Eosinophilic airway disorders

Diseases of the airway are common and make up a significant proportion of the respiratory physician's workload. The major contributors to this situation, such as asthma, chronic obstructive pulmonary disease (COPD), and chronic cough, all result from airway inflammation and often have an overlapping clinical picture, which in some instances makes accurate clinical diagnosis difficult. Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness, and airway inflammation, which is usually eosinophilic. However, the relationship between eosinophilic inflammation and asthma is complex, with only a weak correlation between the severity of airway inflammation and the markers of the severity of asthma, such as Pc20 and FEV1. Eosinophilic bronchitis is characterized by a chronic cough and sputum eosinophilia without airway hyper-responsiveness or variable airflow obstruction. The asthma phenotype is characterized by microlocalization of mast cells in the airway smooth muscle, emphasizing the importance of airway smooth muscle dysfunction in asthma. COPD has generally been considered to be a neutrophilic disease, in contrast to asthma. However, there is increasing evidence that a significant subgroup exists consisting of patients with stable COPD who have chronic airway eosinophilia with a more steroid-responsive disease. This article covers the role of eosinophils in the airway disorders asthma, COPD, and eosinophilic bronchitis.     

Rat models of asthma and chronic obstructive lung disease

The rat has been extensively used to model asthma and somewhat less extensively to model chronic obstructive pulmonary disease (COPD). The features of asthma that have been successfully modeled include allergen-induced airway constriction, eosinophilic inflammation and allergen-induced airway hyperresponsiveness. T-cell involvement has been directly demonstrated using adoptive transfer techniques. Both CD4+ and CD8+ T cells are activated in response to allergen challenge in the sensitized rat and express Thelper2 cytokines (IL-4, IL-5 and IL-13). Repeated allergen exposure causes airway remodeling. Dry gas hyperpnea challenge also evokes increases in lung resistance, allowing exercise-induced asthma to be modeled. COPD is modeled using elastase-induced parenchymal injury to mimic emphysema. Cigarette smoke-induced airspace enlargement occurs but requires months of cigarette exposure. Inflammation and fibrosis of peripheral airways is an important aspect of COPD that is less well modeled. Novel approaches to the treatment of COPD have been reported including treatments aimed at parenchymal regeneration.     

Pharmacological Treatment in Asthma and COPD

Many lines of previous studies have reported that differences and similarities between bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD). The pathological and physiological abnormalities of these diseases have been also discussed. BA and COPD have some similarities such as airflow obstruction, pulmonary inflammation, and airway hyperresponsiveness (AHR). However, both two diseases are regarded different diseases since their mechanisms of development are quite different. Therefore, both two diseases require different assessment, monitoring, and pharmacological treatments. In this paper, we describe the pharmacological treatment of asthma in adults and COPD based on recently updated guideline by the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD), respectively.     

Future treatment to lessen exacerbations of chronic obstructive pulmonary disease

Therapies currently used to reduce exacerbations of chronic obstructive pulmonary disease (COPD) are compounds used almost entirely for asthma therapy. A notable exception is tiotropium, a long-acting parasympatholytic agent. This compound and its precursor, iprotropium, are only occasionally used for asthma therapy. Likewise, leukotriene-modifying drugs are used occasionally for the treatment of COPD. In neither circumstance is there agency-approved indication for these particular cross-over therapies, but the use of long-acting beta(2)-adrenergic compounds and high-solubility inhaled steroids is a mainstay for therapy in both asthma and COPD. Similarly, theophylline, although less often used for either process, is therapeutically applicable to both asthma and COPD. Although overlap syndromes point to the occurrence of a common pathway in some cases, the inflammatory process for asthma and chronic obstructive pulmonary disease (COPD) differs substantially in most cases. Hence, the application of therapies designed to relax airway smooth muscle and ameliorate asthmatic inflammation lacks a therapeutic rationale for a disease characterized by predominant neutrophilic inflammation occurring in the small airways and alveoli. By definition, COPD is poorly reversible airflow obstruction; hence, the use of drugs designed to relax airway smooth muscle is somewhat counterintuitive and does not address the pathophysiological process of the disease.     

