Toll样受体4与支气管哮喘气道高反应

气道高反应性是支气管哮喘的基本特征.气道高反应的机制目前尚未完全阐明.当前支气管哮喘的治疗亦不能有效地抑制气道高反应性和气道重塑.近来发现,Toll样受体是一种属于I型跨膜蛋白的天然免疫模式识别受体.TLR4通过调控气道炎症,促进气道平滑肌增生,参与气道重塑等方式参与气道高反应性过程.本文主要探讨TLR4与在支气管哮喘...     

靶向Toll样受体4治疗支气管哮喘的价值

<正>支气管哮喘(哮喘)是多基因参与的具有遗传易感性的慢性气道炎症性疾病,其发病涉及多种炎症细胞、炎症介质和复杂的细胞因子网络,以血清IgE增高、气道炎症、气道高反应性和气道重塑为显著的临床特征~([1])。Toll样受体(Tolllike receptors,TLR)是果蝇受体Toll同源物,作为固有免疫系统的一种重要的模式识别受体,连接着机体固有免疫和适应性免疫。目前已鉴定人类14种TLR。越来越多的证据表     

地塞米松对支气管哮喘大鼠气道重塑及气道平滑肌中Toll样受体4表达的影响

气道炎症和气道重塑是支气管哮喘(简称哮喘)发生、发展的重要环节,但其发病机制尚未完全明确[1].Toll样受体(Toll like receptor,TLR)是天然免疫和获得性免疫的桥梁[2],研究结果表明,TLR在哮喘的发生、发展中可能起着较为重要的作用[3].地塞米松是治疗哮喘的经典药物,对哮喘的气道炎症和气道重塑均有改善作用,但其作用机制不明.因此,我们将建立哮喘动物模型,从整体水平探讨地塞米松治疗对哮喘气道重塑以及哮喘气道平滑肌中TLR4表达的影响.     

ERK信号传导途径对人气道平滑肌细胞增殖与凋亡及其相关基因表达的影响

气道重塑是慢性支气管哮喘(简称哮喘)的重要病理特征,是哮喘不可逆气流受限和气道高反应性的病理基础 [1-2].气道重塑可加重气道的高反应性,导致肺功能持续性与进行性损害.     

生长因子与气道重塑——生长因子在支气管哮喘气道重塑过程中作用的新进展

支气管哮喘(简称哮喘)是由多种细胞和细胞组分参与的气道慢性炎症性疾病.气道重塑在哮喘早期即可出现,并随着病情进展而加重,参与了哮喘的整个慢性炎症过程,哮喘症状的持续存在、严重程度及气道高反应性均与气道重塑密切相关.因此,理解气道重塑如何促进哮喘进展就成为了更好治疗和管理疾病的关键.生长因子是一类调节细胞生长、分化的多肽类物质,与生长发育、分化、肿瘤等均有密切关系.近年研究显示多种生长因子参与哮喘气道重塑过程.     

054 白介素4受体与支气管哮喘

支气管哮喘(哮喘)是由多种细胞特别是T细胞、肥大细胞和嗜酸粒细胞介导的慢性气道炎症,以气道高反应性和可逆性气道阻塞为特征.白介素4受体(IL-4R)的α亚基作为IL-4和IL-13的受体,参与了哮喘的病理生理过程.本文就IL-4R的生物学功能及其与哮喘关系的研究进展作一.     

Th17细胞及其在支气管哮喘发病中的作用

Th17细胞是一类新型的CD4+T细胞,STAT3、RORγt和RORα等参与了其分化调控.最近,大量研究表明,Th17及其相关的细胞因子在支气管哮喘中起着重要的作用,参与了气道炎症、气道重塑以及气道高反应性.     

