CD4(+) T-lymphocytes regulate airway remodeling and hyper-reactivity in a mouse model of chronic asthma

Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4(+) T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4(+) T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulin-synthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4(+) T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target.     

Remodeling in asthma

Airway remodeling encompasses the structural alterations in asthmatic compared with normal airways. Airway remodeling in asthmatic patients involves a wide array of pathophysiologic features, including epithelial changes, increased smooth muscle mass, increased numbers of activated fibroblasts/myofibroblasts, subepithelial fibrosis, and vascular changes. Multiple cytokines, chemokines, and growth factors released from both inflammatory and structural cells in the airway tissue create a complex signaling environment that drives these structural changes. However, recent investigations have changed our understanding of asthma from a purely inflammatory disease to a disease in which both inflammatory and structural components are equally involved. Several reports have suggested that asthma primarily develops because of serious defects in the epithelial layer that allow environmental allergens, microorganisms, and toxins greater access to the airway tissue and that can also stimulate the release of mediators from the epithelium, thus contributing to tissue remodeling. Lung-resident fibroblasts and smooth muscle cells have also been implicated in the pathogenesis of airway remodeling. Remodeling is assumed to result in persistent airflow limitation, a decrease in lung function, and airway hyperresponsiveness. Asthmatic subjects experience an accelerated decrease in lung function compared with healthy subjects, which is proportionally related to the duration and severity of their disease.     

Impact of inhaled corticosteroids and leukotriene receptor antagonists on airway remodeling

Asthma is a chronic inflammatory disease of the airways that is characterized by the presence of inflammatory cells and remodeling, a term used to define complex morphological changes involving all the structures of the bronchial wall (e.g., goblet cell hyperplasia of the epithelium, thickening of reticular basement membrane, increases of airway smooth muscle[ASM], and blood vessels). An important factor in the pathophysiology of asthma is the recognition that airway inflammation and airway remodeling are linked, as they are in other chronic inflammatory diseases. First-line therapy of persistent asthma involves the use of inhaled corticosteroids to control the underlying inflammation of the airways. Because remodeling of the airway wall is thought to be a result of chronic inflammation within the bronchial wall, it follows that because steroids reduce or reverse inflammation, they may also prevent or modulate remodeling. It has been revealed that steroids improve the subepithelial fibrosis and also significantly reduce airway vascularity. The cysteinyl leukotrienes receptor antagonists may also be helpful regarding the targeting of the inflammation and remodeling in asthma. However,long-term studies were needed to appreciate the prevention and treatment of remodeling by drug therapies.     

The use of computed tomography to assess asthma severity

PURPOSE OF REVIEW: Chronic inflammation in asthma can also lead to airway remodeling, which contributes to airway narrowing. It may be possible to assess and quantify the extent of airway remodeling in vivo using computed tomography. This review examines recent developments in the evaluation of asthma severity using computed tomography, and the effect of treatment assessed by computed tomography. RECENT FINDINGS: Asthma patients have thicker airways on computed tomography scans than do healthy control individuals, and the degree of thickening is related to the severity of disease, airflow obstruction, and airway reactivity. Recent studies have indicated that patients with severe asthma and irreversible airflow obstruction had longer disease duration, a greater inflammatory process and more airway abnormalities, assessed by high-resolution computed tomography, suggestive of airway remodeling. Other studies have shown that high-resolution computed tomography lung density correlates with airflow limitation and lung volume (but not with lung transfer factor), and also correlates with patient age and severity of asthma. More recently, two publications demonstrated the effect of treatment on airway wall thickness and lung density assessed by computed tomography in patients with asthma. SUMMARY: High-resolution computed tomography is one of the most useful tools for imaging airways and parenchyma. Computed tomography scanning may be useful in determining which patients might benefit from more or less treatment. With additional advances in technology, it is likely that quantitative assessment by computed tomography will ultimately be a valuable tool for the study and treatment of chronic airway diseases.     

Rho激酶与哮喘气道高反应性

炎症细胞和结构细胞促进哮喘患者支气管的急性收缩和慢性气道重建。当前哮喘的治疗不能有效地抑制气道高反应性和气道重建。近来发现Rho激酶在哮喘的发病中起重要作用，而Rho激酶抑制剂可抑制气道平滑肌收缩、调节气道平滑肌特异性的基因转录、减轻气道壁增厚和气道炎症，从而减轻急性和慢性气道高反应性。     

Airway inflammation in chronic obstructive pulmonary disease: comparisons with asthma

