific Th_1 cells fail to counterbalance Th_2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest, 1999, 103(2): 175.
[105]Burchard EG, Silverman EK, Rosenwasser LJ, et al. Association between a sequence variant in the IL-4 gene promoter and FEV_1 in
asthma. Am J Respir Crit Care Med, 1999, sep 160 (3): 919-922.(Genbank access M23442)
[106]朱晓华，吴熙，陈强等．白介素—4基因启动子多态性与儿童哮喘关系的研究．中国实用儿科杂志，2002，17(8)：475-477．
[107]Song Z, Caslarro V, Chen R, et al. Polymorphic nucleotides within the human IL-4 promoter that mediate overexpression of the gene. J Immunol, 1996, 156:424.
[108]张嘉琳，陈虹，胡良平等，IL-4、IL-10基因启动子区多态性与儿童哮喘的相关性及对细胞因子表达的影响．哮喘杂志，2002，8(1)：1-5．
[109]王长征．嗜酸性粒细胞与支气管哮喘．中华结核与呼吸杂志，1998，21：562-564．
[110]Platts-Mills TAE. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med, 2001, 164: 1-5.
[111]李明华，殷凯生主编．哮喘病学．第一版．北京：人民卫生出版社，1998，400．
[112]Norzila MZ, Fakes K, Henry RL, et al. IL-8 secretion and neutrophil recruitment accompanyies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med, 2000,161: 769-794.
[113]Fujimoto K, Kubo K, Matsuzawa Y, et al. Eosinophil cationic protein levels in induced sputum correlate with the severity of bronchial asthma. Chest, 1997, 112(5):1241-1247.
[114]Bengtsson U, Knutson TW, Knutson L, et al. Eosinophil cationic protein and histamine after intestinal challenge in patients with cows milk intolerance. J Allergy Clin Immunol, 1997, 100:216-221.
[115]Kita H. The eosinophil:a cytokine-producing cell? J Allergy Clin Immunol, 1997,97(4): 889-892.
[116]Venge H. Serum measurements of eosinophil cationic protein (ECP) in bronchial asthma. Clinical and Experimental Allergy, 1993, 23
(Suppl2): 3-7.
[117]Platts-Mills TAE, Vaughan J, Squillace SP, et al. Sensitisation, astrhma, and a modified TH_2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet, 2001, 357:752-756.
[118]邵莉，朱丽君，许以平．变应原特异性IgE抗体和ECP测定在哮喘中的意义．上海第二医科大学学报，2002，22(3)：254-255．
[119]Bjornsson E, Janson C, Hakansson L, et al. Serum eosinophil cationic protein in relation to bronchial asthma in a young Swedish population. Allergy, 1994, 49(9):730-736.
[120]Busse WW, Coffman RL, Gelfand EW, et al. Mechanisms of persistent airway inflammation in asthma: a role for T cells and T-cell products. Am J Respir Crit Care Med, 1995, 152:388-393.
[121]Platts-Mills TA, Vaughan JW, Carter MC, et al. The role of intervention in established allergy: avoidance of indoor allergens in the treatment of chronic allergic disease. J Allergy Clin Immunol, 2000, 106:787-804.
[122]童朝晖，张宏誉．血清ECP测定在支气管哮喘治疗中的应用．中华微生物和免疫学杂志，1996，16(增刊1)：16-17．
[123]赵斌，王丹琪，夏国光等．过敏性哮喘患者血清细胞因子和IgE含量变化及意义．中华内科杂志，1997，36(12)：822-823．
[124]Bachman KJ, Jarvinen P, Sorva RS. Serum eosinophil cationic protein during treatment of asthma in children. Allergy Clin Immunol, 1993, 92(1): 34-38.
[125]Sanderson CJ. Interleukin 5,eosinophils and disease. Blood, 1992, 79:3101-3104.
[126]Venge P. Hakansson L. Current understanding of the role of the eosinophil granulocyte in asthma. Clin Exp Allergy, 1991, 21:31-37.
[127]Woodfolk JA, Sung SS, Benjamin DC, et al. Distinct human T cell repertoires mediate immediate and delayed-type hyper-sensitivity to
the Trichophyton antigen, Tri r2. J Immunol, 2000, 165:4379-4387.
[128]Haselden BM, Kay AB, Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med, 1999, 189:1885-1894.
[129]冯益真，王金荣，孙中厚等．哮喘患儿血清ECP、IgE、SIL-2R和IL-5水平及其临床意义的研究．医学理论与实践，1999，12(7)，378-380．
[130]何小菊，郭在晨．哮喘患儿血清嗜酸细胞阳离子蛋白的临床观察，北京医科大学学报，1996，103：782-783．
[131]姜维洁，李培成．哮喘患者白介素5和嗜酸细胞阳离子蛋白的改变．现代诊断与治疗，2000，11(2)：113．
[132]Peden DB, Setzer RW, Jr S, et al. Ozone exposure has both a priming effect on allergen-induced responses and an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics. Am J Respir Crit Care Med, 1995. 151: 1336-45.
[133]刘建梅，陈强，余定英等．婴幼儿哮喘与儿童哮喘患儿血清ECP检测的意义．哮喘杂志，2000，6(2)：11-12．
[134]杨铁生．樊春红．支气管哮喘患者血清ECP检测的临床意义．中国医刊，2002，7：126．
[135]周波，张小燕．支气管哮喘患者血清IL-4，ECP测定的临床意义．中国现代医学杂志，2002，12：378．
[136]邓火金，杨振峰，孙滨．哮喘患者痰液炎性标志物检测及意义．国外医学内科分册，1999，26：111-113．
[137]Emili O, Marcia M, Pizzichini M, et al. Indices of airway inflammation in induced sputum reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med, 1996,154: 308-317.
[138]David M, Claman MD, Homer A, et al. Analysis of induced sputum to examine the effects of prednisone or airway inflammation in
asthmatic subject. J Allergy Clin Immunol, 1994,94:861-869.
[139]Sporik R, Squillace SP, Ingram, JM, et al. Mite, cat, and cockroach exposure, allergen sensitization, and asrhma in children: a case-control study of three schools. Thorax, 1999, 54:675-680.
[140]Platts-Mills TA, Woodfolk JA. Cord blood prolixferative responses to inhaled allergens: is there a phenomenon? J Allergy Clin Immunol, 2000, 106:441-443.
