慢性阻塞性肺疾病发病机制及其临床表型间联系的研究进展

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种以进展性、不可逆性气道受限为特征的肺部疾病.肺气肿、伴随气道受限的慢性支气管炎和小气道疾病是COPD常见的三种临床表型.COPD发病机制复杂,涉及各种细胞因子及炎症因子的作用、免疫应答和凋亡等.现就COPD发病机制和临床表型间的研究进展进行总结.     

吸烟、肿瘤坏死因子及其受体与慢性阻塞性肺疾病

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)发病率高.发病机制不清.外界环境的刺激导致气道和血管损伤与修复的失平衡可能与COPD的发生相关.其中吸烟致细胞因子、炎症细胞及炎症介质增多,气道和肺实质慢性炎症,导致气道损伤和重构.最终导致气流受限,在肺气肿的形成中起主要作用.肿瘤坏死因子a是重要的炎症因子,通过其主要受体肿瘤坏死因子受体1参与COPD的形成,在COPD的发生、发展中起重要作用.     

大环内酯类药物在慢性阻塞性肺疾病气道及肺部炎症中的作用

慢性阻塞性肺疾病（COPD）是一种以气流受限为特征的疾病，气流受限不完全可逆、呈进行性发展，与肺部对有害气体或有害颗粒的异常炎症反应有关.所以COPD的实质是肺部的异常炎症反应，其炎症特点为细胞毒性T细胞、单核细胞、中性粒细胞和巨噬细胞数量增多，且释放大量炎症介质，并有高水平的氧化应激，这进一步扩大这种慢性炎症;其炎症部位涉及气道、肺泡壁和肺血管，导致这些组织的功能结构异常，从而引起气流受限、肺气肿和肺动脉高压.所以抗炎治疗在COPD治疗中有重要作用.人们在探索抗炎药物在慢性气道炎症中的作用过程中，发现大环内酯类药物（MA）具有抗炎、免疫调节等作用，且对气道慢性炎症具有肯定的疗效.本文重点介绍MA的生物学特性和分类，抗炎作用及其相关机制，对COPD气道及肺血管炎症及重塑的作用。     

加强对慢性阻塞性肺疾病气道重塑及其发生机制的研究

慢性阻塞性肺疾病(COPD)是以不完全可逆性气流受限为特征,其病理基础为气道壁和肺实质的慢性炎症及结构破坏,最终导致管腔狭窄、肺气肿形成和进行性气流阻力增加。这一过程称为气道重塑。气道重塑是COPD病情不断进展最终引起呼吸衰竭和肺源性心脏病的主要原因。因此,研究其病理改变及发生机制,对改善其防治效果及患者预后具有重要意义,对此应予更多关注。     

免疫反应在慢性阻塞性肺疾病和肺气肿发生及发展过程中的作用

COPD是具有气流受限特征的疾病,气流受限不完全可逆,呈进行性发展,并与肺部对香烟烟雾等有害气体或有害颗粒的异常炎症有关,这种异常炎症累及各级气道、肺实质和肺血管.目前普遍认为,慢性的肺部炎症在COPD和肺气肿形成中起主要作用.近年来研究结果显示,T细胞介导的炎症反应参与COPD和肺气肿的发生与发展过程,并与疾病的严重程度相关,提示免疫反应可能在其中起重要作用.     