Chronic obstructive pulmonary disease (COPD) is a progressive syndrome of expiratory airflow limitation caused by chronic inflammation of the airways and lung parenchyma. The airway inflammatory response in COPD is initiated by smoking in the overwhelming majority of cases, and chronic exposure to cigarette smoke initiates a series of events that causes damage to central airways, peripheral airways, and terminal airspaces, leading to physiologic and clinical abnormalities. Although COPD shares some clinical features with asthma, another prevalent airway inflammatory disease, there are distinct differences in the phenotypic characteristics of airway inflammation between COPD and asthma. The eosinophil is the most prominent inflammatory cell in asthma, with mast cells, lymphocytes, and macrophages playing important but less prominent roles. In COPD the cellular composition of the airway inflammatory infiltrate differs, with neutrophils, macrophages, and lymphocytes assuming prominence and the eosinophil playing a minor role, except in the setting of exacerbations. The contrasting inflammatory phenotypes of asthma and COPD have important implications for clinical and physiologic manifestations of disease, as well as for therapy.     

Upper and lower airway remodelling mechanisms in asthma,allergic rhinitis and chronic rhinosinusitis: The one airway concept revisited

Allergic rhinitis (AR), chronic rhinosinusitis (CRS) and asthma often co‐exist. The one airway model proposes that disease mechanisms occurring in the upper airway may mirror lower airway events. Airway remodelling is the term used to describe tissue structural changes that occur in a disease setting and reflect the dynamic process of tissue restructuring during wound repair. Remodelling has been long identified in the lower airways in asthma and is characterized by epithelial shedding, goblet cell hyperplasia, basement membrane thickening, subepithelial fibrosis, airway smooth muscle hyperplasia and increased angiogenesis. The concept of upper airway remodelling has only recently been introduced, and data so far are limited and often conflicting, an indication that more detailed studies are needed. Whilst remodelling changes in AR are limited, CRS phenotypes demonstrate epithelial hyperplasia, increased matrix deposition and degradation along with accumulation of plasma proteins. Despite extensive research over the past years, the precise cellular and molecular mechanisms involved in airway remodelling remain incompletely defined. This review describes our current rather limited understanding of airway remodelling processes in AR, CRS and asthma and presents mechanisms both shared and distinct between the upper and lower airways. Delineation of shared and disease‐specific pathogenic mechanisms of remodelling between the sinonasal system and the lung may guide the rational design of more effective therapeutic strategies targeting upper and lower airways concomitantly and improving the health of individuals with inflammatory airway diseases.     

Airway inflammation in asthma and chronic obstructive pulmonary disease with special emphasis on the antigen-presenting dendritic cell: influence of treatment with fluticasone propionate

Asthma is a chronic inflammatory disorder of the airways characterized by variable airflow limitation and airway hyperresponsiveness. The type of inflammatory response in asthma is compatible with a major contribution of professional antigen-presenting cells. The airways in chronic obstructive pulmonary disease (COPD) are also markedly inflamed; however, the predominant types of inflammatory cells and the main anatomical site of the lesion appear to differ from those in asthma. COPD is characterized by reduced maximum expiratory flow and slow forced emptying of the lungs. Steroids are the most prominent medication used in the treatment of asthma and COPD; however, the beneficial effect of steroid treatment in COPD is subject of debate. We investigated the efficacy of fluticasone propionate (FP) treatment in atopic asthmatics and in COPD patients with bronchial hyperreactivity who smoke. The effect of the treatment on bronchial hyperreactivity and indices of the methacholine dose–response curve were analysed, as well as indices of inflammation of the airway mucosa with special emphasis on the antigen presenting dendritic cell. Treatment of allergic asthmatic patients resulted in improvement of lung function (FEV₁), a decrease in bronchial hyperresponsiveness and a decrease of maximal airway narrowing. During the FP-treatment of COPD patients, FEV₁ remained stable, while FEV₁ deteriorated significantly in the placebo group. Therefore, steroid treatment may have a beneficial effect in COPD patients with bronchial hyperresponsiveness (BHR). Since immunohistochemical analysis of bronchial biopsy specimens from asthma and COPD patients show disease-specific aspects of inflammation, the anti-inflammatory effect of FP is obtained through modulation of different cell populations in asthma and COPD.     

Review: Pharmacological treatment of airway remodeling: inhaled corticosteroids or antileukotrienes?

