SUMF2在支气管哮喘中的作用

支气管哮喘(简称哮喘)是一种慢性炎症引起的以气道炎症、气道高反应性和气道重塑为特点的呼吸系统疾病,近些年其发病率呈现明显地上升趋势。随着对哮喘发病机制的深入研究,研究者们发现IL-13在哮喘的发病中作为始动因子起到中轴的作用。有研究表明硫酸酯酶修饰因子2(简称SUMF2)不仅可以与IL-13相结合,且可以抑制IL-13的分泌,可以推测SUMF2在哮喘的发病中起到一定的作用可能为哮喘的治疗提供新的思路,对于改善哮喘患者的生活质量同样具有很高的临床价值。     

Th2型细胞因子在支气管哮喘发作过程中的表达

支气管哮喘是由多种细胞特别是肥大细胞、嗜酸性粒细胞和T淋巴细胞参与的慢性气道炎症。对支气管哮喘发病机制的认识近年有重大改变 ,Th2型细胞的作用被认为是支气管哮喘发作过程的中心 ,综述了由Th2型细胞产生的细胞因子在支气管哮喘发病过程中的作用及意义。     

气道上皮细胞在哮喘中的作用

随着现代医学的发展,人们对支气管哮喘发病机制的研究有了进一步发展.支气管哮喘(简称哮喘)是一种由多种细胞,多种细胞因子参与形成的慢性气道炎症性疾病.支气管上皮细胞是气道结构细胞,它是抵抗外界损伤因素的第一道防线,当吸人性刺激物质时,首先激化支气管上皮细胞并破坏支气管上皮细胞的正常结构和生理功能,在应激状态下的上皮细胞通过分泌炎性介质与自身细胞或其他气道结构细胞、炎性细胞、抗原递呈细胞等相互作用,积极参与哮喘的气道慢性炎症发生与发展进程.因此气道上皮损伤是影响哮喘发生发展的重要因素,阐明维持气道上皮正常结构和功能的分子机制是目前防治哮喘的重要课题.本文综述气道上皮在哮喘发生发展中的作用及相关机制研究进展.     

IL-12和支气管哮喘

支气管哮喘是一种气道慢性炎症性疾病。越来越多的事实表明,哮喘的发生与内源性IL-12生成不足有关。IL-12无论单独应用还是作为免疫佐剂,均可逆转哮喘动物模型体内Th1/Th2失衡和抑制气道变态反应性炎症。该文综述了IL-12的生物学效应、IL-12与哮喘的关系、IL-12在哮喘治疗中的作用及其应用。     

水通道蛋白与哮喘

哮喘是全球常见的慢性呼吸道疾病之一,气道炎症细胞积聚、气道慢性炎症和气道高反应性为其三大重要特征。研究发现在哮喘发病过程中,多种炎症细胞、粘膜上皮细胞、肺泡上皮细胞、周围血管内皮细胞等都有水通道蛋白(aquporin,AQP)的异常表达。这些细胞参与哮喘发作时炎症细胞积聚、气道高反应性、粘液异常分泌、肺间质毛细血管通透性改变等多方面反应。AQP在哮喘的发生发展中可能起着重要的作用。在哮喘的诊断方面,除了依据典型的临床症状及支气管激发、舒张实验之外,若AQP在血液嗜酸性粒细胞内或其他组织细胞内的异常表达能作为一种哮喘发病的生化指标,将对哮喘的诊断和防治有突破性的作用。本文就AQP与哮喘的关系进行综述。     

IL-23/Th17轴在变应性哮喘中的研究进展

变应性哮喘是一种由辅助性T细胞（T helper cell,Th cell）调节的慢性炎症性疾病。Th1/Th2的失衡一直被认为是变应性哮喘的发病机制,Th2细胞及其分泌的细胞因子白介素4（interleukin 4,IL-4）、IL-5以及IL-13在变应性哮喘特异性症状的发病中发挥重要作用。最近研究发现Th17细胞及其分泌的IL-17参与变应性哮喘的发展过程,IL-23在Th17细胞维持生存和功能成熟中发挥重要作用,并参与抗原诱导的气道炎症反应。该文对目前IL-23/Th17轴在变应性气道炎症反应中的研究进展作一综述。     

T淋巴细胞在哮喘发病机制中的作用

支气管哮喘(简称哮喘)的本质是慢性气道炎症,是多种炎症细胞(如嗜酸性粒细胞、肥大细胞、T淋巴细胞、中性粒细胞等)和其介质共同参与引起的慢性炎症反应,而T淋巴细胞在其中发挥重要作用。T淋巴细胞目前主要分为四个亚群,分别是Th1、Th2、Th17和Treg亚群。过去曾认为Th1/Th2平衡失调是哮喘发病的关键因素,但近年研究发现Th17/Treg及Th2/Treg的平衡失调在哮喘的发病机制中同样发挥巨大作用,且日益受到重视。本文就T细胞在哮喘发病机制中的作用及研究进展做一综述。     

