FIZZ1在支气管哮喘发病机制中的研究进展

FIZZ1/RELMα是近年来发现的参与肺部慢性炎性疾病的炎症因子,具有促进肺部血管形成及收缩、抗细胞凋亡、诱导上皮下胶原沉积、促进肺成纤维细胞分化等作用.近几年研究显示FIZZ1 在支气管哮喘中发挥重要作用,参与支气管哮喘气道重塑过程,可刺激肺成纤维细胞分化及气道平滑肌增生、促进肺部血管新生、引起气道高反应性及氧化应激.     

基质金属蛋白酶9与慢性肺部炎症性疾病

在慢性阻塞性肺疾病、哮喘和肺囊性纤维化等气道慢性炎症性疾病中,常伴有广泛的气道结构破坏,重构和黏液高分泌等病理改变。中性蛋白酶超家族属的基质金属蛋白酶（matrix metalloproteinase,MMP）,因其能裂解结构性蛋白如胶原和弹性蛋白而在这些病理改变中起着重要作用,其中又以MMP-9（又名白明胶酶B）的作用最为突出而成为研究的热点。MMP-9是一种相对分子质量为92000的Ⅳ型胶原酶,能降解基底膜、细胞外基质和弹力纤维,并参与多种肺部炎症反应,近来还发现其可能参与杯状细胞化生和黏液分泌。本文就其在肺部炎性疾病的作用作一综述。     

表皮生长因子受体与气道黏液高分泌

黏液高分泌是慢性气道炎症性疾病的重要病理特征之一,也是患者病情加剧恶化的重要因素.表皮生长因子受体(EGFR)是一种受体酪氨酸激酶(RTK),在气道黏液高分泌的信号转导通路中居于中心地位,各种炎性介质、病原微生物及其产物、活性氧等可通过多种信号转导通路活化EGFR,活化相关转录因子引起黏蛋白5AC基因表达上调.明确EGFR上下游信号通路势必对慢性气道炎症性疾病的防治提供指导.     

物理医学疗法对气道黏液高分泌的治疗作用

黏液高分泌是慢性气道炎症性疾病包括慢性阻塞性肺疾病(C0PD)、支气管哮喘、囊性纤维化(CF)等共同而重要的病理生理特征,诸多因素如炎症介质、神经调节的改变等都可引起气道上皮的黏液核心蛋白-粘蛋白分泌异常,导致黏液高分泌,进而引起呼吸道反复感染、进行性不可逆性气流阻塞、肺功能渐行下降。胸部物理医学疗法是应用物理学的原理治疗和预防胸部疾病的方法,其目的是充分引流呼吸道分泌物,促使管腔通畅,以维持呼吸道的健康状态。物理医学疗法在气道黏液高分泌中的治疗作用主要表现在以下几个方面:1气道分泌物廓清技术气道分泌物廓清技术…     

气道慢性炎症中黏蛋白5AC基因转录的调节

黏液高分泌是慢性气道炎症性疾病的重要病理特征之一,也是患者病情加剧恶化的重要因素.黏液中增加的黏蛋白主要以5AC为主,是气道黏液高分泌性疾病研究的主要黏蛋白表型.各种炎性介质、病原微生物及其产物、活性氧等能各自通过多种已知的信号转导通路,活化相关转录因子结合到黏蛋白5AC基因启动子上相应位点,促进转录,引起黏蛋白合成增加,其中以丝裂原活化蛋白途径及特殊蛋白-1的作用尤为突出.但目前对刺激因素到达膜受体前发生的一系列激活转换机制尚缺乏全面了解.另外糖皮质激素、维甲酸、甲状腺素等也通过核受体参与调控.各信号通路及转录因子之间还存在相互调节,构成复杂的信号转导网络.了解黏蛋白5AC基因的转录和表达的调控机制势必为深入研究气道黏液高分泌提供重要线索.     

