气道上皮屏障功能异常在支气管哮喘发病中的作用

支气管哮喘(哮喘)的主要表现为咳嗽、咳痰、胸闷和喘息,这些症状的病理生理学基础是气道高反应性和气道慢性嗜酸粒细胞炎症。气道上皮细胞是呼吸道的第一道防线,环境因素和炎症作用的影响引起气道上皮反复损伤、修复和再生导致气道黏膜上皮的组织学改变和功能异常。气道上皮的屏障功能与气道上皮细胞因子胸腺基质淋巴细胞生成素,白细胞介素25和白细胞介素33密切相关,哮喘患者气道上皮屏障的损害增强了气道上皮黏膜对异物的通透性,引起气道上皮细胞、树突状细胞和先天性固有淋巴样细胞(ILC2s)的激活。气道上皮细胞的功能异常以及树突状细胞、Th2细胞和ILC2s的激活形成一个免疫病理单元,引起过敏性气道炎症,在哮喘的发病中发挥重要作用。     

The importance of eosinophil,platelet and dendritic cell in asthma

Asthma is a syndrome of variable airflow obstruction. It is characterized pathologically by bronchial inflammation and remodeling changes. Eosinophil infiltrate in asthma and a relationship between the degree of eosinophil infiltration in airways and severity of asthma has been suggested. Eosinophil has antigen-presenting cells and main role in allergic asthma. Platelets in inflammatory response is very important. It has also been shown that enzymes released by activated platelets play a direct role in the chronic inflammatory events that lead to airway remodeling in asthma. Dendritic cells (DCs) acquire antigen in the airways and then migrate to the draining lymph node where the cells mature and initiate T cell responses. Allergen challenge induces simultaneous increases in the number of DCs in the lungs. Because DCs are crucial in mounting immune responses during ongoing inflammation in the lung and balance of the allergic immune response.     

Role of airway epithelial barrier dysfunction in pathogenesis of asthma

Bronchial asthma is characterized by persistent cough, increased sputum, and repeated wheezing. The pathophysiology underlying these symptoms is the hyper-responsiveness of the airway along with chronic airway inflammation. Repeated injury, repair, and regeneration of the airway epithelium following exposure to environmental factors and inflammation results in histological changes and functional abnormalities in the airway mucosal epithelium; such changes are believed to have a significant association with the pathophysiology of asthma. Damage to the barrier functions of the airway epithelium enhances mucosal permeability of foreign substances in the airway epithelium of patients with asthma. Thus, epithelial barrier fragility is closely involved in releasing epithelial cytokines (e.g., TSLP, IL-25, and IL-33) because of the activation of airway epithelial cells, dendritic cells, and innate group 2 innate lymphoid cells (ILC2). Functional abnormalities of the airway epithelial cells along with the activation of dendritic cells, Th2 cells, and ILC2 form a single immunopathological unit that is considered to cause allergic airway inflammation. Here we use the latest published literature to discuss the potential pathological mechanisms regarding the onset and progressive severity of asthma with regard to the disruption of the airway epithelial function.     

Expressions and Roles of Periostin in Otolaryngological Diseases

Periostin is a 90-kDa member of the fasciclin-containing family; it functions as part of matricellular proteins, and its production by airway epithelial cells is induced by IL-4 and IL-13. Periostin is secreted by fibroblasts and upregulated in the airway epithelia of patients with bronchial asthma; it is considered to contribute to remodeling under this pathological condition. However, despite many studies in diverse research areas, our overall understanding of this intriguing molecule is still inadequate. Here, we integrate the available evidence on periostin expression and its roles in otolaryngological diseases, including allergic rhinitis, chronic rhinosinusitis with nasal polyps, aspirin-induced asthma, organized hematoma, eosinophilic otitis media, and IgG4-related disease. Periostin might be involved as an important structural mediator in pathological processes such as insult and injury, Th2-driven inflammation, extracellular matrix restructuring, fibrosclerosis, tumor angiogenesis, and tissue remodeling.     

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.     