Anti-inflammatory effects of medications used for viral infection-induced respiratory diseases

Respiratory viruses like rhinovirus, influenza virus, respiratory syncytial virus, and coronavirus cause several respiratory diseases, such as bronchitis, pneumonia, pulmonary fibrosis, and coronavirus disease 2019, and exacerbate bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, and diffuse panbronchiolitis. The production of inflammatory mediators and mucin and the accumulation of inflammatory cells have been reported in patients with viral infection-induced respiratory diseases. Interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, and regulated on activation normal T-cell expressed and secreted are produced in the cells, including human airway and alveolar epithelial cells, partly through the activation of toll-like receptors, nuclear factor kappa B and p44/42 mitogen-activated protein kinase. These mediators are associated with the development of viral infection-induced respiratory diseases through the induction of inflammation and injury in the airway and lung, airway remodeling and hyperresponsiveness, and mucus secretion. Medications used to treat respiratory diseases, including corticosteroids, long-acting β₂-agonists, long-acting muscarinic antagonists, mucolytic agents, antiviral drugs for severe acute respiratory syndrome coronavirus 2 and influenza virus, macrolides, and Kampo medicines, reduce the production of viral infection-induced mediators, including cytokines and mucin, as determined in clinical, in vivo, or in vitro studies. These results suggest that the anti-inflammatory effects of these medications on viral infection-induced respiratory diseases may be associated with clinical benefits, such as improvements in symptoms, quality of life, and mortality rate, and can prevent hospitalization and the exacerbation of chronic obstructive pulmonary disease, bronchial asthma, bronchiectasis, and diffuse panbronchiolitis.     

支气管哮喘气道重塑平滑肌增生机制

支气管哮喘是严重影响人类正常生活的慢性疾病之一,尤其是在气道重塑发生之后.由于气道重塑的不可逆,使支气管哮喘的治疗陷入瓶颈状态.气道重塑最主要的病理学改变为气道平滑肌细胞增殖导致的平滑肌层增厚,其原因是机体慢性炎症和长期免疫应答,那么参与炎症反应和免疫应答的细胞因子以及平滑肌细胞的来源就成为研究气道重塑的重要途径.在此...     

An official JRS statement: The principles of fractional exhaled nitric oxide (FeNO) measurement and interpretation of the results in clinical practice

Nitric oxide (NO) is produced in the body and has been shown to have diverse actions in the abundance of research that has been performed on it since the 1970s, leading to Furchgott, Murad, and Ignarro receiving the Nobel Prize in Physiology or Medicine in 1998. NO is produced by nitric oxide synthase (NOS). NOS is broadly distributed, being found in the nerves, blood vessels, airway epithelium, and inflammatory cells. In asthma, inflammatory cytokines induce NOS activity in the airway epithelium and inflammatory cells, producing large amounts of NO. Measurement of fractional exhaled nitric oxide (FeNO) is a simple, safe, and quantitative method of assessing airway inflammation. The FeNO measurement method has been standardized and, in recent years, this noninvasive test has been broadly used to support the diagnosis of asthma, monitor airway inflammation, and detect asthma overlap in chronic obstructive pulmonary disease (COPD) patients. Since the normal upper limit of FeNO for healthy Japanese adults is 37 ppb, values of 35 ppb or more are likely to be interpreted as a signature of inflammatory condition presenting features with asthma, and this value is used in clinical practice. Research is also underway for clinical application of these measurements in other respiratory diseases such as COPD and interstitial lung disease. Currently, there remains some confusion regarding the significance of these measurements and the interpretation of the results. This statement is designed to provide a simple explanation including the principles of FeNO measurements, the measurement methods, and the interpretation of the measurement results.     