慢性阻塞性肺疾病气道炎症在肺动脉重构中的作用

慢性阻塞性肺疾病(COPD)的慢性气道炎症是COPD的重要病理基础,它不仅在气道结构重构中起关键作用,而且在肺动脉重构亦有重要作用,甚至在无低氧血症时已引起肺动脉功能和结构的改变,以平滑肌增殖和细胞外基质在肺动脉内层沉积为特征,伴有肺动脉最大舒张性及最大收缩性降低,肺动脉外膜出现以CD8 T细胞浸润为主的炎症反应,在此期间肺组织中慢性炎症过程引起的肺动脉内皮功能障碍、转移生长因子过度表达、成纤维细胞生长因子及血管内皮生长因子及其受体的改变在肺血管结构重构中起作用。     

《慢性气道炎症性疾病气道黏液高分泌管理中国专家共识》解读

正气道黏液高分泌是慢性气道炎症性疾病最重要的临床生理特征之一,多年来的研究已经逐渐证实气道黏液高分泌在慢性气道炎症性疾病中的发病与临床进展中发挥着重要作用[1-2]。但是在临床实践中,部分患者乃至部分医师仍未充分认识到气道黏液高分泌的重要临床意义,仅仅将其作为慢性气道炎症性疾病的普通症状对待。鉴于此,中华医学会呼吸病学分会组织相关学组专家,制定了《慢性气道炎症性疾病气道黏液高分泌管理中国专家共识》     

慢性阻塞性肺疾病炎症反应的复杂性及治疗新选择

气道炎症反应在COPD的发病中发挥着重要作用,在烟草烟雾等刺激因素作用下引起气道炎症细胞募集,激发先天性和继发性免疫反应,进而导致气管壁增厚,气道重塑,支气管平滑肌张力增加,黏液高分泌和肺实质弹性结构缺失,这是COPD发病的重要基础结构病变.     

Toll样受体4与气道慢性炎症性疾病

气道慢性炎症性疾病如慢性阻塞性肺疾病、支气管哮喘等是在各种内外界刺激因素作用下由气道固有细胞、炎症细胞和炎症因子参与的非特异性炎症性疾病.迄今已发现11种Toll样受体(TLR),均为I型跨膜受体蛋白,广泛表达于支气管上皮细胞、支气管平滑肌细胞、树突状细胞、肺泡巨噬细胞等,因其能感知病原体并直接或间接作出防御反应而在慢性气道炎症性疾病的发生发展中发挥重要作用,其中又以TLR4的作用最为突出而成为研究的热点.故深入认识TLR4与慢性气道炎症性疾病的关系将为临床治疗开辟广阔的前景.     

氧化应激与支气管哮喘气道黏液高分泌研究进展

哮喘是一种以支气管收缩可逆性、肺部炎症及气道重塑为特点的慢性气道炎症性疾病.黏液过度分泌导致气道阻塞、肺功能下降、气道重塑和感染增加.过度的活性氧/活性氮(ROS/RNS)产生造成气道炎症,气道高反应性,气道微血管高通透性和气道黏液高分泌,以及组织损伤和形态的改变.减轻氧化应激或增加抗氧化能够减轻气道嗜酸粒细胞,减少黏液分泌,减轻支气管高反应性.本文就氧化应激与哮喘气道黏液高分泌的关系作一综述.     

Mucous hypersecretion and relationship to cough

A variety of foreign “invaders” such as viruses, bacteria and other particulates e.g., cigarette smoke, are inhaled, deposit on the airway surface and invade the “host.” Mucins produced by the surface airway epithelium and by the submucosal glands are secreted into the airway lumen. Deposited particulates adhere to the mucus and are cleared via mucociliary transport and via cough. Mucins are major constituents of mucus, which is important in the clearance of inhaled materials. Normally, secreted mucus is cleared without symptoms or interference with lung function. However, in obstructive airway diseases such as COPD, asthma, and cystic fibrosis, excessive mucus is produced. Because of the prominence of mucous hypersecretion as a cause of cough, this discussion focuses on mechanisms regulating normal production of mucins and the mechanisms underlying exaggerated mucin secretion in chronic obstructive airway diseases. Mucins are produced by airway epithelial cells via a cascade of signals (the Epidermal Growth Factor Cascade) and secreted on the luminal epithelial surface, often in response to the deposition of inhaled irritants. Normally, only minimal amounts of mucins are secreted, which assist in clearance of the inhaled particulates. However, in disease, additional pathways are induced via positive feedback systems, which lead to mucous hypersecretion. In the large conducting airways, where cough receptors are concentrated, mucous hypersecretion causes stimulation of neural receptors that result in cough. However, in small airways (e.g., bronchioles), because of their small diameters, mucous hypersecretion leads to plugging of the airways. Because there are so many small airways, their plugging is difficult to detect early, and this locus is known as a “silent zone.” In chronic obstructive airway diseases, plugging of small airways may persist and increase over time, finally resulting in severe airway obstruction. Different obstructive airway diseases induce inflammatory signaling (including mucous hypersecretion) via different stimuli, but often via similar signaling pathways. Application of present knowledge of signaling that occurs with mucous hypersecretion can lead to novel therapies for hypersecretion and cough induced in conducting airways and could prevent plugging in small airways that can lead to clinical deterioration and death.     