腺苷受体与支气管哮喘治疗研究新进展

腺苷受体在哮喘气道炎症中的作用已受到广泛的重视,包括促进哮喘患者气道炎症介质合成和分泌,参与支气管哮喘的气道炎症、气道高反应性及支气管收缩反应的发生和发展。本文就腺苷受体在支气管哮喘发病机制中的作用,及其在哮喘治疗中的研究价值作一综述。     

生长因子与气道重塑——生长因子在支气管哮喘气道重塑过程中作用的新进展

支气管哮喘（简称哮喘）是由多种细胞和细胞组分参与的气道慢性炎症性疾病。气道重塑在哮喘早期即可出现,并随着病情进展而加重,参与了哮喘的整个慢性炎症过程,哮喘症状的持续存在、严重程度及气道高反应性均与气道重塑密切相关。因此,理解气道重塑如何促进哮喘进展就成为了更好治疗和管理疾病的关键。生长因子是一类调节细胞生长、分化的多肽类物质,与生长发育、分化、肿瘤等均有密切关系。近年研究显示多种生长因子参与哮喘气道重塑过程。     

CpG的信号传递机制及其在支气管哮喘等过敏性疾病的应用

支气管哮喘在全球范围特别是发达国家的发病率迅速增加.这被认为与患者幼年时期没有充分暴露在细菌或细菌产物环境下而导致过敏易感性增加有关.CpG-脱氧核苷酸是模拟细菌DNA的合成核苷酸链,可以通过Toll样受体(TLR)被细胞识别,并通过TLR/核因子κB(NF-κB)途径和MAPK途径等诱导Th1型细胞反应,下调Th2型细胞反应,调节免疫应答类型.动物实验证实其可以有效抑制哮喘模型的气道炎症、气道高反应性和气道重塑等,在临床实验中亦已开展诸多研究,因此有关CpG及其作用机制的研究可能成为支气管哮喘治疗的新突破口.     

支气管哮喘气道高反应易感基因原钙黏蛋白1研究进展

支气管哮喘关键病理生理特征之一是气道高反应性,气道高反应发生与气道上皮屏障功能缺陷密切相关。研究表明原钙黏蛋白1（protocadherin-1,PCDH1）基因通过影响气道上皮屏障功能进而调控气道高反应性的发生发展。而PCDH1基因影响气道上皮屏障功能的作用机制尚不清楚,需要进一步研究其在气道上皮屏障功能发生发展中的表达、功能以及分子机制,并探索其作用的信号通路。该文对目前气道高反应易感基因PCDH1的研究进展作一综述。     

Airway hyperresponsiveness: the usefulness of airway hyperresponsiveness testing in epidemiology,in diagnosing asthma and in the assessment of asthma severity

The present PhD thesis was conducted at the Respiratory Research Unit at the Pulmonary Department L in Bispebjerg Hospital, Copenhagen, Denmark and describes airway hyperresponsiveness in asthma patients in four studies. The first study concerned risk factors for the development of asthma in young adults in a 12‐year prospective follow‐up study of a random population sample of 291 children and adolescents from Copenhagen, who were followed up from the age of 7–17 years (1986) until the age of 19–29 years (1998). During follow‐up, 16.1% developed asthma, and in these subjects, the most important predictor of asthma development was airway hyperresponsiveness to histamine at baseline. Airway hyperresponsiveness is associated with more severe asthma and a poorer prognosis in terms of more exacerbations and less chance of remission of the disease. The second study described the relation between airway hyper‐responsiveness to methacholine and the quality of life in 691 asthma patients: In asthma patients with airway hyperresponsiveness to methacholine, the quality of life measured with a validated questionnaire (Junipers Asthma Quality of Life Questionnaire) was significantly reduced compared to asthma patients who did not respond to bronchial provocation with methacholine. Airway hyperresponsiveness is not uncommonly observed in non‐asthmatics, and the response to bronchial provocation with methacholine is therefore relatively non‐specific. The mannitol test is a relatively new bronchial provocation test that acts indirectly on the smooth airway muscle cells through the release of mediators from inflammatory cells in the airways; the mannitol could consequently be a more specific test compared with methacholine. The third study showed that out of 16 non‐asthmatics with airway hyperresponsiveness to methacholine, 15 did not respond to bronchial provocation with mannitol Because of the mechanism of action of mannitol, it seems plausible that the response to mannitol is more closely correlated to airway inflammation in asthma compared with the response to methacholine. The fourth study showed that in 53 adult asthma patients, who did not receive treatment with inhaled steroids, there was a positive correlation between the degree of airway inflammation and the degree of airway responsiveness to mannitol as well as to methacholine. The mannitol does, however, have the advantage of being a faster and simpler test to perform, requiring no additional equipment apart from a spirometer. Conclusions: Airway hyperresponsiveness in children and in adolescents without asthma predicts asthma development in adulthood. Asthma patients with airway hyperresponsiveness to methacholine have a poorer quality of life as well as more severe disease and a poorer prognosis compared with asthma patients without airway hyperresponsiveness. Bronchial provocation with mannitol as well as with methacholine were useful for evaluating the severity of asthma and the degree of airway inflammation, and accordingly for determining the need for steroid statement. The mannitol test does, however, have practical advantages over the methacholine test that make it preferable for clinical use.     