IL-33 promotes airway remodeling and is a marker of asthma disease severity

Objective: To investigate the function of interleukin-33 (IL-33) in the asthmatic airway remodeling and the relationship between IL-33 and asthma severity. Methods: IL-33 levels, sputum eosinophils percentage (EOS%), pulmonary function and total immunoglobulin (IgE) were measured for 45 patients with asthma and 40 non-allergic controls. Asthma severity was assessed. The expressions of IL-33 and reticular basement membrane (RBM) on bronchial biopsy specimens from eight asthma patients and eight non-allergic controls were observed after hematoxylin-eosin staining (HE) and immunohistochemical staining. In vitro experiments, real-time polymerase chain reactions and western blotting analysis were used to identify the specific effects of IL-33 administration. Results: Serum IL-33 levels in patients with asthma were higher than those in non-allergic controls. Moreover, in asthmatic patients, serum IL-33 levels were negatively correlated to forced expiratory volume in one second (FEV1, % predicted), and positively correlated to asthma severity. Increased expression of IL-33 and RBM thickening were observed on bronchial biopsy specimens obtained from patients with asthma. Serum IL-33 levels were positively correlated to basement membrane thickness. The production of fibronectin1 and type I collagen in human lung fibroblasts (HLF-1) increased at 24?h after IL-33 treatment in vitro. Pre-treatment with anti-ST2 antibody or fluticasone propionate (FP) suppressed the production of fibronectin1 and types I collagen induced by IL-33. Conclusions: IL-33 is a marker of asthma severity, and may contribute to airway remodeling in asthma by acting on human lung fibroblasts.     

IL-33 is a crucial amplifier of innate rather than acquired immunity

IL-33, a member of the IL-1-related cytokines, is considered to be a proallergic cytokine that is especially involved in Th2-type immune responses. Moreover, like IL-1α, IL-33 has been suggested to act as an "alarmin" that amplifies immune responses during tissue injury. In contrast to IL-1, however, the precise roles of IL-33 in those settings are poorly understood. Using IL-1- and IL-33-deficient mice, we found that IL-1, but not IL-33, played a substantial role in induction of T cell-mediated type IV hypersensitivity such as contact and delayed-type hypersensitivity and autoimmune diseases such as experimental autoimmune encephalomyelitis. Most notably, however, IL-33 was important for innate-type mucosal immunity in the lungs and gut. That is, IL-33 was essential for manifestation of T cell-independent protease allergen-induced airway inflammation as well as OVA-induced allergic topical airway inflammation, without affecting acquisition of antigen-specific memory T cells. IL-33 was significantly involved in the development of dextran-induced colitis accompanied by T cell-independent epithelial cell damage, but not in streptozocin-induced diabetes or Con A-induced hepatitis characterized by T cell-mediated apoptotic tissue destruction. In addition, IL-33-deficient mice showed a substantially diminished LPS-induced systemic inflammatory response. These observations indicate that IL-33 is a crucial amplifier of mucosal and systemic innate, rather than acquired, immune responses.     

The effects of antisense interleukin-4 gene transferred by recombinant adeno-associated virus vector on the airway remodeling in allergic rats

Background: Th2-derived cytokines, including interleukin-4 (IL-4), are considered to play an important role in the development of airway remodeling of asthma. Objectives: Our previous study has demonstrated that a recombinant adeno-associated virus containing antisense against IL-4 gene (rAAV-asIL4) vector could significantly suppress the expression of IL-4 protein and airway inflammation in the rat models of allergic asthma. In this study, we applied the rAAV-asIL4 vector to allergic rats to investigate the effects of anti-IL4 therapy on airway remodeling in allergic asthma. Methods: rAAV-asIL4 was used to infect the ovalbumin (OVA)-sensitized and challenged rats by tail-vein injection. IL-4 protein in bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immunosorbent assay. The number of eosinophils in BALF was counted. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2-positive cells in the peribronchial space were detected by immunohistochemical staining, and collagen deposition beneath the basement membrane was detected by Sirius red stain. The lung tissues were collected for histologic analysis of total bronchial wall area (W_At) and airway smooth muscle area (W_Am). Results: rAAV-asIL4 significantly decreased IL-4 protein in BALF of OVA-sensitized and challenged rats. The number of eosinophils in BALF, the TGF-beta1 and TGF-beta2-positive cells in the peribronchial space were also suppressed. Moreover, the rAAV-asIL4 treatment inhibited the area of Sirius red staining in airways and the increase in W_At and W_Am. Conclusion: These results suggest that rAAV-asIL4 may attenuate the airway remodeling process relevant to the inhibition of airway inflammation. This study provides elementary evidence for the potential utility of rAAV-asIL4 as an approach to gene therapy for asthmatic airway remodeling.     