白介素32在气道炎症反应中的研究进展

在哮喘和慢性阻塞性肺疾病中,气道炎症反应始终贯穿疾病的发生、发展及转归.目前已发现有众多细胞及因子参与气道炎症反应,而白介素32作为一种新发现的细胞因子,很多文献证明其在炎症反应中有不可取代的作用.白介素32主要存在于自然杀伤细胞、T细胞、上皮细胞及外周血的单核细胞中,在自然免疫及特殊免疫中均有重要地位.在炎症反应中,白介素32可诱导某些因子的活性,如白介素类、肿瘤坏死因子α、核因子、促分裂原活化蛋白激酶及各种趋化因子,形成炎症级联式反应,造成气道局部的炎症,甚至引起全身性炎症反应.本文对白介素32在气道炎症中的作用作一综述.     

Asthma-chronic obstructive pulmonary disease overlap syndrome: A diagnostic puzzle for the clinicians

Although asthma and chronic obstructive pulmonary disease (COPD) are distinct airway diseases characterized by chronic inflammation, in some cases distinguishing between them is puzzling. For example, chronic smoking leads asthmatic inflammation to a differentiated pattern resembling the COPD inflammation, and in some cases to fixed obstruction as in COPD, and on the other hand, few COPD patients may present with airway reversibility. ACOS is the condition sharing features encountered both in asthma and COPD. Asthma-COPD overlap syndrome (ACOS) represents a diagnostic challenge in the clinical practice, since there is lack of specific indicators to distinguish it from asthma or COPD, and moreover, genetic risk factors, underlying pathology and molecular pathways, clinical characteristics, therapeutic interventions, response to treatment and prognosis are poorly described. The management of ACOS is recommended to be individualized and should target on the maximum effectiveness with the least side effects. Combination therapy with ICS/LABA or LAMA, or newly developed specific anti-eosinophil therapies and treatments specifically targeting neutrophils might be of relevance in the management of ACOS, but studies are needed in order to assess the response and prognosis. Based on the current knowledge about ACOS thus far, it would be recommended that we approached chronic obstructive airway disease rather by describing than by classifying the disease; this would allow us to have a picture that better describes the disease and to implement an individualized therapeutic approach, according to the custom phenotype. Nevertheless, more studies are needed in order to clarify several important issues with regard to ACOS, such as the genetic risk factors for developing ACOS, the links between genotype and phenotype, the molecular pathways and underlying mechanisms of ACOS, the identification of possible specific biomarkers for diagnosis and targeted treatment, the optimal therapeutic interventions, and finally, the prognosis of ACOS.     

炎性因子在慢性阻塞性肺疾病气道炎症中的作用

COPD是一种以气道慢性炎症为特征之一的慢性呼吸系统疾病,气道炎性反应在COPD占有重要作用。炎性细胞因子是机体内最重要的一类细胞因子,多种炎性细胞因子参与气道炎症的病理生理机制,对肺组织和支气管产生损害,并发肺外效应。在COPD的自然病程中存在炎性细胞因子网络系统,调控COPD的气道炎症的发生发展。     

Pro-inflammatory and immunomodulatory functions of airway smooth muscle: Emerging concepts

Airway smooth muscle (ASM) is the main regulator of bronchomotor tone. Extensive studies show that in addition to their physical property, human airway smooth muscle (ASM) cells can participate in inflammatory processes modulating the initiation, perpetuation, amplification, and perhaps resolution of airway inflammation. Upon stimulation or interaction with immune cells, ASM cells produce and secrete a variety of inflammatory cytokines and chemokines, cell adhesion molecules, and extracellular matrix (ECM) proteins. These released mediators can, in turn, contribute to the inflammatory state, airway hyperresponsiveness, and airway remodeling present in asthma. As our knowledge of ASM myocyte biology improves, novel bioactive factors are emerging as potentially important regulators of inflammation. This review provides an overview of our understanding of some of these molecules, identifies rising questions, and proposes future studies to better define their role in ASM cell modulation of inflammation and immunity in the lung and respiratory diseases.     