[141]Burrows B, Martinez FD, Halonen M, et al. Association of asthma with serum IgE levels and skin-test reactiveity to allergens. N Engl J Med, 1989,320:271-277.
[142]陈瑜，徐根云，钟步云等．哮喘患者血清ECP测定及其临床应用．中国实验诊断学，2000，5：164．
[143]刘中国，王艳燕，王莲芸等．支气管哮喘血清E-选择素与IgE的相关性研究．中华微生物学和免疫学杂志，2001，21(4)：431-434．
[144]Sears MR, Burrows B, Flannery EM, et al. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children, N Engl J Med, 1991, 325:1067-1071.
[145]Virchow JC, Holscher U, Virchow C. Sputum ECP levels correlate with parameters of airflow obstruction. Am J Respir Crit Care Med, 1992,146: 604-6.
[146]张纪岩．肥大细胞和哮喘非特应性炎症．[综述]．国外医学呼吸系统分册．1993，13(4)：185．
[147]邓火金，孙滨，于化鹏等．哮喘患者血T淋巴细胞和嗜酸细胞活化指标的检测及意义．中国急救医学，1999，19(8)：470-471．
[148]崔曼丽，陈升汶，邱晨等．哮喘患者痰液中炎症介质和细胞因子与气道重塑的关系研究．中华结核和呼吸杂志，2002，6：276．
[149]刘宪文，章世贵，李广贺等．哮喘患者花粉皮试和血清总IgE、IL-4表达及激素干预的影响．山东医药，2001，41(6)：19-20．
[150]廖伟，李为明．β_2-肾上腺素受体遗传多态性与哮喘．国外医学遗传学分册，2000，23(1)：4-7．
[151]Barnes PJ. β-adrenoceptors on smooth muscle, nerves and inflammatory, cells. Life Sci, 1993, 52:2101-2109.
[152]Reihsaus E, Innis M, Maclntyre N, et al. Mutaions in the gene encoding for the Beta 2 adrenoceptor in normal and asthmatic subjects. Am Rev Respir Cell Mol Biol, 1993, 8(6): 334-339.
[153]Hall IP, Weatley A, Wilding P, et al. Association of Glu 27 β_2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet, 1995,345:1213-1214.
[154]Helms P, Hopes E, Mcdougall C, et al. The Glu 27 β_2-adrenoceptor polymorphism is associated with childhood asthma. Thorax. 1996, 51 Suppl:15.
[155]Cooper DM, Troisi JK, Grobhoiz M, et al. Epidemiology of a polymorphism of the Beta 2 adrenoceptor gene in asthma. Am J Respir Crit Care Med, 1996,153(Suppl): A254.
[156]Green SA, Turki J, Innis M, et al. Amino-terminal polymorphisms of the human β_2-adrenergic receptor impart distinct agonistpromoted regulatory properties. Biochemistry, 1994,33: 9414-9419.
[157]Dewar JC, Wheatley AP, Venn A, et al. β_2-adrenoceptor polymorphisms are in linkage disequilibrium but are not associated with asthma in an adult population. Clin Exp Allergy, 1998,28:442-448.
[158]Weir TD, Mallek N, Sandford AJ, et al. β_2-Adrenergic receptor haplotypes in mild, moderate, and fatal/near fatal asthma. Am J Respir Crit Care Med, 1998, 158(3): 787-791.
[159]Ramsay CE, Hayden CM, Tiller KJ, et al. Polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness. Clin Exp Allergy, 1999, 29(9): 1195-203.
[160]Holloway JW, Dunbar PR, Riley GA, et al. Association of β_2-adrenergic receptor polymorphism with severe asthma. Clinical and Experimental Allergy, 2000, 30:1097-1103.
[161]Martinez F D, Graves P E, Baidini M, et al. Association between genetic polymorphisms of the β_2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest, 1998,100:3184-3188.
[162]Elliot I, Jeffrey MD, Stephen BL, et al. The effect of polymorphisms of the β_2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med, 2000,162:75-80.
[163]Xu X, Yang J, Chen C, et al. Familial aggregation of pulmonary function in a rural Chinese community. Am J Respir Crit Care Med, 2000,160:1928-1933.
[164]Jamal T, Juno P, Stuart A, et al. Genetic polymorphisms of the β_2-adrenergic receptor in nocturnal and nonnocturnal asthma. J Clin Invest, 1995,95: 1635-1641.
[165]Turki J, Pak J, Green SA, et al. Genetic polymorphisms of the β_2-adrenergic receptor in nocturnal and nonnocturnal asthma .J Clin Invest, 1995, 95:1635-1641.
[166]Deichmann KA, Schmidt A, Heinzmann A, et al. Association studies on β_2-adrenergic polymorphism and enhanced IgE responsiveness in an atopic population. Clin Exp Allergy, 1999, 29:794-799.
[167]Dewar JC, Wilkinson J, Wheatley A, et al. The glutamine 27 β_2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol, 1997,100:261-265.
[168]Bousquet J, Demoly P, Michel FB. Specific immuneotherapy in rhinitis and asthma. Ann Allergy Asthma Immunol, 2001, 87: 38-42.
[169]Wilson AM, Orr LC, Sims EJ, et al. Antiasthmatic effects of mediator blockaàe versus topical coticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med, 2000, 162: 1297-1301.
[170]Elovic AE, Ohyama H, Sauty A, et al. IL-4-dependent regulation of
TGF-alpha and TGF-beta expression in human eosinophils. J Immunol, 1998, 160(12):6121-6127
[171]殷凯生，主编．支气管哮喘现代治疗．南京：江苏科学技术出版社，2000，236-237．
[172]王爱华，李全新．过敏性哮喘患者外周血IL-2、IL-4、IL-6和IL-8水平的变化．中国现代医学杂志，2000，9：457．
[173]Sanford A J, Chagani T, Zhu S, et al. Polymorphisms in the IL-4. IL-4RA and Fc ε RIβ genes and asthma severity. J Allergy Clin Immunol, 2000, 106, 135-140.
