Lung structure and function in COPD.

The pathogenesis of chronic obstructive pulmonary disease (COPD) is related to a chronic innate and adaptive inflammatory immune response to inhaled toxic particles and gases, primarily as a result of the tobacco smoking habit. This inflammatory immune process develops in the lungs of everyone that smokes, and there is an association between the extent and severity of this tissue response and the severity of airflow limitation present in the fraction of the smoking population that develops COPD. This infiltration of inflammatory immune cells into the lung tissue is inextricably linked to a tissue repair and remodeling process that enlarges the bronchial mucus glands, thickens the walls and narrows the lumen of conducting airways <2 mm in diameter. A multivariate analysis has shown that thickening of the walls of the small conducting airways and occlusion of their lumen by inflammatory exudates containing mucus explains more of the variance in the association between FEV1 decline and histology in COPD than the infiltration of the tissue by any inflammatory cell type. Emphysematous destruction of the gas exchanging tissue also contributes to the airflow limitation by reducing the elastic recoil pressure available to drive air out of the lung during forced expiration. This tissue destruction begins in the respiratory bronchioles in very close proximity to the small conducting airways that become the major site of obstruction in COPD. The mechanism(s) that allow small airways to thicken in such close proximity to lung tissue undergoing emphysematous destruction remain a puzzle that needs to be solved. As the accumulation of tissue responsible for thickening the small conducting airways is a very different pathological process from the emphysematous destruction of surrounding gas exchanging tissue, we need a better understanding of the pathogenesis of both processes and better methods of separating their relative contribution to airflow limitation in individuals to adequately prevent and treat COPD.     

Bronchiolitis obliterans organizing pneumonia (BOOP) in a child with mild-to-moderate asthma: evidence of mast cell and eosinophil recruitment in lung specimens

Bronchiolitis obliterans with organizing pneumonia (BOOP) is rarely described in children and little is known about its pathogenesis. This paper reports on an 11-year-old patient suffering from mild-to-moderate asthma. He presented with a retrocardiac density at chest computed tomography scan that was slow to resolve and failed to respond to antibiotic therapy. Open lung biopsy revealed a histological picture with buds of granulation tissue in respiratory bronchioles and alveolar ducts, with organized extensions into the alveoli. The use of monoclonal antibodies on biopsy specimens demonstrated the presence of an inflammatory process affecting not only the thickened alveolar walls, but also the remaining lung parenchyma, the pulmonary arteries, and the bronchioles. The inflammatory infiltrate consisted mainly of mast cells and eosinophils. The clinical condition improved with steroid therapy. To the best of the authors' knowledge, this is the first report of BOOP in an asthmatic child with recruitment of mast cells and eosinophils documented by using monoclonal antibodies.     

Targeting adenosine receptors: novel therapeutic targets in asthma and chronic obstructive pulmonary disease

Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell. There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5'-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H1 receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD. To date, four subtypes (A1, A2A, A2B, A3) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD. This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.     

Targeting Adenosine Receptors

Adenosine, an endogenous signaling nucleoside that modulates many physiological processes has been implicated in playing an ever increasingly important role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). All cells contain adenosine and adenine nucleotides and the cellular production of adenosine is greatly enhanced under conditions of local hypoxia as may occur in inflammatory conditions such as asthma and COPD. In 1983, it was first reported that inhaled adenosine causes dose-related bronchoconstriction in patients with both allergic and non-allergic asthma but not in healthy volunteers. This hyperresponsiveness was also reported in patients with COPD, with those patients who smoked exhibiting a significantly greater response. This bronchoconstrictor effect of adenosine is orchestrated through the stimulation of specific cell membrane receptors and involves an important inflammatory cell, the mast cell.There is substantial evidence which suggests that mast cell activation is central to this unique response to adenosine. Mast cell mediator release makes a significant contribution towards airflow obstruction and the consequent symptoms in patients with asthma. Over the last two decades, researchers have investigated the effect of mast cell inhibitors as well as mast cell mediator receptor antagonists and their role in attenuating the bronchoconstrictor response to inhaled adenosine 5′-monophosphate (AMP). Promising results have been shown using mast cell stabilizers, histamine H₁ receptor antagonists, selective cysteinyl leukotriene-1 receptor antagonists and inhibitors of 5-lipoxygenase and cyclo-oxygenase. Through these findings, the mast cell has been recognized as being a critical inflammatory cell in the adenosine-induced response in patients with asthma and COPD.To date, four subtypes (A₁, A_2A, A_2B, A₃) of adenosine receptors have been cloned each with a unique pattern of tissue distribution and signal transduction. Activation of these receptors has pro- and anti-inflammatory consequences making the development of agonists and/or antagonists at these receptor sites a novel approach in the treatment of patients with asthma and COPD.This review highlights the importance of adenosine in the pathophysiology of asthma and COPD, the critical role of the mast cell and the potential to target the adenosine receptor subtype in patients with asthma and COPD. The complete characterization of these adenosine receptor subtypes in terms of their distribution in humans and the development of selective agonists and antagonists, holds the key to our complete understanding of the role of this important mediator in asthma and COPD.     

