Differences in airway remodeling between asthma and chronic obstructive pulmonary disease

The functional consequence of asthma and chronic obstructive pulmonary disease (COPD) is airflow limitation, which is mostly reversible in asthma and not fully reversible in COPD. In both diseases, inflammatory conditions are associated with cellular and structural changes, referred to as remodeling, and these structural changes may lead to thickening of the airway wall, thereby promoting airway narrowing and airflow limitation. However, the pattern of infilatrated cells and the pattern of structural changes occur differently in the two diseases. In asthma, CD4+, T lymphocytes, eosinophils, and mast cells are the predominant cells involved, whereas COPD, CD8+, T lymphocytes, and macrophages are predominantly involved. In severe cases of asthma and COPD, neutrophil infiltration becomes evident. Regarding structural changes, epithelial injury and early thickening of reticular basement membrane are highly characteristic of the airway wall of asthmatics. Increases in airway smooth muscle mass occur in large airways of severe asthmatics and in small airways of patients with COPD. Thickening of the airway wall, golblet cell hyperplasia, mucous gland hypertrophy, and the luminal obstruction caused by inflammatory exudates and mucous are features of both asthma and COPD. Squamous epithelial metaplasia and airway wall fibrosis are commonly observed characteristics of COPD. Destruction and fibrosis of the alveolar wall occur in COPD but not in asthma. The remodeling processes accompanied by chronic inflammatory infiltrates interact in a complex fashion and contribute to the development of airflow limitation in both asthma and COPD.     

High-resolution computed tomography scan and airway remodeling in children with severe asthma

BACKGROUND: Children with severe asthma have a significantly higher bronchial wall thickness (BWT) on high-resolution computed tomography scan than control children. OBJECTIVE: We sought to determine whether a BWT score correlates with markers of airway remodeling and inflammation. METHODS: In 37 children with severe asthma, we determined reticular basement membrane thickness; number of intraepithelial neutrophils and eosinophils on bronchial biopsy; IFN-gamma, IL-4, IL-5, and eosinophil cationic protein levels and IFN-gamma/IL-4 ratio on bronchoalveolar lavage specimen; and alveolar nitric oxide (NO) concentration and the maximum airway wall NO flux. RESULTS: The BWT score significantly correlated with reticular basement membrane thickening (r = 0.34; P = .04) and NO production by the airway wall (r = 0.45; P = .02). The correlation with the eosinophil cationic protein level was just significant (r = 0.40; P = .05), whereas there was no correlation with IFN-gamma/IL-4 ratio (r = -0.31; P = .08). The BWT score did not correlate with FEV(1) or forced expiratory flow at 25% to 75% of forced vital capacity. CONCLUSION: High-resolution computed tomography scan is a noninvasive technique that might be valuable for quantifying airway remodeling in children with severe asthma. The new generations of multislice computed tomography scanners will allow higher definition and lower radiation exposure and probably give a better assessment of airway remodeling and efficacy of treatment in children with asthma.     

Comparison between hypertonic and isotonic saline-induced sputum in the evaluation of airway inflammation in subjects with moderate asthma

Background Hypertonic saline-indueed sputum has recently been used for the evaluation of airway inflammation in asthma. Objective To assess the effect of hypertonicity on airway inflammation. Methods We compared the inflammatory cell composition of hypertonic saline-induced sputum with that of isotonic saline-induced sputum in 21 asthmatic subjects and, at baseline and 30min after each sputum induction, we measured bronchial hyper-responsiveness to methacholine as an indirect marker to detect increased airway inflammation. On two different days, the patients inhaled hypertonic saline (3–5% NaCl) or isotonic saline (0.9% NaCl) for 30 min via an ultrasonic nebulizer, while monitoring FEV₁. Sputum was collected for inflammatory cell analysis. Results There was no difference in inflammatory cell percentages obtained with the two methods. Eosinophils were >1% in 20 subjects after hypertonic saline and in 16 subjects after isotonic saline, but this difference was not statistically significant. Intraclass correlation coefficients for sputum inflammatory cells obtained with the two methods were +0.642 for eosinophils, +0.644 for neutrophils. +0.544 for lymphocytes and +0.505 for macrophages. Hypertonic saline induced bronchoconstriction in a significantly greater number of subjects than isotonic saline. Also, hypertonic saline increased bronchial responsiveness to methacholine. while isotonic saline did not. Conclusion We conclude that hypertonicity does not affect sputum cell composition, suggesting that inflammatory cells in hypertonic saline-induced sputum are probably preexisting and not acutely recruited in the airways by the hypertonic stimulus. However, the bronchoconstriction and the increase in bronchial hyper-responsiveness after hypertonic saline inhalation may imply the release of inflammatory mediators. This fact must be considered in the evaluation of soluble markers of inflammation in hypertonic salineinduced sputum.     