[174]邓静敏，许辉，施焕中．白细胞介素—4对哮喘患者血清IgE的影响．广西医科大学学报，2000，1：38．
[175]崔爱华，冯益真．TH_1／TH_2类细胞因子失衡与支气管哮喘．医学综述，2002，8(3)：140-142，
[176]Shi HZ, Deng JM, Xu H, et al. Effect of inhaled interleukin-4 on airway hypereactivity inasthmatics. Am J Respir Critical Care Med, 1998, 157: 1818-1821.
[177]拉杰，陈宝元．哮喘发病机理及TH_1／TH_2比例的关系，天津医科大学学报，2002，8(3)：403-406．
[178]Sasaki Y, Ihara K, Ahmed S, et al. Lack of association between Atopic asthma and polymorphisms of the histamine H_1 receptor, histamine H_2 receptor and histamine N-methyitransferase genes. Immunogenetics, 2000,51: 238-240.
[179]Magnan AO, Laurent GM, Camilla CA, et al. Assessment of the Th_1/Th_2 paragigm in whole blood in atopy and asthma: increased IFN-γ-producing CD8~+ T cells in asthma . Am J Respir Crit Care Med, 2000, 161:1790.
[180]徐文玉，王易，周莉莉等．白细胞介-4在过敏性哮喘中的作用[综述]．国外医学卫生学分册，1997，24(1)：15．
[181]郭雪君，李伟，邓伟吾等．T细胞受体Ⅴβ链基因限制性取用与哮喘患者的关系．中华结核和呼吸杂志，2002，2：173．
[182]Stafforini DM. PAF acetylhydrolase gene polymorphisms and asthma severity. Pharmacogenomics, 2001,2(3): 163-175.
[183]Rosenwasser L J, Borish J. Genetics of atopy and asthma: the rationale behind promote-based candidate gene studies(IL-4 and IL-10). Am J Respir Crit Care Meal, 1997, 156:S152-155.
[184]Noguchi EM, Shibasaki T, Arinami K, et al. Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy, 1998, 28:449-453.
[185]Walley AJ, Cookson WOCM. Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy. J Med Genet, 1996, 33:689-692.
[186]Zhu S, Chan YM, Becket AB, et al. Polymorphisms of the IL-4, TNF-α and Fc ε RIβ genes and the risks of allergic disorders in at-risk infants. Am J Respir Crit Care Med, 2000,161 :P1655-1659.
[2] 叶任高，内科学，第五版．北京：人民卫生出版社，2000，32．
[3] 张恩森．哮喘发病机制的研究新进展．医学综述，2001，7(12)：744
[4] 戴爱国，张平．嗜酸性粒细胞凋亡与哮喘呼吸道炎症．中华结核与呼吸杂志，1998，21(4)：243-244．
[5] 黄宏，徐军，钟南山．哮喘患者外周血嗜酸性粒细胞抗体的表达及临床意义．中华结核与呼吸杂志，1998，21(10)：612-614．
[6] 叶世泰，主编．变态反应学．科学出版社，1998，325．
[7] 张丹，杨振峰．哮喘的呼吸道重塑和嗜酸细胞性炎症．医学综述，2001，7(5)：301-303．
[8] Oettgen HC, Geha RS. IgE in asthma and atopy: celluar and molecular connections. J Clin Invest 1999, 104:829-835.
[9] Chang TW. The pharmacological basis of anti-IgE therapy. Nat Biotechnol, 2000, 18:157-162.
[10] Venge Per. The monitoring of inflammation by specific cellular markers. Scand J Clin Lab Invest 1994, Suppl 219: 47-54.
[11] Ahlstedt S, Peterson CGB, Enander I. Update in allergy testing in childhood asthma: how do you know whether you are successfully controlling the patient's inflammation? Pediatr Pulmonol. 1995, Suppl 11:32-33.
[12] Venge Per. Role of Eosinophils in childhood asthma inflammation. Pediatr Pulmonol. 1995, Suppl 11:34-35.
[13] Woolley KL, Adelroth E, Woolley MJ, et al. Effects of allergen challenge on eosinophil cationic protein, and granulocyte-macrophage colony-stimulating factor in mild asthma. Am J Respir Crit
Care Med, 1995, 151:1915-1924.
[14] Sporik R, Ingram JM, Price W, et al. Association of asthma with serum IgE and skin test reactivity to allergens among children living at high altitude. Am J Respir Crit Care Med, 1995, 151:1388-1392.
[15] 郭晓明，赖克方，王长征等．哮喘豚鼠嗜酸性粒细胞凋亡及凋亡相关基因表达的研究．中华结核与呼吸杂志，1998，21(12)：708．
[16] 严永东，盛锦云，郁晰等．哮喘患儿血清嗜酸细胞阳离子蛋白、总IgE及外周血嗜酸细胞水平的变化及临床意义．中国实用儿科杂志，2000,8：325．
[17] 杨铁生，樊春红．发作期哮喘患者激素治疗前后血清ECP水平的变化及意义．上海医学检验杂志，2000，6：219．
[18] Sunyer J, Anto JM, Sabria J, et al. Relationship between serum IgE and airway responsiveness in adult; with asthma. J Allergy Clin Immunol, 1995,95:699-706.
[19] Squillace SP, Spoirk RB, Rakes G, et al. Sensitization to dust mites as a dominant risk factor for asthma among adolescents living in central Virginia: multiple regression analysis of a population-based study. Am J Respir Crit Care Med, 1997, 156: 1760-1764.
[20] Lau S, Illi S, Sommerfeld C, et al. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Multicentre Allergy Study Group. Lancet, 2000, 356:1392-1397.
[21] 张景波，杨建华，倪玉美等．支气管哮喘患者血清嗜酸细胞阳离子蛋白的变化．细胞与分子免疫学杂志，2000，1：37-39．
[22] 徐辉，王建东，罗炎杰等．哮喘患者诱导痰嗜酸细胞阳离子蛋白、白细胞介素5水平的改变及其意义．急诊医学，2000，3：121．
[23] 邓念强，王琦筠，万德胜等．无症状气道高反应性与血清特异性IgE及血清嗜酸细胞阳离子蛋白的相关性研究．中华结核与呼吸杂志，2000，6：213．
[24] 孙宝清，黄海鹭，王远照等．支气管哮喘患者血清特异性IgE与
ECP的关系．广州医学院学报，1998,4：175．
[25] 王莲芸，王怀云，赵嘉惠等．支气管哮喘患者sVCAM-1和ECP的分析．上海免疫学杂志，2000，5：235．
[26] 王翔．IL-5和ECP在支气管哮喘病因中的作用．四川医学，2000，12：654．
[26] Wang W, Halmurat U. Association between serum measurements of eosinophil cationic protein、total IgE and specific IgE with bronchial asthma in Uygur population. 2003,3.