慢性气道炎症大鼠肺血管结构和生长因子变化的实验研究

目的探讨慢性气道炎症与肺血管重建的相关关系以及慢性气道炎症对斑管内皮生长因子（VEGF）及内皮素-1（ET-1）的影响。方法复制慢性支气管炎和肺气肿动物模型。用图像分析仪观察支气管肺组织和肺血管结构病理变化情况。酶联免疫法检测血清VEGF。放射免疫法测定血浆ET-1水平。结果模型组大鼠发生明显的慢性气道炎症和肺气肿改变。细小支气管中膜肌层增厚，但肺血管结构与对照组比较无明显改变．血清VEGF和血浆ET-书平与对照组比较亦无显著性差异（P〉0．05）。结论 慢性气道炎症对大鼠肺血管重建和、VEGF和ET-1无明显直接影响。但慢性气道炎症的持续发展是慢性阻塞性肺疾病（COPD）产生低氧的主要病理基础，因此对COPD的防治重点之一应放在气道炎症的防治。     

NLRP3炎症小体及其激活产物在慢性阻塞性肺疾病中的作用研究进展

慢性阻塞性肺疾病(COPD)是一种常见的以持续气流受限为特征的疾病,与气道和肺对有毒颗粒或气体的慢性炎症反应增强有关.COPD发病率、致死率高,造成了严重的经济和社会负担.然而迄今为止,没有一种治疗COPD的药物可以有效地阻止疾病的进展.目前认为,气道和肺部的慢性炎症是导致COPD发生发展的主要机制.然而促使炎症产生并大量扩散的机制尚不清楚.炎症小体最近被发现在呼吸系统疾病的炎症发生发展中发挥重要作用.种种证据表明香烟烟雾导致NLRP3炎症小体的活化,促使IL-1β和IL-18的成熟和释放增多,可能在COPD的慢性炎症中发挥重要作用,为临床上治疗COPD提供了新的思路.     

核因子κB在慢性阻塞性肺疾病发病机制中的作用

核因子κB(nuclear factor kappa B,NF-κB)是一种广泛存在于体内多种细胞的核转录因子,与免疫,肿瘤的发生、发展,细胞凋亡的调节以及胚胎发育等有着密切联系,是一种重要的核转录因子.慢性阻塞性肺疾病(chronic obstructive pulmonary diseases,COPD)是一种以气道、肺实质和肺血管的慢性炎症为特征的疾病.NF-κB作为信号转导途径中的枢纽,活化的失调与COPD的发生和发展密切相关,参与COPD的多种发病机制.本文就NF-κB及其在COPD的中的作用作一综述.     

中性粒细胞在慢性阻塞性肺疾病中的作用

慢性阻塞性肺疾病(chronic obstructive pneumonia discase,COPD)是以不完全可逆的气流受限为特征的慢性炎症性疾病.中性粒细胞可能在COPD的发展过程中发挥主要作用.活化的中性粒细胞释放蛋白酶、活性氧和细胞因子,引起肺组织损伤,最终导致气道黏液高分泌,气流受限和肺气肿.     

炎症在慢性阻塞性肺疾病相关肺动脉高压发病机制中的作用的研究进展

慢性阻塞性肺疾病(COPD)是以气道、肺实质、肺血管慢性炎症为主要特征的慢性肺疾病.肺动脉高压是COPD的主要并发症.近年来新的研究表明,COPD相关肺动脉高压的主要发病机制除缺氧外,炎症介质如白介素16、C反应蛋白、肿瘤坏死因子α、内皮素1等及炎症细胞如中性粒细胞、T淋巴细胞、巨噬细胞、肥大细胞等也起重要作用.     

肺气肿动物模型研究进展

阻塞性肺气肿（肺气肿）是慢性阻塞性肺疾病（COPD）的主要病理表现,已成为研究中的焦点。多种实验性肺气肿动物模型的研究对揭示COPD的遗传背景、诱发因素、发病机制及新药的开发起了极大的促进作用。最近,有大量研究数据显示,细胞凋亡在COPD发病中起重要作用。本文就肺气肿动物模型的构建方法及其研究进展作一综述。     

Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

The mammalian target of rapamycin (mTOR) signalling pathway regulates fundamental metabolic processes such as inflammation, autophagy and apoptosis, all of which influence cell fate. Recent experimental data suggest that mTOR signalling is involved in many diseases, including lung diseases, but with contrasting data. Overexpression of mTOR and its signalling proteins have been linked to lung cell senescence and development of emphysema, pulmonary hypertension and inflammation. On the other hand, mTOR inhibitors, as rapamycin and/or its derivatives, restore corticosteroid sensitivity in peripheral blood mononuclear cells from chronic obstructive pulmonary disease (COPD) patients, and overexpression of mTOR suppresses cigarette smoke-induced inflammation and emphysema, suggesting that induction of mTOR expression/activity might be useful to treat COPD. This apparent discrepancy is due to complex and heterogenic enzymatic pathway of mTOR. Translation of pre-clinical positive data on the use of mTOR inhibitors to COPD therapy needs a more in-depth knowledge of mTOR signalling.     

Functional significance of apoptosis in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease characterized by an abnormal inflammatory response of the lungs to noxious particles and gases. Cigarette smoking remains a major risk factor in COPD development. Accumulating evidence suggests that apoptosis, a regulated form of cell death, may play an important role in COPD pathogenesis. Increased numbers of apoptotic cells can be detected in lung tissue and airways of human subjects with COPD, relative to normal lungs or those from smokers without COPD. Alveolar wall destruction associated with emphysema development, may involve increased apoptosis of alveolar structural cells. Several intervention-induced apoptotic models (e.g., cigarette smoke, vascular-endothelial growth factor inhibition, and interferon-gamma) cause emphysematous changes in vitro and in vivo. Increased apoptosis in COPD can also imply defects in the normal physiological clearance of apoptotic cells. Additional factors that relate to perpetuation of the pathogenesis of COPD, including protease/antiprotease imbalance, inflammation and oxidative stress, may mutually promote apoptosis or contribute to impaired clearance of apoptotic cells. Given that cigarette smoking is the most common cause of COPD, identification of the pathways of cigarette smoke-induced apoptosis may further the understanding of COPD pathogenesis. However, apoptosis rate is not diminished after cessation of cigarette smoking, indicating that other mechanisms perpetuate apoptosis in COPD. Therefore, understanding functional relationships between apoptosis and protease/antiprotease imbalance, inflammation, oxidative stress and other factors potentially involved in COPD pathogenesis may uncover crucial therapeutic targets.     

Therapeutic Effects of SRT2104 on Lung Injury in Rats with Emphysema via Reduction of Type II Alveolar Epithelial Cell Senescence

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and severe diseases worldwide with high societal and health care costs. The pathogenesis of COPD is very complicated, and no curative treatment is available. Cellular senescence promotes the development of COPD. Type II alveolar epithelial cells (AECII) play a momentous role in lung tissue repair and maintenance of alveolar homeostasis. Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to chronic inflammation and oxidative stress, regulates many pathophysiological changes including stress resistance, apoptosis, inflammation, and cellular senescence. This study aimed to investigate whether the pharmacological SIRT1 activator SRT2104 protects against AECII senescence in rats with emphysema. Our findings confirmed that SRT2104 administration reduced the pathological characteristics of emphysema and improved lung function parameters, including pulmonary resistance, pulmonary dynamic compliance, and peak expiratory flow. Moreover, SRT2104 treatment upregulated the expression of surfactant proteins A and C, SIRT1, and forkhead box O 3a (FoxO3a), decreased senescence-associated-β-galactosidase (SA-β-gal) activity, increased SIRT1 deacetylase activity, and downregulated the levels of p53 and p21. Therefore, SRT2104 administration protected against AECII senescence in rats with emphysema via SIRT1/FoxO3a and SIRT1/p53 signaling pathways and may provide a novel potential therapeutic strategy for COPD.     