Chronic stable asthma is characterized by inflammation of the airway wall, with abnormal accumulation of basophils, eosinophils, lymphocytes, mast cells, macrophages, dendritic cells, and myofibroblasts. Airway inflammation is not limited to severe asthma, but is also found in mild and moderate asthma. This inflammation results in a peculiar type of lymphocytic infiltration whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyper-responsiveness. The term "airway remodeling" in bronchial asthma refers to structural changes that occur in conjunction with, or because of, chronic airway inflammation. Airway remodeling results in alterations in the airway epithelium, lamina propria, and submucosa, leading to thickening of the airway wall. Consequences of airway remodeling in asthma include incompletely reversible airway narrowing, bronchial hyper-responsiveness, airway edema, and mucus hypersecretion; these effects may predispose subjects with asthma to exacerbations and even death due to airway obstruction. To avoid this progression, it is important to follow an adequate treatment aimed at interacting and modifying the inflammatory process. Inhaled corticosteroids remain the cornerstone of asthma management. Altough several drugs, such as ketotifen, sodium cromoglycate, sodium nedocromil, and theophylline have anti-inflammatory properties, they are less effective than corticosteroids. Antileukotrienes are a new class of anti-inflammatory drugs that interfere directly with leukotriene receptors. The aim of this brief review is to delineate the effects of inhaled corticosteroids and antileukotriene drugs on inflammation and remodeling.     

Involvement of distal airways in a chronic model of experimental asthma

BACKGROUND: Bronchial asthma is characterized by chronic airway inflammation and airway remodelling which occurs in both proximal and distal airways. These changes are associated with development of airway hyper-responsiveness and airflow limitation. OBJECTIVE: This study was aimed to analyse whether chronic inhalative allergen challenges in mice lead to morphological and physiological changes comparable with this phenotype. METHODS: For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed by aerosol allergen challenges on 2 consecutive days per week for 12 weeks. RESULTS: In chronically challenged mice, tissue inflammation in proximal as well as distal airways was observed with a predominance of lymphocytes within the cellular infiltrate. In contrast, inflammation in the airway lumen decreased over time. These changes were associated by a shift in bronchoalveolar lavage-cytokine levels from IL-4, IL-5 and TNF-alpha production (during the acute phase) towards markedly increased levels of TGF-beta during the chronic phase. Goblet cell hyperplasia and subepithelial fibrosis occurred throughout the airway tree. In terms of lung function, chronically challenged mice developed persistent bronchial hyper-responsiveness and progressive airflow limitation. Six weeks after OVA aerosol discontinuation, airway inflammation still persisted although lung function was normalized. CONCLUSION: These data indicate that our model of chronic aerosol allergen challenges leads to a phenotype of experimental asthma with participation of distal airways and persistence of inflammation thereby resembling many morphological and physiological aspects of human bronchial asthma.     

Airway smooth muscle: a modulator of airway remodeling in asthma

Asthma is a disease characterized, in part, by airway hyperresponsiveness and inflammation. Although asthma typically induces reversible airway obstruction, in some patients with asthma, airflow obstruction can become irreversible. Such obstruction might be a consequence of persistent structural changes in the airway wall caused by the frequent stimulation of airway smooth muscle (ASM) by contractile agonists, inflammatory mediators, and growth factors. Traditional concepts concerning airway inflammation have focused on trafficking leukocytes and on the effects of inflammatory mediators, cytokines, and chemokines secreted by these cells. Recent studies suggest that ASM cells might modulate airway remodeling by secreting cytokines, growth factors, or matrix proteins and by expressing cell adhesion molecules and other potential costimulatory molecules. These ASM cell functions might directly or indirectly modulate submucosal airway inflammation and promote airway remodeling.     

Severe upper airway obstruction during sleep

Few disorders may manifest with predominantly sleep-related obstructive breathing. Obstructive sleep apnea (OSA) is a common disorder, varies in severity and is associated with significant cardiovascular and neurocognitive morbidity. It is estimated that between 8 and 18 million people in the United States have at least mild OSA. Although the exact mechanism of OSA is not well-delineated, multiple factors contribute to the development of upper airway obstruction and include anatomic, mechanical, neurologic, and inflammatory changes in the pharynx. OSA may occur concomitantly with asthma. Approximately 74% of asthmatics experience nocturnal symptoms of airflow obstruction secondary to reactive airways disease. Similar cytokine, chemokine, and histologic changes are seen in both disorders. Sleep deprivation, chronic upper airway edema, and inflammation associated with OSA may further exacerbate nocturnal asthma symptoms. Allergic rhinitis may contribute to both OSA and asthma. Continuous positive airway pressure (CPAP) is the gold standard treatment for OSA. Treatment with CPAP therapy has also been shown to improve both daytime and nighttime peak expiratory flow rates in patients with concomitant OSA and asthma. It is important for allergists to be aware of how OSA may complicate diagnosis and treatment of asthma and allergic rhinitis. A thorough sleep history and high clinical suspicion for OSA is indicated, particularly in asthma patients who are refractory to standard medication treatments.     