[27] Newman-Taylor A. Environmental determinants of asthma. Lancet, 1995, 345:296-299.
[28] Becklake MR, Ernst P. Environmental factors. Lancet, 1997, 350: 10-13.
[29] 况少青，张宇舟，陈苎．基因组扫描—遗传病相关基因定位的有力工具．中华医学遗传学杂志，1997，14：99-103．
[30] 罗慰慈主编．现代呼吸病学．第一版，北京：人民军医出版社，1997，271．
[31] 周斌，刘宏，殷明．哮喘药物的基因组学研究进展．中国临床药理学杂志，2003，19(1)：63-66．
[32] Pearlman DS. Pathophysiology of the inflammatory response. J Allergy Clin Immunol, 1999, 104: S132-S137.
[33] Fahy JV, Corry DB, Boushey HA. Airway inflammation and remodeling in asthma. Curr Opin Pulm Med, 2000, 6:15-20.
[34] Sandford A, Weir T, Pare P.The genetics of asthma. Am J Respir Crit Care Mod ,1996,153:1749-1765.
[35] Weiss ST. Gene by environment interaction and asthma. Clin Exp Allergy, 1999, 29 Suppl 2:96-9.
[36] 赵华，杜晓娟，林丽渊等．中国人哮喘易感性与染色体5q~(31-33)区连锁关系的初步研究．中华儿科杂志，1998，36(12)：713-716．
[37] Postma DS, Bleecker ER, Amelung PJ, et al. Genetic susceptibility to asthma-bronchial hyperresponsiveness coinherited with a major
gene for atopy. N Engl J Med, 1995,333:894-900.
[38]Daniels SE, Bhattacharrya S, James A, et al. A genome-wide search for quantitative trait loci underlying asthma. Nature, 1996, 383:247-250.
[39]Thomas NS, Wilkinson J, Holgate ST. The candidate region approach to the genetics of asthma and allergy. Am J Respir Crit Care Med, 1997, 156:S144-151.
[40]Thomas NS, Holgate ST. Candidate locus approach for studying the genetics of asthma and atopy. Monaldi Arch Chest Dis, 1997, 52: 296-302.
[41] 刘春涛，谢敏，王曾礼．几种新发现的与哮喘有关的细胞因子．国外医学内科学分册，2000，3：165．
[42]Demoly P, Bousquet J. Genetics of asthma and atopy. J Soc Biol, 2000, 194(1): 39-42.
[43] 姜丽敏，朱惠如，章晓冬，支气管哮喘遗传相关基因的研究．现代康复，2001，5：217．
[44] 徐军．支气管哮喘(一)哮喘的基因治疗．实用医学杂志，2001，6：372．
[45]Williams CM, Galli SJ. The diverse potential effector and immuneoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol, 2000, 105:847-859.
[46]Young RP, Sharp PA, Lynch JR, et al. Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13. J Med Genet, 1992,29:236-238.
[47]Suzuki I, Hizawa N, Yamaguchi E, et al. Association between a C+33T polymorphism in the IL-4 promoter region and total serum IgE levels. Clin Exp Allergy. 2000; 30(12): 1746-9.
[48]Meyers DA, Postma DS, Panhuysen CI, et al. Evidence for a locus regulating total serum IgE levels mapping to chromosome 5. Genomics, 1994, 23:464-470.
[49] Marsh DG, Neely JD, Breazeale DR, et al. Linkage analysis of IL-4 and other chromosome 5q~(31.1) markers and total serum immunoglobulin E concentrations. Science, 1994,264:1152-1156.
[50] Hijazi Z, Haider MZ. Interleukin-4 gene promoter polymorphism [C590-T] and asthma in Kuwaiti Arabs.Int Arch Allergy. Immunol, 2000, 122(3): 190.
[51] Chouchane IL, Sfar R, Bousaffara A, et al. A repeat polymorphism in interleukin-4 gene is highly associated' with specific clinical phenotypes of asthma, Int Arch Allergy Immunol, 1999, 120:50-55.
[52] 高光凯，王士雯，张进川．中国北方汉族人群支气管哮喘患者β_2肾上腺素能受体基因多态性研究．中华结核和呼吸杂志，2000，23(2)：93-97．
[53] 伏瑾，陈虹，胡良平等．β_2-肾上腺素能受体基因的多态性与哮喘及其临床表型的关系．中华医学遗传学杂志，2002，19(1)：41-45．
[54] 戴路明，王曾礼，张亚平等．β_2受体遗传多态性与支气管哮喘患者肺功能关系研究．中华结核和呼吸杂志，2002，25(9)：554-555．
[55] 高金明，林耀广，邱长春等．β_2-肾上腺素能受体基因多态性和支气管哮喘的关系，中国医学科学院学报，2002，24(6)：626-631．
[56] 邱玉英，殷凯生．β_2肾上腺素受体遗传多态性与血清总IgE关系的研究．中华结核和呼吸杂志，2002，1：37．
[57] Liggett S B. Polymorphisms of the β_2-adrenergic receptor and asthma. Am J Respir Crit Care Med, 1997,156:156-162.
[58] Liggett S B. Molecular and genetic basis of β_2-adrenergic receptor function. J Allergy Clin Immunol, 1999, 103:42-46.
[59] Green SA, Turki J, Innis M, et al. Aminoterminal polymorphisms of the human β_2-adrenergic receptor impart distinct agonistpromoted regulatory properties. Biochemistry, 1994, 33:9414-9419.
[60] Green SA, Turki J, Bejarano P, et al. Influence of β_2-adrenergic receptor genotypes on signal transduction in human airway smooth muscle cells. Am J Respir Cell Mol Biol, 1995,13:25-33.
[61] 苄如濂．β肾上腺素受体激动剂．见：周汉良，陈季强主编．呼吸药理学与治疗学．第一版．北京：人民卫生出版社，1999，258-259．
[62] Kobilka BK, Frielle HG, Dohlman MA, et al. Delineation of theintronless naturee of the genes for the human and hamster β_2-adrenergic receptor and their promoter regions. J Biol Chem. 1996,262:7321-7327.
