过敏性哮喘：速发反应,迟发反应与持续气道高反应性及其机制

哮喘是气道慢性炎症性疾病，气道高反应性为其病理生理特征。过敏性哮喘患者吸入致敏原后半数以上出现双相气道反应，即速发生反应（ＥＡＲ）与迟发反应（ＬＡＲ），部分只出现速发反应。此外，致敏原的吸入可导致非特异性气道反应性升高（ＡＲ）。三者共同构成持续气道高反应性。本篇综述过敏性哮喘气道反应各时相的病理基础，阐明其细胞、分子生物学机制，对哮喘的治疗和发病机制的进一步研究具重要的参考价值。     

气道平滑肌细胞在哮喘气道重构时的增殖机制

传统的观点认为慢性气道炎症、可逆性气流阻塞和气道高反应性是支气管哮喘的三大特征。但近年大量的研究发现，哮喘患经常出现不可逆或部分不可逆气流阻塞及持续的气道高反应性，目前医学界认为其原因是气道发生了改变即气道重构(airway remodeling)。其中气道平滑肌细胞(ASMC)增殖在气道重构中占有十分重要的地位，并与气道的高反应性和药物疗效密切相关。     

气道平滑肌细胞在哮喘气道重构时的增殖机制

传统的观点认为慢性气道炎症、可逆性气流阻塞和气道高反应性是支气管哮喘的三大特征。但近年大量的研究发现,哮喘患者经常出现不可逆或部分不可逆气流阻塞及持续的气道高反应性,目前医学界认为其原因是气道发生了改变即气道重构(airwayremodeling)[1]。其中气道平滑肌细胞(ASMC)增殖在气道重构中占有十分重要的地位并与气道的高反应性和药物疗效密切相关。近年ASMC已成为哮喘研究的一个新热点,Hierst[2]提出应把ASMC作为哮喘研究的标靶。本文就ASMC的增殖机制的研究进展作一综述。1ASMC的增殖与气道重构气道重构的形态学研究结果…     

垂体腺苷酸环化酶激活肽与支气管哮喘

支气管哮喘（简称哮喘）是儿童最常见的慢性疾病之一，对儿童的健康造成很大威胁。气道慢性炎症、气道高反应性及气道重塑是哮喘的基本特征。大量的研究发现垂体腺苷酸环化酶激活肽（PACAP）具有多种生物学活性，参与免疫调节、炎症反应、呼吸节律、氧化应激等。明确PACAP在哮喘中的发病机制，有望成为哮喘药物研究的新方法和新策略。     

类胰蛋白酶与支气管哮喘

支气管哮喘（bronchial asthma，简称哮喘）是由嗜酸性粒细胞、肥大细胞、T细胞、中性粒细胞等多种细胞和细胞组分参与的慢性气道炎症性疾病。这种慢性炎症导致气道反应性增高，出现广泛多变的可逆性气流受限。目前，关于哮喘的发病机制仍未完全阐明，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。哮喘免疫学机制方面近来研究较多，其中类胰蛋白酶是近年来倍受注意的肥大细胞分泌性介质，它高度选择表达于肥大细胞，在其分泌颗粒中以全酶活性形式大量储存，一旦被释放，类胰蛋白酶表现出持续活性，通过多种途径参与哮喘发病，是哮喘研究领域的又一热点。本文就类胰蛋白酶生物学特点及其与哮喘的关系作一综述。     

神经生长因子与哮喘气道炎症

气道炎症是引起支气管哮喘患者气道高反应性、气道重构、通气障碍和疾病慢性化的关键。神经生长因子(NGF)对多种免疫细胞有调节作用,且是诱导气道感觉神经元可塑性的强有力的介质,目前研究认为NGF可能在哮喘气道急慢性炎症中扮演重要角色。     

支气管哮喘治疗新进展概述

近年来,支气管哮喘的诊治工作取得了长足的进步。概括地说,包括以下６个方面。１　一个新理论支气管哮喘的气道炎症学说,已被国内外广大学者们接受。该学说认为支气管哮喘是一种气道变态反应炎症性疾病。由嗜酸细胞、肥大细胞和淋巴细胞等多种炎症细胞介导的气道炎症,引起了气道高反应性和广泛的、可逆性气流阻塞症状。该理论认为,气道变态反应炎症（炎症细胞及其释出的炎性介质）引起的迟发相哮喘反应比速发相哮喘反应更具临床重要性。该理论不仅阐明了气道高反应性和临床哮喘症状形成的病理基础,还给支气管哮喘的治疗学带来了革命性…     

支气管哮喘气道重构的机制及对气道生理功能的影响

支气管哮喘的三大特征包括慢性气道炎症、可逆性气流阻塞及气道高反应性。近年来,气道重构在哮喘中的作用越来越受到重视。它对哮喘的气道功能、自然病程、药物疗效及预后等多方面都有明显的影响。随着气道重构的组织病理学特征被逐渐揭示出来,这种病理学改变的发生机制及其与气道生理功能的关系更为引人注目。     