Ischemia/reperfusion injury: The role of immune cells

Ischemia/reperfusion (I/R) injury is an inflammatory condition that is characterized by innate immunity and an adaptive immune response. This review is focused on the acute inflammatory response in I/R injury, and also the adaptive immunological mechanisms in chronic ischemic disease that lead to increased vulnerability during acute events, in relation to the cell types that have been shown to mediate innate immunity to an adaptive immune response in I/R, specifically myocardial infarction. Novel aspects are also highlighted in respect to the mechanisms within the cardiovascular system and cardiovascular risk factors that may be involved in the inflammatory response accompanying myocardial infarction. Experimental myocardial I/R has suggested that immune cells may mediate reperfusion injury. Specifically, monocytes, macrophages, T-cells, mast cells, platelets and endothelial cells are discussed with reference to the complement cascade, toll-like receptors, cytokines, oxidative stress, renin-angiotensin system, and in reference to the microvascular system in the signaling mechanisms of I/R. Finally, the findings of the data summarized in this review are most important for possible translation into clinical cardiology practice and possible avenues for drug development.     

Mast cells in allergy and host defense.

Mast cells have been implicated in the pathogenesis of allergic diseases and in inflammatory responses associated with pathological immune and disease-related processes including fibrosis, autoimmune pathology, and neoplasia. Recent findings in animal models of bacterial infection also suggest that mast cells may have a protective role in host defense against pathogens in innate immunity along with the probable role of mast cells in acquired immunity against parasitic infections. Mast cells are strategically located at the host-environment interface and may provide an early defense against an invading pathogen. Mast cells express an array of adhesion and immune receptors that may assist in the recognition of invading pathogens. When activated, these cells then synthesize and release key immunoregulatory cytokines, one consequence of which is to mobilize a rapid and vigorous inflammatory response. However, although it has been demonstrated that mast cells may have a role in innate immunity in defined in vitro and animal models, it remains to be determined whether mast cells are protective in innate immune responses in humans.     

Structural abnormalities and inflammation in COPD: a focus on small airways

Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation associated with airway remodelling and inflammation of both large and small airways. The site of airflow obstruction in COPD is located in the small airways, justifying a focus on this compartment. The structural abnormalities that are found in bronchioles with a diameter less than 2mm are characterized by increased airway wall thickness with peribronchial fibrosis, and by luminal obstruction by mucous exudates. Destruction of alveolar walls, the hallmark of emphysema, may be related to protease-antiprotease imbalance, and to mechanisms involving apoptosis, senescence, and autoimmunity. Cigarette smoke inhalation triggers the recruitment of innate immune cells (neutrophils and macrophages) and putatively adaptive immunity mediated via T and B lymphocytes and lymphoid follicles in the small airways. These data suggest a potential role for therapies that can target remodelling and inflammation in the small airways of patients with COPD.     