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。     

2型固有淋巴细胞在过敏性疾病发生中的作用

过敏性疾病尤其是支气管哮喘(简称哮喘)一直被认为是由Th2细胞介导的炎症反应.近期研究发现,2型固有淋巴细胞(type-2 innate lymphoid cell,ILC2)作为一种先天性免疫细胞,同样参与哮喘发生的始动环节.该细胞可产生Th2型细胞因子IL-13、IL-5从而应答受损上皮组织释放的IL-33及IL-25,不仅仅作用于固有免疫的初级阶段,还介导获得性免疫相关功能,这使得先天性及获得性两种免疫系统之间存在了某种特殊的联系,也给研究过敏性哮喘发生机制带来了新的思路.     

血小板活化在哮喘发病中的意义

目的　探讨血小板活化在哮喘发病中的作用。方法　利用酶联免疫法及流式细胞仪分别测定 6 2例哮喘患者和 18名正常对照者血浆 11 去氢血栓烷B2 (11 DH TXB2 )、血栓烷 (TXB2 )浓度和血小板膜CD 6 2P的表达情况 ,并利用荧光酶联免疫法测定部分血清嗜酸细胞阳离子蛋白 (ECP)水平。结果　症状性哮喘组血浆 11 DH TXB2 浓度为 (33 2± 2 7)ng/L ,血小板CD 6 2P阳性百分比为 (2 3 8±3 0 ) % ,平均荧光强度为 2 75± 0 2 9;与健康对照组和缓解组比较差异有显著性 (P分别 <0 0 1、<0 0 5 )。缓解期哮喘与健康对照组比较仅血浆 11 DH TXB2 浓度差异有显著性 (P <0 0 5 )。哮喘发作时血小板活化水平与血清ECP及一秒钟用力呼气容积占预计值百分比 (FEV1占预计值百分比 )、最大呼气流量 (PEF)相关。结论　哮喘发作时存在血小板的异常活化 ,其活化程度与哮喘气道炎症及病情有一定相关性 ,血小板可能通过影响嗜酸细胞功能参与哮喘的发病     

The airway epithelium in asthma: Developmental issues that scar the airways for life?

While allergies are very common, affecting ～40% of the population in most Western countries, only a proportion of allergic people develop asthma. This highlights the importance of tissue and cell specific mechanisms that contribute to the disease. As the interface between the inhaled environment and the internal environment of the lung, the epithelium normally possesses numerous mechanisms to maintain an effective protective barrier. However, the inability of the airway epithelium of asthmatics to effectively defend the lung against normally innocuous inhaled agents strongly suggests that asthma must involve defects in the epithelial barrier rather than being primarily an allergic disease. Evidence is accumulating that in asthma, the epithelium does not go through normal stages of development and differentiation and as a consequence, remain somewhat “immature”. This in turn leads to a chronic cycle of dysregulated damage and repair which ultimately impacts on the airways function by increasing inflammation, but also by initiating processes that ultimately lead to changes to the structure and function of the airway.     

The Role of Interleukin-33 in Rhinitis

IL-33, a member of the IL-1 cytokine family and a ligand to receptor ST2, has great potential to induce a T helper 2-type inflammatory response. IL-33 is proven to be released by epithelial cells during their injury by different environmental stimuli such as airborne allergens, viruses, and air pollutants. IL-33 acting as an endogenous danger signal is termed an alarmin. As such, this cytokine is considered to play a crucial role in an allergic inflammatory disease such as rhinitis. Recent investigations regarding the IL-33/ST2 axis involvement in Th2 inflammatory response and pathogenesis of rhinitis have been reviewed. The role of IL-33 as a novel promising therapeutic target has also been discussed.     

Understanding asthma pathophysiology.