Leukocyte function and chronic bronchitis

Chronic bronchitis is a condition of mucous hypersecretion. It represents an interface between airway structures, cigarette smoke, and inflammatory cells. Chronic bronchitis is a late complication of smoking, typically occurring after 30 pack years. Stable patients have mucous hypersecretion and little evidence of acute inflammation. In contrast, during acute attacks of bronchitis, an intense accumulation of neutrophils occurs in the airways. Mechanisms of injury to airway structures include chemicals and reactive oxygen species within cigarette smoke, and secreted products of recruited neutrophils. Recent studies demonstrate that secreted products of polymorphonuclear leukocytes (PMNs) can cause secretory cell metaplasia and increase mucous production. Thus, the role of the PMN in chronic mucous hypersecretion appears to be a significant one. Cessation of cigarette smoking remains a most important aspect of caring for patients with chronic mucous hypersecretion.     

中性粒细胞弹性蛋白酶抑制剂对慢性炎症气道高分泌的干预作用

目的 了解慢性炎症气道黏液高分泌发生的分子机制。方法 利用大鼠慢支炎模型，对其进行中性粒细胞弹性蛋白酶(NE)抑制剂-Sivelestat干预后，采用酶联免疫吸附试验(ELISA)及原位杂交方法分别检测支气管肺泡灌洗液(BALF)中黏蛋白(MUC)含量以及肺组织粘蛋白基因MUC5AC转录水平的表达。结果 Sivelestat明显降低慢性气道炎症大鼠气道黏蛋白含量，并从转录水平降低MUC的分泌。结论 NE是炎症气道黏液高分泌发生的重要始动因素。NE抑制剂在慢性阻塞性肺病的治疗中表现出潜在的临床应用价值。     

Chronic exposure to sulfur dioxide. Physiologic and histologic evaluation of dogs exposed to 50 or 15 ppm

Seven adult mongrel dogs were exposed to SO2 gas at 2 different concentrations (15 and 50 ppm) on a daily basis for 5 to 11 months. Mucous hypersecretion and airway obstruction (a sustained increase in pulmonary resistance) developed in 4 dogs exposed to 50 ppm SO2. Histologic examination of the dogs' airways demonstrated epithelial thickening and an increase in size of the mucous glands. No inflammatory cell infiltration of the airways was noted and, in addition, responsiveness to inhaled histamine and methacholine did not change. The increase in lung resistance correlated with increase in mucous gland volume and airway wall thickening, but not with any change in airway responsiveness. Dogs exposed to 15 ppm SO2 showed minimal histologic and physiologic changes compared with control dogs. Previous work with a similar model of chronic bronchitis, using higher level SO2 exposure, has demonstrated an association of airway inflammation with decreased responsiveness to inhaled bronchoconstrictors. In the present study, with a lower exposure level to SO2 (50 versus 200 ppm), we found similar histologic findings associated with airway obstruction, but in the absence of airway inflammation, responsiveness to inhaled bronchoconstrictors was unchanged. This supports the theory that chronic airway inflammation may be associated with decreased responsiveness to inhaled bronchoconstrictors. This contrasts with the hyperresponsiveness induced by acute exposure to irritant gases noted by others.     

Sulfur-dioxide-induced bronchitis in dogs. Effects on airway responsiveness to inhaled and intravenously administered methacholine

Chronic bronchitis was induced in 7 dogs of mixed breed by chronic exposure to SO2 gas. Within the first 2 to 4 wk of exposure, the dogs developed cough and mucous hypersecretion, chronic airway obstruction (increased pulmonary resistance), and persistent lung inflammation as demonstrated by an increase in the number of neutrophils recovered in the bronchoalveolar lavage (BAL) fluid. Airway responsiveness to methacholine aerosol decreased 2- to 3-fold within 8 wk of SO2 exposure. In contrast, airway responsiveness to intravenous administration of methacholine did not change. The data suggest that the decreased airway responsiveness observed during persistent pulmonary inflammation in SO2-exposed dogs is not due to an altered state of airway contractile elements but likely reflects expression of an inhibitory influence of the mucoepithelial barrier.     