Matrix Metalloproteinases in the Pathogenesis of Asthma and COPD

While asthma is an inflammatory disorder of the airways involving mediators released from mast cells and eosinophils, inflammation alone is insufficient to explain the chronic nature of the disease. Recent progress in the understanding of disease pathogenesis has revealed that airway remodeling, which is at least in part due to an excess of extracellular matrix (ECM) deposition in the airway wall, plays a significant role in airflow obstruction. Matrix metalloproteinases (MMPs) have been suggested to be the major proteolytic enzymes to induce airway remodeling in asthma and COPD. It has been widely accepted that different inflammatory processes are involved in asthma and COPD with different inflammatory cells, mediators, and responses to treatments. Despite these different processes, airflow obstruction and airway remodeling characterize these two diseases. MMP-2 and -9 have been reported to be involved in the pathogenesis of airway remodeling in both diseases and MMP-12, in addition to these MMPs, in the pathogenesis of COPD. In this review, we discuss the current views on the role of MMPs in the pathogenesis of bronchial asthma and COPD. Anti-MMP therapy could theoretically be useful to prevent airway remodeling in asthma and COPD. However, to date no clinical data are available regarding the efficacy of anti-MMP therapies in the treatment of patients with asthma and COPD.     

细菌感染导致慢性阻塞性肺疾病大鼠模型的探讨

目的　探讨细菌在慢性阻塞性肺疾病（ＣＯＰＤ） 发病中的作用。方法　将Ｗｉｓｔａｒ 大鼠１０５只分为３ 组,每组３５ 只。应用多次经鼻腔注入肺炎克雷伯杆菌菌液或肺炎链球菌菌液的呼吸道感染方法试制ＣＯＰＤ大鼠模型,观察其气道形态改变,检测动脉血氧分压（ＰａＯ２） 、血二氧化碳分压（ＰａＣＯ２）和右心室收缩压（ＲＶＳＰ） 。结果　肺炎克雷伯杆菌感染组第１ 周起和肺炎链球菌感染组第４ 周起,大鼠各级细支气管上皮细胞明显损伤。第４ 周起,两感染组大鼠各级支气管慢性炎症明显,管壁增厚（Ｐ＜０－０１） ,管腔明显狭窄（Ｐ＜０－０５）, 有肺气肿形成。两感染组ＲＶＳＰ明显升高（Ｐ＜ ０－０１）。细支气管伴行肺小动脉管壁明显增厚。第１６ 周, 肺炎克雷伯杆菌感染组ＰａＯ２ 下降（Ｐ＜０－０５） ,ＰａＣＯ２ 上升（Ｐ＜０－０１） 。结论　以适量肺炎克雷伯杆菌或肺炎链球菌多次经鼻腔注入大鼠肺内可引起小气道炎症和肺气肿。结合血气分析和ＲＶＳＰ变化情况证实,所建模型具有ＣＯＰＤ的主要特征。     

The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research

Chronic obstructive pulmonary disease (COPD) progression is characterized by accumulation of inflammatory mucous exudates in the lumens of small airways, and thickening of their walls, which become infiltrated by innate and adaptive inflammatory immune cells. Infiltration of the airways by polymorphonuclear and mononuclear phagocytes and CD4 T cells increases with COPD stage, but the cumulative volume of the infiltrate does not change. By contrast, B cells and CD8 T cells increase in both the extent of their distribution and in accumulated volume, with organization into lymphoid follicles. This chronic lung inflammation is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Why these pathologic abnormalities progress in susceptible individuals, even after removal of the original noxious stimuli, remains mysterious. However, important clues are emerging from analysis of pathologic samples from patients with COPD and from recent discoveries in basic immunology. We consider the following relevant information: normal limitations on the innate immune system's ability to generate adaptive pulmonary immune responses and how they might be overcome by tobacco smoke exposure; the possible contribution of autoimmunity to COPD pathogenesis; and the potential roles of ongoing lymphocyte recruitment versus in situ proliferation, of persistently activated resident lung T cells, and of the newly described T helper 17 (Th17) phenotype. We propose that the severity and course of acute exacerbations of COPD reflects the success of the adaptive immune response in appropriately modulating the innate response to pathogen-related molecular patterns ("the Goldilocks hypothesis").     

The airway epithelium is central to the pathogenesis of asthma.