Th1／Th2迁移与支气管哮喘研究进展

支气管哮喘是由多种炎症细胞和细胞组分参与的气道慢性炎症疾病。发病机制尚未明了,但作为一种免疫调节异常性疾病已取得大多学者的共识。支气管哮喘是一种Th1／Th2细胞数量及其功能失衡,主要表现为Th2数量及其功能优势的疾病。     

IL-17家族与哮喘

支气管哮喘(bronchial asthma,简称哮喘)是一种常见的慢性气道炎症性疾病,急性发作可危及生命。研究表明,细胞因子白介素17(interleukin-17,IL-17)家族成员在哮喘的发病过程中发挥着重要的作用,其中IL-17A、IL-17F和IL-17E与哮喘密切相关,是目前的研究热点。现对IL-17家族不同成员与哮喘发病机制的相关研究进展作一综述。     

非编码RNA参与调控哮喘T细胞功能的研究进展

支气管哮喘(简称哮喘)是一种以气道炎性反应、高反应性及气道重塑为特征的慢性炎症性疾病,T细胞在其中发挥着至关重要的作用。非编码RNA (non-coding RNA, ncRNA)是转录组中不编码蛋白质的RNA分子,主要包括微小RNA (microRNA,miRNA)、长链非编码RNA (long non-coding RNA, lncRNA)、环状RNA (circular RNA, circRNA)等,广泛存在于真核生物基因组中,参与调控多种生物学过程。已有研究表明,ncRNA在哮喘T细胞的活化及转换等过程中起着重要作用,其具体作用机制及临床应用值得深入探讨。本文综合分析了近年来miRNA、lncRNA和circRNA在哮喘T细胞功能调控中的研究进展,为更好地理解哮喘发病机制和提高诊断水平提供新思路,同时也为利用ncRNA的调节潜能开发治疗策略提供理论依据。     

Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness, inflammation and airway remodeling

Asthma is a chronic inflammatory disease characterized by reversible bronchial constriction, pulmonary inflammation and airway remodeling. Current standard therapies for asthma provide symptomatic control but fail to target the underlying disease pathology. Furthermore, no therapeutic agent is effective in preventing airway remodeling. Interleukin 13 (IL-13) is a pleiotropic cytokine produced mainly by T cells. A substantial amount of evidence suggests that IL-13 plays a critical role in the pathogenesis of asthma. Therefore, a neutralizing anti-IL-13 monoclonal antibody could provide therapeutic benefits to asthmatic patients. To test the concept we have generated a neutralizing rat anti-mouse IL-13 monoclonal antibody, and evaluated its effects in a chronic mouse model of asthma. Chronic asthma-like response was induced in ovalbumin (OVA) sensitized mice by repeated intranasal OVA challenges. After weeks of challenge, mice developed airway hyperresponsiveness (AHR) to methacholine stimulation, severe airway inflammation, hyper mucus production, and subepithelial fibrosis. When given at the time of each intranasal OVA challenge, anti-IL-13 antibody significantly suppressed AHR, eosinophil infiltration, proinflammatory cytokine/chemokine production, serum IgE, and most interestingly, airway remodeling. Taken together, these results strongly suggest that a neutralizing anti-human IL-13 monoclonal antibody could be an effective therapeutic agent for asthma.     

Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease

Excessive production of airway mucus is a cardinal feature of bronchial asthma and chronic obstructive pulmonary disease (COPD) and contributes to morbidity and mortality in these diseases. IL-13, a Th2-type cytokine, is a central mediator in the pathogenesis of bronchial asthma, including mucus overproduction. Using a genome-wide search for genes induced in airway epithelial cells in response to IL-13, we identified pendrin encoded by the SLC26A4 (PDS) gene as a molecule responsible for airway mucus production. In both asthma and COPD mouse models, pendrin was up-regulated at the apical side of airway epithelial cells in association with mucus overproduction. Pendrin induced expression of MUC5AC, a major product of mucus in asthma and COPD, in airway epithelial cells. Finally, the enforced expression of pendrin in airway epithelial cells in vivo, using a Sendai virus vector, rapidly induced mucus overproduction in the lumens of the lungs together with neutrophilic infiltration in mice. These findings collectively suggest that pendrin can induce mucus production in airway epithelial cells and may be a therapeutic target candidate for bronchial asthma and COPD.     

Interleukin-17 regulation: an attractive therapeutic approach for asthma

Interleukin (IL)-17 is recognized to play a critical role in numerous immune and inflammatory responses by regulating the expression of various inflammatory mediators, which include cytokines, chemokines, and adhesion molecules. There is growing evidence that IL-17 is involved in the pathogenesis of asthma. IL-17 orchestrates the neutrophilic influx into the airways and also enhances T-helper 2 (Th2) cell-mediated eosinophilic airway inflammation in asthma. Recent studies have demonstrated that not only inhibitor of IL-17 per se but also diverse regulators of IL-17 expression reduce antigen-induced airway inflammation, bronchial hyperresponsiveness, and Th2 cytokine levels in animal models of asthma. This review will summarize the role of IL-17 in the context of allergic airway inflammation and discuss the therapeutic potential of various strategies targeting IL-17 for asthma.     