白介素13与气道高反应性

气道高反应性是呼吸道疾病最常见的临床表现，它是气道对非特异性刺激反应亢进的一种状态，与气道炎症、气道重构相并列，是支气管哮喘的重要病理变化之一。而在肺部的其它疾病，如慢性阻塞性肺疾病、急性支气管炎、支气管扩张、过敏性肺炎、肺结核等也有不同程度的表现。目前认为气道炎症是气道高反应性的重要基础，尤其是Th2型细胞因子IL-4、IL-13、IL-5、IL-9、IL-10等的增多，     

支气管哮喘气道重构的机制及对气道生理功能的影响

支气管哮喘的三大特征包括慢性气道炎症，可逆性气流阻塞及气道高反应性。近年来，气道重构在哮喘中的作用越来越受到重视，它对哮喘的气道功能，自然病程，药物疗效及预后等多方面都有明显的影响，随着气重柢的组织病理学特征被逐渐揭示出来，这种病理学改变的学生机制及其与气道生理功能的关系更为引人注目。     

Airway inflammation and remodeling in asthma

An important advance in our understanding of the pathophysiology of asthma has been the discovery that airway inflammation is not confined to severe asthma but also characterizes mild and moderate asthma. Inflammation in asthma may be the result of a peculiar type of lymphocytic inflammation whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyperresponsiveness. The term "airway remodeling" in asthma refers to structural changes that occur in conjunction with, or because of, chronic airway inflammation. Airway remodeling results in alterations in the airway epithelium, lamina propria, and submucosa, leading to thickening of the airway wall. The consequences of airway remodeling in asthma may include incompletely reversible airway narrowing, bronchial hyperresponsivenesss, airway edema, and mucus hypersecretion. Airway remodeling in asthma thus may predispose persons with asthma to asthma exacerbations and even death from airway obstruction caused by smooth muscle contraction, airway edema, and mucus plugging. Although much has been learned in the past 25 years about the pathophysiology of airway inflammation and airway remodeling in asthma, important questions remain about the relation between airway inflammation and remodeling, the natural history of airway remodeling, and the effects of current asthma treatments on remodeled airways.     

Mechanisms of airway remodeling in asthma.

Asthma is a chronic inflammatory disease characterized by reversible airflow limitation and airway hyperresponsiveness. Persistent inflammation in airway tissues may lead to structural changes known as airway remodeling and consequently airway obstruction that is not fully reversible and progressive loss of lung function over time. It is generally accepted that airway remodeling is closely related to progression of airway hyperresponsiveness, and the severity of asthma. The structural changes observed in chronic persistent asthma, which includes airway smooth muscle hypertrophy and hyperplasia, collagen deposition to sub-epithelial basement membrane, hyperplasia of goblet cells, thickening of airway mucosa and an increase in vascularity, are derived from airway inflammation. For instance, the thickened airway mucosa might be produced by cytokines and growth factors released from inflammatory cells and airway epithelial cells, and associated with bronchial hyperreactivity and asthma severity. To date, many studies have identified candidate mechanisms and mediators for these observed structural changes, which are thus potential targets in the treatment of asthma. In this review, we describe the recent knowledge of the mechanisms and clinical implications of airway remodeling in asthma.     

Inhibitory Effects of Anti-Immunoglobulin E Antibodies on Airway Remodeling in A Murine Model of Chronic Asthma

Background: Airway remodeling is one of the cardinal features of asthma and is thought to play a pivotal role in refractory or persistent asthma. Immunoglobulin E (IgE) has a major effect on the pathogenesis of asthma. The aim of this study was to investigate the effects of anti-IgE antibody not only on airway inflammation and bronchial hyperresponsiveness, but also on airway remodeling in a murine model of chronic asthma. Methods: The authors developed a mouse model of chronic asthma in which ovalbumin (OVA)-sensitized female BALB/c-mice were exposed to intranasal OVA administration twice a week for 3 months. Anti-IgE antibodies were administered intravenously starting on the 38th day and once a month thereafter for 3 months during the intranasal OVA challenge. Results: Mice that were chronically exposed to OVA developed sustained eosinophilic airway inflammation and airway hyperresponsiveness (AHR) to methacholine and showed increased levels of collagen, hydroxyproline, and α-smooth muscle actin, as compared with control mice. Treatment with anti-IgE antibody inhibited the development of AHR, eosinophilic inflammation, and airway remodeling. Moreover, anti-IgE antibody treatment reduced the levels of interleukin (IL)-5 and IL-13 in the bronchoalveolar lavage fluids, although it did not affect the levels of IL-10, transforming growth factor-β, and activin A. Conclusion: These results suggest that anti-IgE antibody treatment modulates the airway inflammation and remodeling associated with chronic allergen challenge. The inhibition of inflammation may be related to the regulation of Th2 cytokines. However, the mechanisms underlying the blocking of airway remodeling by anti-IgE antibody remain to be elucidated.     