The effect of inhaled heparin on airway responsiveness to histamine and leukotriene D4.

Inhaled heparin has been shown to reduce the early and late phase of asthmatic reactions and suppress an allergen-induced increase in bronchial hyperreactivity. The mechanism involved in the control of bronchial hyperreactivity in asthma by heparin is still not understood. The purpose of this study was to investigate the effect of inhaled heparin on the airway response to histamine and leukotriene D4. Children with a typical history of mild allergic asthma participated in this randomized, double-blind, placebo-controlled cross-over study. Subjects underwent provocation challenge tests with histamine or leukotriene D4 before and after inhalation of heparin and placebo. Twenty-three patients completed the study. We showed that placebo did not affect the bronchial hyperreactivity to histamine or leukotriene. A single dose of inhaled heparin significantly decreased bronchial hyperreactivity to histamine and leukotriene in children with mild asthma. Results of our study suggest that inhaled heparin, because of its antiallergic and/or anti-inflammatory properties, modifies airway hyperresponsiveness in children with allergic asthma.     

Bronchial hyperresponsiveness: the need for a distinction between hypersensitivity and excessive airway narrowing

Bronchial hyperresponsiveness is currently defined as an increase in sensitivity to a wide variety of airway narrowing stimuli. Most patients with asthma and chronic obstructive pulmonary disease (COPD) exhibit such an enhanced sensitivity. In asthma, in particular, this hypersensitivity is accompanied by excessive degrees of airway narrowing. This raises the question as to whether measures of sensitivity, e.g. the provocative concentration or dose producing 20% fall in FEV1 (PC20 or PD20), comprise all the relevant information in bronchial hyperresponsiveness. In adjunct to model studies, there is experimental evidence in man that the potential mechanisms of bronchial hyperresponsiveness can be divided into those causing hypersensitivity and those responsible for the increase in the maximal attainable degree of airway narrowing. The recognition and distinction of these components of hyperresponsiveness have clinical implications in the diagnosis and therapy of asthma and COPD. Bronchial hyperresponsiveness is a composite functional disorder, which requires treatment of each of its components.     

Does bronchial hyperresponsiveness in asthma matter?

Bronchial hyperresponsiveness is a fundamental component of the asthmatic inflammatory process causing airway narrowing on exposure to a bronchoconstrictor stimulus. This in turn causes patients to experience symptoms of breathlessness, chest tightness, cough and wheeze. Bronchial challenge tests can be performed in the laboratory to establish the degree of bronchial hyperresponsiveness to both direct and indirect stimuli. The extent to which asthma pharmacotherapy attenuates bronchial hyperresponsiveness is therefore an important measure of efficacy. This review article discusses the effects of inhaled and oral asthma treatment upon bronchial hyperresponsiveness and highlights how, in conjunction with conventional measures of asthma control, it can be used as an aid to optimally manage patients.     