Enhanced release of thromboxane A(2) after exposure of human airway epithelial cells to meconium.

Meconium aspiration syndrome (MAS) is a cause of significant morbidity and mortality in the perinatal period. Despite the clinical relevance of MAS, its pathogenesis is poorly understood. Epithelial cell-derived prostanoids are involved in the regulation of several cellular functions within the lung, including the control of tone and reactivity of airway and vascular smooth muscle. In this study, we evaluated whether exposure to meconium affects the metabolic function of human airway epithelial cells. Monolayers of A549 cells, a transformed human epithelial cell line, were incubated with various concentrations of meconium. Control cells were incubated with serum-free medium in a similar manner. The supernatant fluid was removed at various time points and assayed for thromboxane A(2) (TXA(2)) production. The latter was accomplished by measuring its immediate and stable metabolite thromboxane B(2), using an enzyme-linked immunosorbent assay (ELISA). In selected experiments, the modulatory effects of indomethacin (10(-6) M), dexamethasone (10(-6) M), and L-nitroarginine methyl ester (L-NAME, 10(-6) M) on TXA(2) production were evaluated. Results were expressed in terms of pg/mg protein (mean +/- SE). We found that exposure to meconium produced a significant release of TXA(2) from A549 cells. Indomethacin, dexamethasone, and in part, L-NAME inhibited meconium-induced release of TXA(2). Our findings demonstrate that meconium enhances the production of thromboxanes from A549 cells, suggesting that airway epithelial cells and their metabolic products may play an important role in the pathogenesis of MAS.     

Mechanisms of pathogenesis in allergic asthma: Role of interleukin‐23

Asthma is a chronic airway inflammatory disease characterized by intense leukocyte and eosinophilic infiltration accompanied by mucus hypersecretion and tissue hyperresponsiveness. Recent evidence suggests that T‐helper (Th)2 cells and their cytokine products orchestrate the pathology of asthma. In addition, Th17 cells are implicated in the pathogenesis of antigen‐induced airway inflammation. The Th17 related cytokine interleukin (IL)‐23 plays important roles in many immunological diseases, such as experimental autoimmune encephalomyelitis, rheumatoid arthritis, psoriasis and inflammatory bowel disease. Several reports describe the role of IL‐23 in the pathogenesis of allergic asthma in both human and mice. IL‐23 leads to neutrophil infiltration in the airway of asthmatic mice, which is characteristic of severe asthma resulting from Th17 development and subsequently IL‐17 secretion. IL‐23 can also promote eosinophil infiltration in the airway, which is a hallmark of allergic asthma. These studies suggest that IL‐23 could be a promoting factor in the development of allergic asthma and likewise would be a target for asthma therapy. In support of this view, trials of anti‐IL‐23 therapy have been attempted in human and mouse asthma models with encouraging outcomes. This review presents the role of IL‐23 in asthma according to recent clinical trials and animal model studies. The proposed mechanisms of IL‐23‐induced airway inflammation and the agents currently being tested that target IL‐23 related pathways are discussed.     

过氧化物酶体增殖物激活受体γ及其配体与气道黏液高分泌

气道黏液高分泌足慢性气道疾病如慢性阻塞性肺疾病、支气管哮喘、肺囊性纤维化、支气管扩张等共同而重要的病理特征之一,与气道疾病的发生、发展转归有密切关系.过氧化物酶体增殖物激活受体γ是一类由致密分子构成依赖配体激活的核转录因子.近年研究认为,过氧化物酶体增殖物激活受体γ及其配体能拮抗气道炎症反应,能对气道黏液分泌发挥调节作用.     

过氧化物酶体增殖物激活受体γ及其配体与气道黏液高分泌

气道黏液高分泌足慢性气道疾病如慢性阻塞性肺疾病、支气管哮喘、肺囊性纤维化、支气管扩张等共同而重要的病理特征之一,与气道疾病的发生、发展转归有密切关系.过氧化物酶体增殖物激活受体γ是一类由致密分子构成依赖配体激活的核转录因子.近年研究认为,过氧化物酶体增殖物激活受体γ及其配体能拮抗气道炎症反应,能对气道黏液分泌发挥调节作用.