Asthma is an inflammatory disorder principally involving the conducting airways and characterised by infiltration of the airway wall with a range of inflammatory cells driven in large part by activation of Th2-type lymphocytes, mast cells and eosinophils. However a key component of asthma is the structural change that involves all of the elements of the airway wall. Here evidence is presented to suggest that the airway epithelium in asthma is fundamentally abnormal with increased susceptibility to environmental injury and impaired repair associated with activation of the epithelial-mesenchymal trophic unit (EMTU). In addition to adopting an activated phenotype, the barrier function of the epithelium is impaired through defective tight junction formation thereby facilitating penetration of potentially toxic or damaging environmental insults. Activated and repairing epithelial cells generate a range of growth factors that are involved in the early life origins of this disease as well as its progression in the form of mucous metaplasia and airway wall remodeling. By placing the epithelium at the forefront of asthma pathogenesis, different approaches to treatment can be devised focused more on protecting vulnerable airways against environmental injury rather than focusing on suppressing airway inflammation or manipulating the immune response.     

Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria

Balanced induction of proinflammatory and type I IFN responses upon activation of Toll-like receptors (TLRs) determines the outcome of microbial infections and the pathogenesis of autoimmune and other inflammatory diseases. Mast cells, key components of the innate immune system, are known for their debilitating role in allergy and autoimmunity. However, their role in antimicrobial host defenses is being acknowledged increasingly. How mast cells interact with microbes and the nature of responses triggered thereby is not well characterized. Here we show that in response to TLR activation by Gram-positive and -negative bacteria or their components, mast cells elicit proinflammatory but not type I IFN responses. We demonstrate that in mast cells, bound bacteria and TLR ligands remain trapped at the cell surface and do not undergo internalization, a prerequisite for type I IFN induction. Such cells, however, can elicit type I IFNs in response to vesicular stomatitis virus which accesses the cytosolic retinoic acid-inducible gene I receptor. Although important for antiviral immunity, a strong I IFN response is known to contribute to pathogenesis of several bacterial pathogens such as Listeria monocytogenes. Interestingly, we observed that the mast cell-dependent neutrophil mobilization upon L. monocytogenes infection is highly impaired by IFN-β. Thus, the fact that mast cells, although endowed with the capacity to elicit type I IFNs in response to viral infection, elicit only proinflammatory responses upon bacterial infection shows that mast cells, key effector cells of the innate immune system, are well adjusted for optimal antibacterial and antiviral responses.     

Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1

Mast cells are immune sentinels that participate in the defense against bacteria and parasites. Resident within the joint, mast cells become activated in human rheumatoid arthritis and are implicated in the pathogenesis of experimental murine synovitis. However, their arthritogenic role remains undefined. Using a model of autoantibody-induced arthritis, we show that mast cells contribute to the initiation of inflammation within the joint by elaboration of IL-1. Mast cells become activated to produce this cytokine via the IgG immune complex receptor FcgammaRIII. Interestingly, mast cells become dispensable for the perpetuation of arthritis after delivery of IL-1, highlighting the contribution of this lineage to arthritis induction. These findings illuminate a mechanism by which mast cells can participate in the pathogenesis of autoimmune inflammatory arthritis and provide insights of potential relevance to human rheumatoid arthritis.     

Adenosine-receptor subtypes: their relevance to adenosine-mediated responses in asthma and chronic obstructive pulmonary disease.

Adenosine administration by inhalation elicits concentration-related bronchoconstriction in subjects with asthma and chronic obstructive pulmonary disease (COPD). The mechanisms of adenosine-induced bronchoconstriction appear to involve a selective interaction with activated mast cells with subsequent release of preformed and newly-formed mediators. Further evidence linking adenosine signalling to asthma and COPD comes from the finding that many cell types that play important roles in the exacerbation of these conditions express adenosine receptors and demonstrate relevant effects through stimulation of these receptors. Therefore, blockade of these receptors may be a valuable approach to the treatment of asthma and chronic obstructive pulmonary disease. Promising adenosine-receptor targets for novel therapeutics of asthma and chronic obstructive pulmonary disease have recently been identified in a number of inflammatory cell types, including mast cells, eosinophils, lymphocytes, neutrophils, and macrophages. The recent characterisation of the A2B receptors indicates the human lung mast cell as one of the most strategic cellular targets.     