[63] Aziz I, Hall IP, Mcfarlane LC, et al. Beta2-adrenoceptor regulation and bronchodilator sensitivity after regular treatment with formoterol in subjects with stable asthma. J Allergy Clin Immunol, 1998,101:337-341.
[64] Mcgraw DW, Liggett SB. Coding block and 5 leader cistron polymorphisms of the beta2-adrenergic receptor. Clin Exp Allergy, 1999, 4(Suppl):43-45.
[65] Lipworth BJ, Hall IP, Aziz I, et al. Beta2-adrenoceptor polymorphism and brochoprotective sensitivity with regular short and long acting beta2-agonist therapy. Clin Sci (Colch),1999,96:253-259.
[66] Green SA, Cole M, Jacinto M, et al. A polymorphism of the human Beta 2 adrenoceptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor. Biol Chem, 1993,268(19): 23116-23121.
[67] Moore PE, Laporte JD, Abraham JH, et al. Polymorphism of the β_2-adrenergic receptor gene and desensitization in human airway smooth muscle. Am J Respir Crit Care Med. 2000, 162:2117-2124.
[68] Fenech A, Hall IP. Pharmacogenetics of asthma. Br J Clin Pharmacol, 2002,53: 3-15.
[69] Hurley DM, Acclli D, Stratakis CA, et al. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest, 1991, 87: 680-686.
[70] Panarelli M, Holloway CD, Fraser R, et al. Glucocorticoid receptor polymorphism, skin vasoconstriction and other metabolic intermediate phenotypes in normal human subjects. J Clin Endocrinol Metab, 1998, 83:1846-1852.
[71] Xie HG, Stein CM, Kim RB, et al. Frequency of functionally important beta-2 adrenoceptor polymorphisms varies markedly among African-American, Caucasian and Chinese individuals. Pharmacogenomics, 1999,9:511-516.
[72] Scott MGH, Swan C, Wheatley AP, et al. Identification of novel polymorphisms within the promoter region of the human beta(2) adrenergic receptor gene. Br J Pharmacol, 1999, 126: 841-844.
[73] Lima JJ, Thomason DB, Mohamed MHN, et al. Impact of genetic polymorphisms of the β_2-adrenergic receptor on albuterol hronchodilator pharmacodynamics. Clin Pharmacol Ther, 1999, 65: 519-525.
[74] Lima JJ, Mohamed MH, Self TH, et al. Importance of beta(2)-adrenergic receptor genotype, gender and race on albuterol-evoked bronchodilation in asthmatics. Pulm Pharmacol Ther, 2000, 13: 127-134.
[75] Lipworth BJ, Dempsey OJ, Aziz I, et al. Effects of adding a leukotriene antagonist or a long-acting beta(2)-agonist in asthmatic patients with the glycine-16 beta(2)-adrenoceptor genotype. Am J Med, 2000, 109, 114-121.
[76] Ward GM Jr, Woodfolk JA, Hayden ML, et al. Treatment of late-onset asthma with fluconazole. J Allergy Clin Immunol, 1999, 104(3Pt 1): 541-546.
[77] Tan S, Hall IP, Dewar J, et al. Association between β_2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitization in moderately severe stable asthmatics. Lancet, 1997. 350: 995-999.
[78] Lipworth BJ, Dempsey OJ, Aziz I. Functional antagonism with
formoterol and salmeterol in asthmatic patients expressing the homozygous glycine-16 beta(2)-adrenoceptor polymorphism. Chest, 2000, 118:321-328.
[79]Israel E, Drazen JM, Liggett SB, et al. The effect of polymorphisms of the beta(2)-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med, 2000, 162: 75-80.
[80]Taylor DR, Drazen JM, Herbison GP, et al. Asthma exacerbations during long term beta agonist use: influence of beta(2) adrenoceptor polymorphism. Thorax, 2000, 55: 762-767.
[81]支气管哮喘防治指南(支气管哮喘的定义、诊断、治疗、疗效判断标准及教育和管理方案)．中华结核和呼吸杂志，1997，20(5)：261-267．
[82]Burney PGJ, Laitinen LA, Perdrizet S. et al. Validity and repeatability of the IUATLD (1984) Bronchial Symptoms Questionnaire: an international comparison. Eur Respir J, 1989,2:940-945.
[83]李秋根，刘江红，雷建平等．血清和诱导痰嗜酸细胞阳离子蛋白在检测布地奈德治疗支气管哮喘气道炎症中的作用．治疗哮喘药物临床应用有奖征文论文汇编．中华结核和呼吸杂志编委会，2002，11：61-62．
[84]UniCAP体外检测临床应用指南．南京美瑞制药有限公司诊断试剂部2002，10．
[85]钟南山，黄海鹭．正常人群血清嗜酸细胞阳离子蛋白(ECP)水平的测定．嗜酸细胞阳离子蛋白(ECP)临床应用文集，南京美瑞制药有限公司诊断试剂部2002，10．
[86]Kowalski ML, Woszczek G, Borowiec M. Distribution of theβ_2-adrenoceptor polymorphisms in atopic and non-atopic patients. J Allergy Clin Immunol, 1997,100:338.
[87]Nijkamp F, Engels P, Henricks P, et al. Mechanisms of β-adrenergic receptor regulation in lungs and its implications for physiological responses. Physiol Rev, 1992,72:323-367.
[88]Hancox RJ, Sears MR, Taylor DR. Polymorphism of the β_2-adrenoceptor and the response to long-term β_2-agonist therapy in asthma. Eur Respir J. 1998,11:589-593.
[89]Holroyd KJ, Levitt RC, Dragwa DC, et al. Evidence for β_2 adrenergic receptor(ADRB2) polymorphism at amino acid 16 as a risk factor for bronchial hyperresponsiveness(BHR). Am J Respir Crit Care Med, 1995,151:673.
[90]Bleecker ER, Postma DS, Meyers DA, et al. Evidence of multiple genetic susceptibility loci for asthma. Am J Respir Crit Care Med, 1997,156:113-116.
[91]Wang ZX, Chen CZ, Niu TH, et al. Association of asthma with β_2-adrenergic receptor gene polymorphism and cigarette smoking. Am J Respir Crit Care Med, 2001,163:1404-1409.