支气管哮喘中核因子κB治疗靶点

转录因子可能在慢性气道疾病的病理生理中扮演重要角色,并可能是一类新颖的抗炎治疗靶点.核因子κB(nuclear factor kappa B,NF-κB)可能是支气管哮喘(简称哮喘)发病的关键环节.N F-κB靶点的药理抑制剂和基因沉默均已初显平喘端倪.NF-κB亚单位是动物肺部变态反应性炎症和气道高反应性所必需.亚单位可能是哮喘NF-κB治疗靶点的未来研究重点与希望所在,尤其是c-Rel亚单位.     

Does Bronchial Hyperresponsiveness in Asthma Matter?

Bronchial hyperresponsiveness is a fundamental component of the asthmatic inflammatory process causing airway narrowing on exposure to a bronchoconstrictor stimulus. This in turn causes patients to experience symptoms of breathlessness, chest tightness, cough and wheeze. Bronchial challenge tests can be performed in the laboratory to establish the degree of bronchial hyperresponsiveness to both direct and indirect stimuli. The extent to which asthma pharmacotherapy attenuates bronchial hyperresponsiveness is therefore an important measure of efficacy. This review article discusses the effects of inhaled and oral asthma treatment upon bronchial hyperresponsiveness and highlights how, in conjunction with conventional measures of asthma control, it can be used as an aid to optimally manage patients.     

Unimodal distribution of bronchial hyperresponsiveness to methacholine in asthmatic patients.

Distribution of bronchial hyperresponsiveness to methacholine was assessed in 791 consecutive patients who were referred to the outpatient clinic of the pulmonary department due to asthmatic or persistent lower airway symptoms. Bronchial asthma was diagnosed in 319 patients. Clinical sensitivity of methacholine challenge for the disease was 89 percent and specificity, 76 percent. The degree of bronchial hyperresponsiveness in the entire group of asthmatic patients was unimodally log normal distributed. Of the 82 patients with allergic rhinitis without concurrent asthma, 27 percent had bronchial hyperresponsiveness, but of a markedly lesser degree than in the hyperresponsive asthmatic patients. In 49 patients with chronic bronchitis, 22 percent had hyperresponsiveness. The present data indicate that the degree of bronchial hyperresponsiveness in asthmatic patients is unimodally distributed, supporting the view that both genetic and environmental factors have an impact upon its development. Although the degree of bronchial hyperresponsiveness in asthma is more pronounced than in allergic rhinitis or in chronic bronchitis, a marked overlap exists.     

Role of macrophage migration inhibitory factor in ovalbumin-induced airway inflammation in rats.

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that reportedly counteracts the anti-inflammatory effect of endogenous glucocorticoids. There have only been a few reports that demonstrate a potential link between MIF and bronchial asthma. In an attempt to further clarify the precise role of MIF in asthma, the present authors examined the effect of anti-MIF antibody (Ab) on airway inflammation and airway hyperresponsiveness in an ovalbumin-immunised rat asthma model. Actively immunised Brown Norway rats received ovalbumin inhalation with or without treatment of anti-MIF Ab. The levels of MIF in bronchoalveolar lavage fluid were significantly elevated after the ovalbumin challenge. An immunohistochemical study revealed positive immunostaining for MIF in bronchial epithelium, even in nonsensitised rats, and the MIF staining in bronchial epithelium was enhanced after the ovalbumin challenge. Anti-MIF Ab significantly decreased the number of total cells, neutrophils and eosinophils in the bronchoalveolar lavage fluid of the ovalbumin-challenged rats, and also attenuated the ovalbumin-induced airway hyperresponsiveness to ovalbumin and methacholine. However, anti-MIF Ab did not affect the level of serum ovalbumin-specific IgE, suggesting that anti-MIF Ab did not suppress immunisation itself. The results indicate that macrophage migration inhibitory factor plays a crucial role in airway inflammation and airway hyperresponsiveness in asthma.