Basic science for the clinician 53: mast cells

Mast cells stand at the interface between the innate immune system and the acquired (adaptive) immune response, serving as sentinels detecting invaders and directing a concerted and coordinated response. Mast cells reside immediately under body surfaces and within lymph nodes, near blood vessels and nerves, perfectly situated to for early detection and defense. They secrete a wide array of prostanoids, cytokines, chemokines, and other proteins mediators and modifiers of a variety of immune and inflammatory functions and bear surface markers suggesting broad functions, including as antigen-presenting cells. Although usually not given their due in medical school lectures, there is great likelihood that mast cells will be implicated in the pathogenesis of rheumatoid arthritis, scleroderma, multiple sclerosis, and perhaps cancer. Thus, better insights into mast cell functions and mast cell-derived effector molecules should command our attention as we move forward in better understanding disease immunopathogenesis and directed intelligent therapeutics development.     

IL-21与COPD发病机制的研究进展

IL-21是近年来发现的一种细胞因子,主要由活化的 CD4+T 细胞产生,在 Th17细胞中大量分泌,IL-21与其受体结合后,参与免疫应答与炎症反应.COPD是一种由吸烟所诱发的 T 细胞介导的炎症及自身免疫性的疾病.COPD的发病机制复杂,其中免疫失衡在 COPD发生发展中起着重要作用,多种细胞因子的变化与 COPD有关,IL-21就是其中的一种.本文就 IL-21与 COPD 的气道炎症、肺气肿、肺动脉高压的发病机制的研究作一综述.     

Emerging anti-inflammatory strategies for COPD

The hallmark of chronic obstructive pulmonary disease (COPD) is an enhanced or abnormal inflammatory immune response of the lungs to inhaled particles and gases, usually from cigarette smoke, characterised by increased numbers of neutrophils, activated macrophages and activated T-lymphocytes (Tc1 and Th1 cells). Therefore, suppression of the inflammatory response is a logical approach to the treatment of COPD. Despite the inflammatory nature of COPD, currently available anti-inflammatory therapies provide little or no benefit in COPD patients and may have detrimental effects. For this reason, there is an urgent need to discover effective and safe anti-inflammatory treatments that might prevent the relentless progression of the disease. In recent years, attention has largely been focused on inhibition of recruitment and activation of inflammatory cells, and on antagonism of their products. In this review, we put together a summary of the state-of-the-art development of clearly and/or potentially useful anti-inflammatory strategies in COPD.     

Pathophysiology of airflow limitation in chronic obstructive pulmonary disease

The airflow limitation that defines chronic obstructive pulmonary disease (COPD) is the result of a prolonged time constant for lung emptying, caused by increased resistance of the small conducting airways and increased compliance of the lung as a result of emphysematous destruction. These lesions are associated with a chronic innate and adaptive inflammatory immune response of the host to a lifetime exposure to inhaled toxic gases and particles. Processes contributing to obstruction in the small conducting airways include disruption of the epithelial barrier, interference with mucociliary clearance apparatus that results in accumulation of inflammatory mucous exudates in the small airway lumen, infiltration of the airway walls by inflammatory cells, and deposition of connective tissue in the airway wall. This remodelling and repair thickens the airway walls, reduces lumen calibre, and restricts the normal increase in calibre produced by lung inflation. Emphysematous lung destruction is associated with an infiltration of the same type of inflammatory cells found in the airways. The centrilobular pattern of emphysematous destruction is most closely associated with cigarette smoking, and although it is initially focused on respiratory bronchioles, separate lesions coalesce to destroy large volumes of lung tissue. The panacinar pattern of emphysema is characterised by a more even involvement of the acinus and is associated with alpha1 antitrypsin deficiency. The technology needed to diagnose and quantitate the individual small airway and emphysema phenotypes present in people with COPD is being developed, and should prove helpful in the assessment of therapeutic interventions designed to modify the progress of either phenotype.     

COPD相关T淋巴细胞亚群的新功能

肺部慢性非特异性炎症被认为是COPD发生发展的病理基础,淋巴细胞在调节 COPD气道炎症中发挥重要的作用.研究发现,效应T细胞、抑制性 T细胞与耗竭 T细胞三者在 COPD的炎症调节中发挥着不同的正负调节效应,它们分化上互相关联,功能上互相拮抗,一旦发生免疫失衡,可加重气道结构的破坏、加速COPD的进展和恶化.