[92]Ulbrecht M, Hergeth MT, Wist M, et al. Association of beta (2)-adrenoreceptor variants with bronchial hyperresponsiveness. Am J Respir Crit Care Med, 2000,161(2 pt 1): 469-74.
[93]J.萨姆布鲁克，D.W.拉塞尔主编．分子克隆实验指南(第三版)北京：科学出版社，2002：302-532．
[94]Burrows B, Sears MR, Flannery GP, et al. Relations of bronchial responsiveness to allergy skin test reactivity, lung function, respiratory symptoms, and diagnoses in thirteen-year-old New Zealand children. J Allergy Clin Immunol, 1995,95:548-556.
[95]Ying S, Durham SR, Corrigan CJ, et al. Phenotype of cells expressing mRNA for Th2-type(interleukin-4 and interleukin-5) and Th1-type(interleukin-2 and interferon-gamma) cytokines in bronchialveolar lavage and bronchial biopsyes from atopic asthmatics and normal control subjects. Am J Respir Cell Mol Biol. 1995, 12:477-487.
[96]Kenyon NJ, Kelly EA, Jarjour NN. Enhanced cytokine generation by peripheral blood mononuclear cells in allergic and asthma subjects.
Ann Allergy Asthma Immunol, 2000,85(2): 115.
[97]Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in moderate atopic asthma:a phase Ⅰ/Ⅱ randomized placebocontrolled trial. Am J Respir Crit Care Med, 1999, 160:1816-1823.
[98]阳显慧．白细胞介素—5在哮喘发病机制中的作用．医学综述，2001,7(4): 195-197.
[99]Ackerman V, Marini M, Vittori E, et al. Detection of cytokines and their cell sources in bronchial specimens from asthmatic patients. Relationship to atopic status, symptoms, and level of airway hyperresponsiveness. Chest. 1994,105(3):687-696.
[100]Teramoto T, Fukao T, Tashita H, et al. Serum IgE level is negatively correlated with the ability of peripheral mononuclear cells to produce interferon gamma(IFNgamma):Evidence of reduced expression of IFN gamma mRNA in atopic patients. Clin Exp Allergy, 1998, 28(1):74.
[101]Gosset P, Tillie-Leblond I, Janin A, et al. Expression of E-selectin, ICAM-1 and VCAM-1 on bronchial biopasies from allergic and nonallergic asthmatic patients. Int Arch Allergy Immunol, 1995, 106(1):67-69.
[102]钱小顺．哮喘嗜酸粒细胞凋亡的调控．国外医学呼吸系统分册，2000，20(1)：6-9．
[103]Humbert M, Durham SR, Ying S, et al. IL-5 m RNA and protein in bronchial biopsies from Atopic and non-atopic asthmatics: Evidence against "intrinsic" asthma being a distinct immunopathological entity. Am J Respir Crit Care Med. 1996, 154: 1497-1504.
[104]Hansen G, Berry G, Dekruyff RH, et al. Allergen-specific Th_1 cells fail to counterbalance Th_2 cell-induced airway hyperreactivity but cause severe airway inflammation. J Clin Invest, 1999, 103(2): 175.
[105]Burchard EG, Silverman EK, Rosenwasser LJ, et al. Association between a sequence variant in the IL-4 gene promoter and FEV_1 in
asthma. Am J Respir Crit Care Med, 1999, sep 160 (3): 919-922.(Genbank access M23442)
[106]朱晓华，吴熙，陈强等．白介素—4基因启动子多态性与儿童哮喘关系的研究．中国实用儿科杂志，2002，17(8)：475-477．
[107]Song Z, Caslarro V, Chen R, et al. Polymorphic nucleotides within the human IL-4 promoter that mediate overexpression of the gene. J Immunol, 1996, 156:424.
[108]张嘉琳，陈虹，胡良平等，IL-4、IL-10基因启动子区多态性与儿童哮喘的相关性及对细胞因子表达的影响．哮喘杂志，2002，8(1)：1-5．
[109]王长征．嗜酸性粒细胞与支气管哮喘．中华结核与呼吸杂志，1998，21：562-564．
[110]Platts-Mills TAE. The role of immunoglobulin E in allergy and asthma. Am J Respir Crit Care Med, 2001, 164: 1-5.
[111]李明华，殷凯生主编．哮喘病学．第一版．北京：人民卫生出版社，1998，400．
[112]Norzila MZ, Fakes K, Henry RL, et al. IL-8 secretion and neutrophil recruitment accompanyies induced sputum eosinophil activation in children with acute asthma. Am J Respir Crit Care Med, 2000,161: 769-794.
[113]Fujimoto K, Kubo K, Matsuzawa Y, et al. Eosinophil cationic protein levels in induced sputum correlate with the severity of bronchial asthma. Chest, 1997, 112(5):1241-1247.
[114]Bengtsson U, Knutson TW, Knutson L, et al. Eosinophil cationic protein and histamine after intestinal challenge in patients with cows milk intolerance. J Allergy Clin Immunol, 1997, 100:216-221.
[115]Kita H. The eosinophil:a cytokine-producing cell? J Allergy Clin Immunol, 1997,97(4): 889-892.
[116]Venge H. Serum measurements of eosinophil cationic protein (ECP) in bronchial asthma. Clinical and Experimental Allergy, 1993, 23
(Suppl2): 3-7.
[117]Platts-Mills TAE, Vaughan J, Squillace SP, et al. Sensitisation, astrhma, and a modified TH_2 response in children exposed to cat allergen: a population-based cross-sectional study. Lancet, 2001, 357:752-756.
[118]邵莉，朱丽君，许以平．变应原特异性IgE抗体和ECP测定在哮喘中的意义．上海第二医科大学学报，2002，22(3)：254-255．
[119]Bjornsson E, Janson C, Hakansson L, et al. Serum eosinophil cationic protein in relation to bronchial asthma in a young Swedish population. Allergy, 1994, 49(9):730-736.
[120]Busse WW, Coffman RL, Gelfand EW, et al. Mechanisms of persistent airway inflammation in asthma: a role for T cells and T-cell products. Am J Respir Crit Care Med, 1995, 152:388-393.