Airway hyperresponsiveness and airway obstruction in transgenic mice. Morphologic correlates in mice overexpressing interleukin (IL)-11 and IL-6 in the lung

Understanding the sources of variation in airway reactivity and airflow is important for unraveling the pathophysiology of asthma, obstructive lung disease, and other pulmonary disorders. Transgenic expression of two closely related cytokines in the mouse lung produced opposite effects on these parameters. Interleukin (IL)-6 did not alter basal airways resistance and decreased methacholine responsiveness, whereas IL-11 caused airways obstruction and increased airway responses to methacholine. To clarify these differences we examined histologic sections and used morphometry to compare bronchiolar and parenchymal dimensions in 1- to 2-mo-old transgenic mice expressing IL-6 or IL-11 and littermate control mice. Both transgenic strains showed similar emphysema-like airspace enlargement, nodular peribronchiolar collections of mononuclear cells, thickening of airway walls, and subepithelial airway fibrosis. When compared with littermate control mice, the IL-6 mice showed an approximately 50% increase in the caliber of their bronchioles and an increase in airway wall thickness that was in proportion to the increase in the size of their airways. In contrast, the remodeling response was more robust in the IL-11 transgenic mice. It was also seen in airways with normal external and luminal diameters and thus was out of proportion to the caliber of their airways. These results support the hypothesis that structural alterations and resulting caliber changes of respiratory airways can have important effects on airway physiology and reactivity.     

Clinical assessment of airway remodeling in asthma

Airway remodeling is an established feature of asthma. Histologic examination is essential in the assessment of remodeling that is a pathologic concept. Examinations of autopsied or resected lung have enabled detailed morphologic and morphometric studies and have provided fundamental knowledge of airway remodeling in asthma. However, such materials are only accidentally available, and clinical information may often be insufficient in autopsied cases. Bronchoscopic mucosal biopsy has been widely used since the 1980s, and has contributed substantially to basic investigations of inflammation and remodeling. However such specimens are limited in size and depth, limited to central airways, and the procedure might be too invasive to be repeated. Remodeling can also be assessed indirectly. Pulmonary function tests to evaluate chronic airflow obstruction are available in clinical settings and suitable for screening or mass studies, but they may be affected by concomitant diseases or short-term asthma control. Computed tomography (CT) has recently been utilized to assess remodeling. It cannot discern pathologic details but provides a broader range of airway/lung morphology and may be less invasive compared to biopsy. In addition to classic subjective evaluations, quantitative assessment has been reported for central airway dimensions, such as airway wall area, luminal area and wall thickness, and for peripheral airway abnormality or air trapping as measured by decreased lung attenuation or increased mosaic perfusion. This article summarizes the merits and limitations of various methods to assess airway remodeling, and describes the details of methodologies, interpretations, pathophysiologic relevance, and future directions of asthmatic airway remodeling assessed by CT.     

Outpatient treatment of chronic obstructive pulmonary disease: comparisons with asthma

Chronic obstructive pulmonary disease (COPD) is a progressive syndrome of expiratory airflow limitation caused by chronic inflammation of the airways and lung parenchyma. The airway inflammatory response in COPD is initiated by smoking in the overwhelming majority of cases, and chronic exposure to cigarette smoke initiates a series of events that cause damage to central airways, peripheral airways, and terminal airspaces, leading to physiologic and clinical abnormalities. The contrasting inflammatory phenotypes of asthma and COPD have important implications for clinical and physiologic manifestations of disease, as well as for therapy. The outpatient treatment of COPD differs from the approach used in asthma and can be divided into 3 subgroups: health care maintenance, drug therapy, and nondrug therapy. Smoking cessation, regular spirometry, and immunization are important components of health care maintenance. Drug therapy consists of optimal bronchodilator therapy supplemented, when necessary, with either inhaled corticosteroids or theophylline. Nondrug therapies include pulmonary rehabilitation, supplemental oxygen, and surgery.     

Asthma therapy and airway remodeling

Asthma is characterized by variable degrees of chronic inflammation and structural alterations in the airways. The most prominent abnormalities include epithelial denudation, goblet cell metaplasia, subepithelial thickening, increased airway smooth muscle mass, bronchial gland enlargement, angiogenesis, and alterations in extracellular matrix components, involving large and small airways. Chronic inflammation is thought to initiate and perpetuate cycles of tissue injury and repair in asthma, although remodeling may also occur in parallel with inflammation. In the absence of definite evidence on how different remodeling features affect lung function in asthma, the working hypothesis should be that structural alterations can lead to the development of persistent airway hyperresponsiveness and fixed airway obstruction. It is still unanswered whether and when to begin treating patients with asthma to prevent or reverse deleterious remodeling, which components of remodeling to target, and how to monitor remodeling. Consequently, efforts are being made to understand better the effects of conventional anti-inflammatory therapies, such as glucocorticosteroids, on airway structural changes. Animal models, in vitro studies, and some clinical studies have advanced present knowledge on the cellular and molecular pathways involved in airway remodeling. This has encouraged the development of biologicals aimed to target various components of airway remodeling. Progress in this area requires the explicit linking of modern structure-function analysis with innovative biopharmaceutical approaches.     