Airway smooth muscle and fibroblasts in the pathogenesis of asthma

Asthma is a disease characterized by marked structural changes within the airway wall. These changes include deposition of extracellular matrix proteins and an increase in the numbers of airway smooth muscle cells and subepithelial fibroblasts. Both these cell types possess properties that would enable them to be involved in remodeling and inflammation. These properties include the production of a variety of cytokines; growth factors and fibrogenic mediators; proliferation, migration and release of extracellular matrix proteins; matrix metalloproteinases; and their tissue inhibitors. Airway smooth muscle and subepithelial fibroblasts are likely to be key players in the asthmatic airway pathophysiology through their interaction with each other, inflammatory cells, and other mesenchymal cells, such as the epithelium. Current asthma therapies lack the ability to completely prevent or reverse the remodeling of the airways, therefore indicating the need for new therapeutic strategies to counter this important aspect of asthma.     

COPD: current therapeutic interventions and future approaches.

Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-alpha. Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kappaB and phosphoinositide-3 kinase-gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B(4) antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema. More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.     

Exhaled markers of inflammatory lung diseases: ready for routine monitoring?

Assessing airway inflammation is important for investigating the underlying mechanisms of many lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). Yet these are not measured directly in routine clinical practice because of the difficulties in monitoring inflammation. The presence and type of airway inflammation can be difficult to detect clinically, and may result in delays in initiating appropriate therapy. Non-invasive monitoring may assist in differential diagnosis of lung diseases, assessment of their severity and response to treatment. There is increasing evidence that breath analysis may have an important place in the diagnosis and clinical management of asthma, COPD, primary ciliary dyskinesia (PCD) and other major lung disease. The article reviews whether current noninvasive measurements of exhaled gases, such as nitric oxide (NO), hydrocarbons, inflammatory markers exhaled breath condensate (EBC) are ready for routine use in clinical practice.     

Local and systemic inflammation in chronic obstructive pulmonary disease

There is growing evidence for systemic inflammation in chronic obstructive pulmonary disease (COPD). Increased circulating levels of inflammatory cytokines and acute phase proteins occur in stable disease, and COPD exacerbations are notably associated with pulmonary and systemic inflammation. Although the course of inflammation is determined by the balance between pro- and antiinflammatory mediators, in COPD most attention has focused on the former. During exacerbation, however, upregulation of antiinflammatory markers occurs. The main causes of systemic inflammation in COPD remain to be elucidated, although systemic hypoxia is a candidate factor. Although a relationship between lung and systemic inflammation has been suggested, experimental evidence indicates no direct correlations in the regulation of inflammation in the pulmonary and systemic compartments. Longitudinal studies are needed to unravel the role of systemic inflammation in the course of COPD, to analyze the role of acute exacerbations on the chronicity of inflammation, and to evaluate the response of systemic inflammation to different interventions. Emphasis should be placed on the identification of signaling pathways induced and/or altered in skeletal muscle by inflammation, as muscle wasting is a prominent feature of chronic inflammatory disease conditions and contributes significantly to impaired physical functioning and health status in COPD.     

Regulation of inflammatory cell function by corticosteroids

Different inflammatory cell profiles are observed in the lungs of patients with asthma versus those with chronic obstructive pulmonary disease (COPD). In asthma, several key mediators have been implicated, including tumor necrosis factor-alpha and interleukin (IL)-1beta, together with cytokines derived from type 2 T-helper lymphocytes, such as IL-4, IL-5, and IL-13. In fact, inhibitors of IL-4 and IL-5 show promise as therapeutic agents. In COPD, the predominant inflammatory cell types are CD8(+) T lymphocytes, macrophages, and neutrophils. Glucocorticoids inhibit eosinophils in asthma, neutrophils in COPD and severe asthma, mast cells and basophils in asthma and COPD, and macrophages in COPD. However, it is generally assumed that neutrophils are less sensitive to glucocorticoids than are eosinophils and T cells, and that macrophages from patients with COPD are less sensitive to steroid treatment under certain circumstances. These differences in the responsiveness of activated inflammatory cells may help to explain why inhaled corticosteroid treatment has been more beneficial for patients with asthma than for patients with COPD.