[121]Platts-Mills TA, Vaughan JW, Carter MC, et al. The role of intervention in established allergy: avoidance of indoor allergens in the treatment of chronic allergic disease. J Allergy Clin Immunol, 2000, 106:787-804.
[122]童朝晖，张宏誉．血清ECP测定在支气管哮喘治疗中的应用．中华微生物和免疫学杂志，1996，16(增刊1)：16-17．
[123]赵斌，王丹琪，夏国光等．过敏性哮喘患者血清细胞因子和IgE含量变化及意义．中华内科杂志，1997，36(12)：822-823．
[124]Bachman KJ, Jarvinen P, Sorva RS. Serum eosinophil cationic protein during treatment of asthma in children. Allergy Clin Immunol, 1993, 92(1): 34-38.
[125]Sanderson CJ. Interleukin 5,eosinophils and disease. Blood, 1992, 79:3101-3104.
[126]Venge P. Hakansson L. Current understanding of the role of the eosinophil granulocyte in asthma. Clin Exp Allergy, 1991, 21:31-37.
[127]Woodfolk JA, Sung SS, Benjamin DC, et al. Distinct human T cell repertoires mediate immediate and delayed-type hyper-sensitivity to
the Trichophyton antigen, Tri r2. J Immunol, 2000, 165:4379-4387.
[128]Haselden BM, Kay AB, Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med, 1999, 189:1885-1894.
[129]冯益真，王金荣，孙中厚等．哮喘患儿血清ECP、IgE、SIL-2R和IL-5水平及其临床意义的研究．医学理论与实践，1999，12(7)，378-380．
[130]何小菊，郭在晨．哮喘患儿血清嗜酸细胞阳离子蛋白的临床观察，北京医科大学学报，1996，103：782-783．
[131]姜维洁，李培成．哮喘患者白介素5和嗜酸细胞阳离子蛋白的改变．现代诊断与治疗，2000，11(2)：113．
[132]Peden DB, Setzer RW, Jr S, et al. Ozone exposure has both a priming effect on allergen-induced responses and an intrinsic inflammatory action in the nasal airways of perennially allergic asthmatics. Am J Respir Crit Care Med, 1995. 151: 1336-45.
[133]刘建梅，陈强，余定英等．婴幼儿哮喘与儿童哮喘患儿血清ECP检测的意义．哮喘杂志，2000，6(2)：11-12．
[134]杨铁生．樊春红．支气管哮喘患者血清ECP检测的临床意义．中国医刊，2002，7：126．
[135]周波，张小燕．支气管哮喘患者血清IL-4，ECP测定的临床意义．中国现代医学杂志，2002，12：378．
[136]邓火金，杨振峰，孙滨．哮喘患者痰液炎性标志物检测及意义．国外医学内科分册，1999，26：111-113．
[137]Emili O, Marcia M, Pizzichini M, et al. Indices of airway inflammation in induced sputum reproducibility and validity of cell and fluid-phase measurements. Am J Respir Crit Care Med, 1996,154: 308-317.
[138]David M, Claman MD, Homer A, et al. Analysis of induced sputum to examine the effects of prednisone or airway inflammation in
asthmatic subject. J Allergy Clin Immunol, 1994,94:861-869.
[139]Sporik R, Squillace SP, Ingram, JM, et al. Mite, cat, and cockroach exposure, allergen sensitization, and asrhma in children: a case-control study of three schools. Thorax, 1999, 54:675-680.
[140]Platts-Mills TA, Woodfolk JA. Cord blood prolixferative responses to inhaled allergens: is there a phenomenon? J Allergy Clin Immunol, 2000, 106:441-443.
[141]Burrows B, Martinez FD, Halonen M, et al. Association of asthma with serum IgE levels and skin-test reactiveity to allergens. N Engl J Med, 1989,320:271-277.
[142]陈瑜，徐根云，钟步云等．哮喘患者血清ECP测定及其临床应用．中国实验诊断学，2000，5：164．
[143]刘中国，王艳燕，王莲芸等．支气管哮喘血清E-选择素与IgE的相关性研究．中华微生物学和免疫学杂志，2001，21(4)：431-434．
[144]Sears MR, Burrows B, Flannery EM, et al. Relation between airway responsiveness and serum IgE in children with asthma and in apparently normal children, N Engl J Med, 1991, 325:1067-1071.
[145]Virchow JC, Holscher U, Virchow C. Sputum ECP levels correlate with parameters of airflow obstruction. Am J Respir Crit Care Med, 1992,146: 604-6.
[146]张纪岩．肥大细胞和哮喘非特应性炎症．[综述]．国外医学呼吸系统分册．1993，13(4)：185．
[147]邓火金，孙滨，于化鹏等．哮喘患者血T淋巴细胞和嗜酸细胞活化指标的检测及意义．中国急救医学，1999，19(8)：470-471．
[148]崔曼丽，陈升汶，邱晨等．哮喘患者痰液中炎症介质和细胞因子与气道重塑的关系研究．中华结核和呼吸杂志，2002，6：276．
[149]刘宪文，章世贵，李广贺等．哮喘患者花粉皮试和血清总IgE、IL-4表达及激素干预的影响．山东医药，2001，41(6)：19-20．
[150]廖伟，李为明．β_2-肾上腺素受体遗传多态性与哮喘．国外医学遗传学分册，2000，23(1)：4-7．
[151]Barnes PJ. β-adrenoceptors on smooth muscle, nerves and inflammatory, cells. Life Sci, 1993, 52:2101-2109.
[152]Reihsaus E, Innis M, Maclntyre N, et al. Mutaions in the gene encoding for the Beta 2 adrenoceptor in normal and asthmatic subjects. Am Rev Respir Cell Mol Biol, 1993, 8(6): 334-339.
[153]Hall IP, Weatley A, Wilding P, et al. Association of Glu 27 β_2-adrenoceptor polymorphism with lower airway reactivity in asthmatic subjects. Lancet, 1995,345:1213-1214.
[154]Helms P, Hopes E, Mcdougall C, et al. The Glu 27 β_2-adrenoceptor polymorphism is associated with childhood asthma. Thorax. 1996, 51 Suppl:15.
[155]Cooper DM, Troisi JK, Grobhoiz M, et al. Epidemiology of a polymorphism of the Beta 2 adrenoceptor gene in asthma. Am J Respir Crit Care Med, 1996,153(Suppl): A254.