Asthma is best described as a chronic disease that involves inflammation of the pulmonary airways and bronchial hyperresponsiveness that results in the clinical expression of a lower airway obstruction that usually is reversible. Physiologically, bronchial hyperresponsiveness is documented by decreased bronchial airflow after bronchoprovocation with methacholine or histamine. Other triggers that provoke airway obstruction include cold air, exercise, viral upper respiratory infection, cigarette smoke, and respiratory allergens. Bronchial provocation with allergen induces a prompt early phase immunoglobulin E (IgE)-mediated decrease in bronchial airflow (forced expiratory volume in 1 second) followed in many patients by a late-phase IgE-mediated reaction with a decrease in bronchial airflow for 4-8 hours. The gross pathology of asthmatic airways displays lung hyperinflation, smooth muscle hypertrophy, lamina reticularis thickening, mucosal edema, epithelial cell sloughing, cilia cell disruption, and mucus gland hypersecretion. Microscopically, asthma is characterized by the presence of increased numbers of eosinophils, neutrophils, lymphocytes, and plasma cells in the bronchial tissues, bronchial secretions, and mucus. Initially, there is recruitment of leukocytes from the bloodstream to the airway by activated CD4 T-lymphocytes. The activated T-lymphocytes also direct the release of inflammatory mediators from eosinophils, mast cells, and lymphocytes. In addition, the subclass 2 helper T-lymphocytes subset of activated T-lymphocytes produces interleukin (IL)-4, IL-5, and IL-13. IL-4 in conjunction with IL-13 signals the switch from IgM to IgE antibodies. The cross-linkage of two IgE molecules by allergen causes mast cells to degranulate, releasing histamine, leukotrienes, and other mediators that perpetuate the airway inflammation. IL-5 activates the recruitment and activation of eosinophils. The activated mast cells and eosinophils also generate their cytokines that help to perpetuate the inflammation. Regardless of the triggers of asthma, the repeated cycles of inflammation in the lungs with injury to the pulmonary tissues followed by repair may produce long-term structural changes ("remodeling") of the airways. This review will discuss in greater detail the relationships of inflammation and airway hyperresponsiveness to the pathophysiology of asthma.     

Group 2 innate lymphoid cells in human asthma

Asthma is characterized by increased airway hyperresponsiveness, reversible airflow limitation, and remodeling due to allergic airway inflammation. Asthma has been proposed to be classified into various phenotypes by cluster analyses integrating clinical information and laboratory data. Recently, asthma has been classified into two major endotypes, Type 2-high and Type 2-low asthma, and various subtypes based on the underlying molecular mechanisms. In Type 2-high asthma, Th2 cells, together with group 2 innate lymphoid cells (ILC2s), produce type 2 cytokines such as IL-4, IL-5, IL-9, and IL-13, which play crucial roles in causing airway inflammation. The roles of ILC2s in asthma pathogenesis have been analyzed primarily in murine models, demonstrating their importance not only in IL-33- or papain-induced innate asthma models but also in house dust mite (HDM)- or ovalbumin (OVA)-induced acquired asthma models evoked in an antigen-specific manner. Recently, evidence regarding the roles of ILC2s in human asthma is also accumulating. This minireview summarizes the roles of ILC2s in asthma, emphasizing human studies.     

变应性鼻炎和哮喘患者血清IL-9、IL-4、IL-5变化及临床意义

目的探讨血清IL-9、IL-4、IL-5在变应性鼻炎、支气管哮喘（哮喘）、变应性鼻炎合并哮喘中的作用。方法采用双抗体夹心ELISA法检测哮喘组、过敏性鼻炎组、过敏性鼻炎合并哮喘（合并组）患者及查体健康者（对照组）的血清IL-9、IL-4、IL-5。结果与对照组比较,三组患者的血清IL-4、IL-5、IL-9均明显升高（P均〈0．01）;其中血清IL-5合并组高于哮喘组及过敏性鼻炎组（P〈0．01,〈0．05）,过敏性鼻炎组高于哮喘组（P〈0．01）;IL-4合并组高于哮喘组（P〈0．05）。结论IL-4、IL-5、IL-9参与过敏性鼻炎和哮喘的发病,三组患者均表现为Th2型细胞因子过度表达;变应性鼻炎合并哮喘的炎症程度较高,哮喘和鼻炎也有不同炎症反应。     

High-resolution computed tomography findings are correlated with disease severity in asthma