Essential oils and its bioactive compounds modulating cytokines: A systematic review on anti-asthmatic and immunomodulatory properties

BackgroundAsthma, the main inflammatory chronic condition affecting the respiratory system, is characterized by hyperresponsiveness and reversible airway obstruction, recruitment of inflammatory cells and excessive production of mucus. Cytokines as biochemical messengers of immune cells, play an important role in the regulation of allergic inflammatory and infectious airway processes. Essential oils of plant origin are complex mixtures of volatile and semi volatile organic compounds that determine the specific aroma of plants and are categorized by their biological activities.PurposeWe reviewed whether essential oils and their bioactive compounds of plant origin could modulate cytokines’ immune responses and improve asthma therapy in experimental systems in vitro and in vivo.MethodsElectronic and manual search of articles in English available from inception up to November 2018 reporting the immunomodulatory activity of essential oils and their bioactive compounds for the management of asthma. We used PubMed, EMBASE, Scopus and Web of Science. Publications reporting preclinical experiments where cytokines were examined to evaluate the consequence of anti-asthmatic therapy were included.Results914 publications were identified and 13 were included in the systematic review. Four articles described the role of essential oils and their bioactive compounds on bronchial asthma using cell lines; nine in vivo studies evaluated the anti-inflammatory efficacy and immunomodulating effects of essential oil and their secondary metabolites on cytokines production and inflammatory responses. The most important immunopharmacological mechanisms reported were the regulation of cytokine production, inhibition of reactive oxygen species accumulation, inactivation of eosinophil migration and remodeling of the airways and lung tissue, modulation of FOXP3 gene expression, regulation of inflammatory cells in the airways and decreasing inflammatory mediator expression levels.ConclusionPlant derived essential oils and related active compounds have potential therapeutic activity for the treatment of asthma by modulating the release of pro-inflammatory (TNF-α, IL-1β, IL-8), Th17 (IL-17), anti-inflammatory (IL-10), Th1 (IFN-γ, IL-2, IL-12) and Th2 (IL-4, IL-5, IL-6, IL-13) cytokines and the suppression of inflammatory cell accumulation.     

The airway epithelium in asthma

Asthma is a T lymphocyte-controlled disease of the airway wall caused by inflammation, overproduction of mucus and airway wall remodeling leading to bronchial hyperreactivity and airway obstruction. The airway epithelium is considered an essential controller of inflammatory, immune and regenerative responses to allergens, viruses and environmental pollutants that contribute to asthma pathogenesis. Epithelial cells express pattern recognition receptors that detect environmental stimuli and secrete endogenous danger signals, thereby activating dendritic cells and bridging innate and adaptive immunity. Improved understanding of the epithelium's function in maintaining the integrity of the airways and its dysfunction in asthma has provided important mechanistic insight into how asthma is initiated and perpetuated and could provide a framework by which to select new therapeutic strategies that prevent exacerbations and alter the natural course of the disease.     

Absence of the complement anaphylatoxin C3a receptor suppresses Th2 effector functions in a murine model of pulmonary allergy

Asthma is a chronic inflammatory disease of the lung resulting in airway obstruction. The airway inflammation of asthma is strongly linked to Th2 lymphocytes and their cytokines, particularly IL-4, IL-5, and IL-13, which regulate airway hyperresponsiveness, eosinophil activation, mucus production, and IgE secretion. Historically, complement was not thought to contribute to the pathogenesis of asthma. However, our previous reports have demonstrated that complement contributes to bronchial hyperreactivity, recruitment of airway eosinophils, IL-4 production, and IgE responses in a mouse model of pulmonary allergy. To define the complement activation fragments that mediate these effects, we assessed the role of the complement anaphylatoxin C3a in a mouse model of pulmonary allergy by challenging C3aR-deficient mice intranasally with a mixed Ag preparation of Aspergillus fumigatus cell culture filtrate and OVA. Analysis by plethysmography after challenge revealed an attenuation in airway hyperresponsiveness in C3aR-deficient mice relative to wild-type mice. C3aR-deficient mice also had an 88% decrease in airway eosinophils and a 59% reduction in lung IL-4-producing cells. Consistent with the reduced numbers of IL-4-producing cells, C3aR-deficient mice had diminished bronchoalveolar lavage levels of the Th2 cytokines, IL-5 and IL-13. C3aR knockout mice also exhibited decreases in IgE titers as well as reduced mucus production. Collectively, these data highlight the importance of complement activation, the C3a anaphylatoxin, and its receptor during Th2 development in this experimental model and implicate these molecules as possible therapeutic targets in diseases such as asthma.     

Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease

To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of chronic lung disease with pathology that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after an infection with a common type of respiratory virus is cleared to only trace levels of noninfectious virus. Chronic inflammatory disease is generally thought to depend on an altered adaptive immune response. However, here we find that this type of disease arises independently of an adaptive immune response and is driven instead by interleukin-13 produced by macrophages that have been stimulated by CD1d-dependent T cell receptor-invariant natural killer T (NKT) cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a previously undescribed NKT cell-macrophage innate immune axis.     

IL13 activates autophagy to regulate secretion in airway epithelial cells

Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.