Dissociation of inflammatory and epithelial responses in a murine model of chronic asthma

To study pathogenetic mechanisms in chronic asthma, we employed a novel experimental model that replicates characteristic features of the human disease. Chronic inflammation and epithelial changes, specifically localized to the airways, were induced by repeated exposure of systemically sensitized BALB/c mice to low mass concentrations of aerosolized ovalbumin for 6 weeks. The contribution of Th2 cytokine-driven inflammation to the development of airway lesions and hyperreactivity was assessed in cytokine-deficient mice. In interleukin-5-deficient animals, intraepithelial eosinophils and chronic inflammatory cells in the lamina propria of the airways were markedly decreased; however, these animals developed epithelial hypertrophy and subepithelial fibrosis comparable with that observed in sensitized wild type mice. Airway hyperreactivity to inhaled methacholine did not develop in interleukin-5-deficient mice. In contrast, interleukin-4-deficient mice exhibited no decrease in airway inflammation, but had significantly greater epithelial hypertrophy and subepithelial fibrosis, as well as exaggerated hyperreactivity to methacholine. We conclude that interleukin-5, but not interleukin-4, plays a central role in the development of chronic inflammation of the airways and the induction of airway hyperreactivity. Furthermore, chronic epithelial and fibrotic changes occur independently of interleukin-5 and are not required for the development of airway hyperreactivity. The dissociation between airway wall remodeling and airway hyperreactivity has important implications for therapeutic approaches to chronic asthma.     

Cytokines and growth factors in airway remodeling in asthma

Airway remodeling in asthma is defined by several structural changes including epithelial cell mucus metaplasia, an increase in peribronchial smooth muscle mass, subepithelial fibrosis, and angiogenesis. Cytokines, chemokines, and growth factors released from inflammatory and structural cells in the airway are considered to play a pivotal role in the development of remodeling. Studies of allergen induced airway remodeling in transgenic mice suggest an important role for TGF-beta, VEGF, Th2 cytokines (IL-5, IL-9, IL-13), and epithelial derived NF-kappaB regulated chemokines in airway remodeling. Although studies of bronchial biopsies from human asthmatics also demonstrate expression of TGF-beta, VEGF, IL-5, IL-9, IL-13, and NF-kappaB regulated chemokines, further human intervention studies are required in which individual cytokines or chemokines are neutralized to define their role in airway remodeling.     

Reversibility of airway inflammation and remodelling following cessation of antigenic challenge in a model of chronic asthma

BACKGROUND: Asthma is associated with recruitment of eosinophils, accumulation of chronic inflammatory cells in the airway walls, subepithelial fibrosis and other structural changes of airway wall remodelling. The role of ongoing exposure to allergens in their pathogenesis remains unclear. OBJECTIVE: To examine whether changes of inflammation and remodelling were reversible following cessation of antigenic challenge in a mouse model of chronic asthma. METHODS: BALB/c mice sensitized to ovalbumin (OVA) were chronically challenged by inhalation of a low mass concentration of antigen for 8 weeks, leading to development of acute-on-chronic airway inflammation, subepithelial fibrosis and other changes of airway wall remodelling. Epithelial injury was assessed by immunohistochemistry, while inflammation and remodelling were quantified by appropriate histomorphometric techniques. Regression of lesions was assessed in animals examined at 1, 2 and 4 weeks after exposure to OVA ceased. RESULTS: We did not find evidence of airway epithelial injury in this model of low-level chronic inhalational exposure to antigen. Persistence of the recruitment of eosinophils and chronic inflammatory cells in the airway walls was dependent on continuing antigenic challenge, as was persistence of mucous cell hyperplasia/metaplasia. Subepithelial fibrosis and epithelial hypertrophy exhibited delayed reversibility following cessation of exposure to antigen, possibly related to matrix-associated accumulation of transforming growth factor-beta(1). CONCLUSION: In chronic asthma, low-level antigenic challenge may be required to maintain the inflammatory response in the airway wall, but airway remodelling may persist in its absence.