YKL-40在支气管哮喘发病中的作用

支气管哮喘(简称哮喘)是一种慢性气道炎症,以气道高反应性和气道重塑为主要特征.YKL-40是新近发现的炎症因子,为哺乳动物体内的甲壳素酶蛋白家族一员.近年研究结果表明YKL-40与哮喘发病关系密切.本文就YKL-40在哮喘发病中的作用予以综述.     

A critical appraisal of methods used in early clinical development of novel drugs for the treatment of asthma

Asthma is a heterogeneous disorder characterized by chronic airway inflammation, hyperresponsiveness and remodeling. Being the hallmark of asthma, airway inflammation has become the most important target for therapeutic agents. Consequently, during the past decade various semi-and non-invasive methods have been explored to sample the airway inflammation in asthma. In this review, we provide a practical overview of the current status of various sampling techniques including sputum induction, exhaled breath analysis, and bronchoprovocation tests (BPTs). We focus on their applicability for monitoring in clinical practice and in intervention trials in asthma.     

Airway remodeling in asthma and irreversible airflow limitation-ECM deposition in airway and possible therapy for remodeling-.

Airway remodeling in asthma is characterized by goblet cell hyperplasia, subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells. The airway wall thickness increases because of subepithelial fibrosis, and hyperplasia and hypertrophy of the airway smooth muscle cells and submucosal glands. Airway remodeling, therefore, can often cause irreversible airflow limitation and an increase of airway hyperresponsiveness. Recent studies have described the molecular and cellular mechanisms of collagen deposition in the airway wall such as subepithelial fibrosis. Fibroblasts or myofibroblasts play a critical role in the exaggerated deposition of collagen in asthmatic airways. Bone marrow derived fibroblasts may play a role in fibrotic remodeling in asthmatic airways. Airway remodeling is induced by cytokines and mediators produced in chronic allergic airway inflammation. Since, once formed, remodeling is resistant to asthma therapy, early intervention with inhaled corticosteroid should be considered to prevent the progress of airway remodeling.     

CpG-寡核苷酸与支气管哮喘

Th1／Th2失衡是支气管哮喘的重要免疫学发病机制,近年在支气管哮喘的发病机制中取得较大进展,CD4^＋T辅助细胞按其分泌的细胞因子不同分为Th1和Th2细胞,Th1反应可以抑制Th2反应,抑制气遭慢性炎症,含有未甲基化CpG结构的寡核苷酸是近年研究较多的一种调节Th1／Th2平衡的免疫制剂,本文就其调节Th1／Th2平衡在支气管哮喘治疗中的应用前景作一综述。     

Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation

Asthma is associated with airway remodeling. Evidence of platelet recruitment to the lungs of asthmatics after allergen exposure suggests platelets participate in various aspects of asthma; although their importance is unknown in the context of airway remodeling, their involvement in atherosclerosis is established. Studies from our laboratory have shown a requirement for platelets in pulmonary leukocyte recruitment in a murine model of allergic lung inflammation. Presently, the effects of platelet depletion and corticosteroid administration on airway remodeling and lung function were examined. Ovalbumin (OVA)-sensitized mice, exposed to aerosolized OVA for 8 weeks, demonstrated epithelial and smooth muscle thickening, and subepithelial reticular fiber deposition in the distal airways. The depletion of platelets via an immunologic (antiplatelet antisera) or nonimmunologic (busulfan) method, markedly reduced airway remodeling. In contrast, dexamethasone administration did not affect epithelial thickening or subepithelial fibrosis, despite significantly inhibiting leukocyte recruitment. Thus, pathways leading to certain aspects of airway remodeling may not depend on leukocyte recruitment, whereas platelet activation is obligatory. OVA-sensitized mice exhibited airway hyperresponsiveness (AHR) compared with sham-sensitized mice following chronic OVA exposure. Neither platelet depletion nor dexamethasone administration inhibited chronic AHR; thus, mechanisms other than inflammation and airway remodeling may be involved in the pathogenesis of chronic AHR.     

An updated model of clinical asthma.

A model of asthma, based on the Expert Panel Report but updated to allow for the independence of bronchial hyperresponsiveness from airway inflammation, is presented. The updated model of asthma can be summarized: (1) AI = f1(Allergen)-f2(AI); (2) BHR = f3(Allergen)-f4(BHR); (3) PR = f5(AI); (4) Asthma = f6(AI + BHR + PR); where AI is airway inflammation, Allergen is sensitization by allergen, BHR is bronchial hyperreactivity, and PR is pulmonary remodeling. The updated model demonstrates that preventing bronchial hyperreactivity will not prevent the lung destruction associated with asthmatic pulmonary remodeling. The updated model of clinical asthma presented here helps to provide a basis for computer simulation of chronic asthma.