Pathogenesis of emphysema: from the bench to the bedside

Chronic obstructive pulmonary disease (COPD) is characterized physiologically by expiratory flow limitation and pathologically by alveolar destruction and enlargement and small and large airway inflammation and remodeling. An imbalance between protease and antiprotease activity in the lung is proposed as the major mechanism resulting in emphysema. The imbalance is mostly due to an increase in the numbers of alveolar macrophages and neutrophils. Emphysema can also develop from increased alveolar wall cell death and/or failure in alveolar wall maintenance. Chronic inflammation and increased oxidative stress contribute to increased destruction and/or impaired lung maintenance and repair. Genetic factors may play an important role in disease susceptibility because only a minority of smokers develops emphysema. Recent literature implicates surfactant instability, malnutrition, and alveolar cell apoptosis as possible etiologies. Identification of cellular and molecular mechanisms of COPD pathogenesis is an area of active, ongoing research that may help to determine therapeutic targets for emphysema.     

Pathogenesis of chronic obstructive pulmonary disease

It is currently believed that the most important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD) is inflammation of the small airways caused by inhaled particles and gases. In this context, a disturbance of the physiological balance between proteases and antiproteases develops that may cause lung emphysema. Moreover, oxidative stress seems to be important, as it may enhance the inflammatory reaction. The development of emphysema may also involve a loss of alveolar cells by apoptosis. Finally, several studies have indicated that a systemic inflammation is induced by COPD that may be of relevance to the development of systemic components that are observed in COPD patients.     

Pathogenese der COPD

It is currently believed that the most important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD) is inflammation of the small airways caused by inhaled particles and gases. In this context, a disturbance of the physiological balance between proteases and antiproteases develops that may cause lung emphysema. Moreover, oxidative stress seems to be important, as it may enhance the inflammatory reaction. The development of emphysema may also involve a loss of alveolar cells by apoptosis. Finally, several studies have indicated that a systemic inflammation is induced by COPD that may be of relevance to the development of systemic components that are observed in COPD patients.     

间充质干细胞移植治疗慢性阻塞性肺疾病的相关研究进展

慢性阻塞性肺疾病(COPD)是一种重要的慢性呼吸系统疾病,主要包括慢性支气管炎和肺气肿,患病人数多,病死率高,由于其缓慢进行性发展,COPD是以上调炎症过程导致诸如上皮细胞凋亡、终末肺泡间隔及肺泡外基质蛋白水解事件发生为特征,严重影响患者的劳动能力和生活质量.近来一些研究揭示,间充质干细胞对肺组织的修复和再生有重要作用...     

Bronchoalveolar lavage in COPD: fluid recovery correlates with the degree of emphysema.

Bronchoscopy with bronchoalveolar lavage (BAL) is an important research tool for assessing airway inflammation in a variety of inflammatory lung diseases. In chronic obstructive pulmonary disease (COPD), BAL recovery is often low, making analysis of the recovered fluid difficult to interpret. The present authors hypothesised that the degree of emphysema may predict BAL recovery. A total of 20 COPD patients (mean age 57 yrs, range 49-69) with a median (interquartile range) forced expiratory volume in one second (FEV1) of 51 (33-69)% predicted underwent BAL. Matched "healthy" smokers and nonsmokers served as controls. Emphysema index in COPD patients was calculated on computed tomography scan as the percentage of the right lung with pixels <-950 Hounsfield units. The carbon monoxide diffusing capacity of the lung (DL,CO) was determined by the single-breath method. COPD patients had lower BAL recovery than controls. COPD patients with an emphysema index <1 had higher BAL recovery than patients with an emphysema index >1. BAL recovery correlated negatively to emphysema index and positively to DL,CO. However, no correlation was found between recovery and FEV1. In conclusion, the extent of emphysema evaluated by computed tomography-scan index and carbon monoxide diffusing capacity of the lung may predict a low bronchoalveolar lavage recovery in chronic obstructive pulmonary disease patients. These parameters may, therefore, be useful when chronic obstructive pulmonary disease patients are selected for bronchoscopy with bronchoalveloar lavage. The present study underlines the importance of careful phenotyping of chronic obstructive pulmonary disease patients.