[156]Green SA, Turki J, Innis M, et al. Amino-terminal polymorphisms of the human β_2-adrenergic receptor impart distinct agonistpromoted regulatory properties. Biochemistry, 1994,33: 9414-9419.
[157]Dewar JC, Wheatley AP, Venn A, et al. β_2-adrenoceptor polymorphisms are in linkage disequilibrium but are not associated with asthma in an adult population. Clin Exp Allergy, 1998,28:442-448.
[158]Weir TD, Mallek N, Sandford AJ, et al. β_2-Adrenergic receptor haplotypes in mild, moderate, and fatal/near fatal asthma. Am J Respir Crit Care Med, 1998, 158(3): 787-791.
[159]Ramsay CE, Hayden CM, Tiller KJ, et al. Polymorphisms in the beta2-adrenoreceptor gene are associated with decreased airway responsiveness. Clin Exp Allergy, 1999, 29(9): 1195-203.
[160]Holloway JW, Dunbar PR, Riley GA, et al. Association of β_2-adrenergic receptor polymorphism with severe asthma. Clinical and Experimental Allergy, 2000, 30:1097-1103.
[161]Martinez F D, Graves P E, Baidini M, et al. Association between genetic polymorphisms of the β_2-adrenoceptor and response to albuterol in children with and without a history of wheezing. J Clin Invest, 1998,100:3184-3188.
[162]Elliot I, Jeffrey MD, Stephen BL, et al. The effect of polymorphisms of the β_2-adrenergic receptor on the response to regular use of albuterol in asthma. Am J Respir Crit Care Med, 2000,162:75-80.
[163]Xu X, Yang J, Chen C, et al. Familial aggregation of pulmonary function in a rural Chinese community. Am J Respir Crit Care Med, 2000,160:1928-1933.
[164]Jamal T, Juno P, Stuart A, et al. Genetic polymorphisms of the β_2-adrenergic receptor in nocturnal and nonnocturnal asthma. J Clin Invest, 1995,95: 1635-1641.
[165]Turki J, Pak J, Green SA, et al. Genetic polymorphisms of the β_2-adrenergic receptor in nocturnal and nonnocturnal asthma .J Clin Invest, 1995, 95:1635-1641.
[166]Deichmann KA, Schmidt A, Heinzmann A, et al. Association studies on β_2-adrenergic polymorphism and enhanced IgE responsiveness in an atopic population. Clin Exp Allergy, 1999, 29:794-799.
[167]Dewar JC, Wilkinson J, Wheatley A, et al. The glutamine 27 β_2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families. J Allergy Clin Immunol, 1997,100:261-265.
[168]Bousquet J, Demoly P, Michel FB. Specific immuneotherapy in rhinitis and asthma. Ann Allergy Asthma Immunol, 2001, 87: 38-42.
[169]Wilson AM, Orr LC, Sims EJ, et al. Antiasthmatic effects of mediator blockaàe versus topical coticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med, 2000, 162: 1297-1301.
[170]Elovic AE, Ohyama H, Sauty A, et al. IL-4-dependent regulation of
TGF-alpha and TGF-beta expression in human eosinophils. J Immunol, 1998, 160(12):6121-6127
[171]殷凯生，主编．支气管哮喘现代治疗．南京：江苏科学技术出版社，2000，236-237．
[172]王爱华，李全新．过敏性哮喘患者外周血IL-2、IL-4、IL-6和IL-8水平的变化．中国现代医学杂志，2000，9：457．
[173]Sanford A J, Chagani T, Zhu S, et al. Polymorphisms in the IL-4. IL-4RA and Fc ε RIβ genes and asthma severity. J Allergy Clin Immunol, 2000, 106, 135-140.
[174]邓静敏，许辉，施焕中．白细胞介素—4对哮喘患者血清IgE的影响．广西医科大学学报，2000，1：38．
[175]崔爱华，冯益真．TH_1／TH_2类细胞因子失衡与支气管哮喘．医学综述，2002，8(3)：140-142，
[176]Shi HZ, Deng JM, Xu H, et al. Effect of inhaled interleukin-4 on airway hypereactivity inasthmatics. Am J Respir Critical Care Med, 1998, 157: 1818-1821.
[177]拉杰，陈宝元．哮喘发病机理及TH_1／TH_2比例的关系，天津医科大学学报，2002，8(3)：403-406．
[178]Sasaki Y, Ihara K, Ahmed S, et al. Lack of association between Atopic asthma and polymorphisms of the histamine H_1 receptor, histamine H_2 receptor and histamine N-methyitransferase genes. Immunogenetics, 2000,51: 238-240.
[179]Magnan AO, Laurent GM, Camilla CA, et al. Assessment of the Th_1/Th_2 paragigm in whole blood in atopy and asthma: increased IFN-γ-producing CD8~+ T cells in asthma . Am J Respir Crit Care Med, 2000, 161:1790.
[180]徐文玉，王易，周莉莉等．白细胞介-4在过敏性哮喘中的作用[综述]．国外医学卫生学分册，1997，24(1)：15．
[181]郭雪君，李伟，邓伟吾等．T细胞受体Ⅴβ链基因限制性取用与哮喘患者的关系．中华结核和呼吸杂志，2002，2：173．
[182]Stafforini DM. PAF acetylhydrolase gene polymorphisms and asthma severity. Pharmacogenomics, 2001,2(3): 163-175.
[183]Rosenwasser L J, Borish J. Genetics of atopy and asthma: the rationale behind promote-based candidate gene studies(IL-4 and IL-10). Am J Respir Crit Care Meal, 1997, 156:S152-155.
[184]Noguchi EM, Shibasaki T, Arinami K, et al. Association of asthma and the interleukin-4 promoter gene in Japanese. Clin Exp Allergy, 1998, 28:449-453.
[185]Walley AJ, Cookson WOCM. Investigation of an interleukin-4 promoter polymorphism for associations with asthma and atopy. J Med Genet, 1996, 33:689-692.
[186]Zhu S, Chan YM, Becket AB, et al. Polymorphisms of the IL-4, TNF-α and Fc ε RIβ genes and the risks of allergic disorders in at-risk infants. Am J Respir Crit Care Med, 2000,161 :P1655-1659.