BACKGROUND: The structural changes in the airways of asthmatics are also referred to as remodeling and can be identified using high-resolution computerized tomography (HRCT). OBJECTIVES: To find out whether there are any abnormal HRCT features which can be attributed to asthma and their clinical correlates, and any differences of abnormal HRCT features between asthmatics and patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed (HRCT) scans to assess airway remodeling in 160 nonsmoker asthmatics compared with 27 patients with COPD. RESULTS: Bronchial wall thickening, hyperlucency, centrilobular prominence, bronchiectasis, thick linear opacities and mucoid impaction were all correlated with disease severity in asthma. FEV(1) values were inversely correlated with bronchial wall thickening, hyperlucency, mucoid impaction, linear shadows, centrilobular prominence and bronchiectasis. In addition, thick linear opacities, mucoid impaction and bronchiectasis were more prominent in those patients with a long duration of asthma. Bronchial wall thickening, thick linear opacities, mucoid impaction, bronchiectasis and emphysema were more prominent in COPD patients compared with asthmatics. There was no difference with regard to age, mean values of FEV(1) and the duration of asthma between allergic and nonallergic asthmatics as well as abnormal HRCT findings. CONCLUSIONS: COPD patients have more prominent HRCT findings as compared with asthmatics. In the asthmatics, abnormal HRCT findings are more prominent with increased severity, decreased FEV(1) values and the duration of asthma. The remodelling of airways in allergic asthmatics did not differ from that in their nonallergic counterparts as determined by HRCT.     

结核分支杆菌抗原85B DNA疫苗转染人气道上皮细胞对哮喘患者Th1/Th2平衡的调节作用

目的　研究结核分支杆菌抗原 85B(简称Ag85B)DNA疫苗经人气道上皮转化后的培养上清液对尘螨过敏哮喘患者外周血单个核细胞 (PBMC)Th1/Th2细胞因子释放的调控作用。方法亚克隆构建表达Ag85B基因的真核表达载体pMG Ag85B ,经脂质体介导转化离体培养气道上皮细胞16HBE ,并收集转化细胞培养上清液 ,用逆转录 聚合酶链反应 (RT PCR)方法检测转基因气道上皮Ag85BmRNA水平的表达 ,螨过敏哮喘组 (18例 )和正常组 (13例 )PBMC在离体单独与螨或与Ag85B转染上清液共同培养 ,酶联免疫吸附测定 (ELISA)法测定其培养上清液中白介素 5 (IL 5 )、γ干扰素 (IFN γ)的水平。结果　RT PCR法扩增转染的 16HBE细胞中有 992bp长度的预期片断。无刺激状态下 ,哮喘患者和正常人PBMC培养上清液的IL 5、IFN γ无差异 ,螨刺激可促进哮喘患者PBMC分泌IL 5 ,刺激和未刺激处理分别为 (17 1± 1 9)pg/ml和 (11 9± 0 9)pg/ml(P =0 0 2 ) ;螨 +Ag85B转染上清液与单纯螨刺激比较 ,前者IFN γ水平显著高于后者 ,分别为 (111 5± 15 9)pg/ml和 (5 8 8± 7 8)pg/ml(P =0 0 4 ) ,IFN γ/IL 5的比值分别为 7 2± 4 8和 4 9± 2 5 (P =0 0 8)。正常人不同刺激方法间比较 ,所有指标差异均无显著性 (P >0 0 5 )。结论　螨过敏的变应性     

Cellular localization of interleukin 13 receptor alpha2 in human primary bronchial epithelial cells and fibroblasts.

BACKGROUND: Interleukin (IL) 13 is a key cytokine in asthma, regulating fibrosis, airway remodeling, induction of immunoglobulin E synthesis by B cells, bronchial hyperresponsiveness, and mucus production. IL-13 signals through the type II IL-4 receptor (IL-4R), which is composed of the IL-4Ralpha and the IL-13Ralpha1 chains. Another IL-13 binding chain, IL-13Ralpha2, binds IL-13 with high affinity but has no known signaling capability and is thought to serve as a decoy receptor providing tight regulation of IL-13 responses. METHODS: In this study, we investigated the cellular localization of IL-13Ralpha2 in human primary bronchial epithelial cells and fibroblasts using flow cytometry and confocal microscopy, as well as the in vivo expression of IL-13Ralpha2 in the human bronchial mucosa by means of immunohistochemistry. RESULTS: IL-13Ralpha2 is predominantly an intracellular rather than a membrane-bound molecule in both human primary bronchial epithelial cells and fibroblasts and displays a diffuse granular cytoplasmic distribution in both cell types. IL-13Ralpha2 protein is expressed in vivo in the human bronchial mucosa with its expression being higher in bronchial epithelial cells than bronchial fibroblasts both in vivo and in vitro. CONCLUSIONS: IL-13Ralpha2 is expressed by both human primary bronchial epithelial cells and fibroblasts as an intracellular protein with a diffuse cytoplasmic distribution. In vivo, IL-13Ralpha2 is expressed in the human airway mucosa mainly by bronchial epithelial cells.