细胞周期蛋白E在哮喘大鼠肺组织中的表达及其与气道重塑的关系

目的:通过测定哮喘大鼠肺组织中细胞周期蛋白E(cyclin E)的表达,研究cyclin E在哮喘气道重塑中的作用。方法:20只Wistar大鼠随机分为哮喘组和对照组,每组10只。用鸡卵清白蛋白(OVA)溶液致敏及激发复制哮喘模型。HE染色观察气道炎症;图像分析测量气道管壁厚度;流式细胞仪测定外周血单个核细胞细胞周期时相分布;免疫组化法检测cyclin E的表达情况;实时定量(real-time)RT-PCR测定肺组织中cyclin E mRNA水平表达;Western blotting法检测肺组织中cyclin E蛋白的表达。结果:哮喘组大鼠支气管管壁厚度较对照组增加(P0.01);哮喘组外周血单个核细胞S期、S+G2/M期百分率均较对照组增加,而G0/G1期百分率较对照组降低(均P0.01);哮喘组肺组织中cyclin E mRNA和蛋白水平的相对表达量较对照组高(均P0.01);肺组织中cyc-lin E蛋白的相对表达量与支气管管壁厚度呈正相关(P0.01)。结论:Cyclin E在哮喘大鼠肺组织中表达增加,其表达的上调可使细胞周期的G1期缩短,进而可能通过促进细胞的分裂增殖而参与哮喘气道重塑的发生发展。     

Association of airway hyperresponsiveness with reduced quality of life in patients with moderate to severe asthma.

BACKGROUND: Airway hyperresponsiveness (AHR) is an indicator of poor asthma control. Asthma patients with AHR to methacholine have been shown to have a poorer quality of life compared with asthma patients without AHR, but it is not clear to what degree this is a result of more severe disease in patients with AHR. OBJECTIVES: To describe the relationship between AHR and quality of life in asthma patients and to determine the impact of the severity of asthma on this relationship. METHODS: Data from 691 asthma patients were analyzed to describe the relationship between the impact of AHR to methacholine (cumulative dose of methacholine required to provoke a 20% decrease in forced expiratory volume in 1 second, < or = 8 micromol) on quality of life (measured by the Asthma Quality of Life Questionnaire) of asthma patients in relation to the severity of asthma (according to the Global Initiative for Asthma guidelines). RESULTS: Asthma patients with AHR had more severe asthma and a poorer quality of life compared with asthma patients without AHR. Furthermore, the quality of life decreased with increasing severity of asthma. However, regression analysis showed an independent association between both the presence of AHR and the severity of asthma and quality of life, as well as an interaction between the effects of these 2 factors. Finally, subgroup analysis showed that the impact of AHR on the quality of life was only clinically significant in moderate to severe asthma but not in mild asthma. CONCLUSIONS: AHR is associated with a negative impact on the quality of life of asthma patients that is partly independent of the severity of asthma.     

KyoT2 downregulates airway remodeling in asthma

The typical pathological features of asthma are airway remodeling and airway hyperresponsiveness (AHR). KyoT2, a negative modulator of Notch signaling, has been linked to asthma in several previous studies. However, whether KyoT2 is involved in the regulation of airway remodeling or the modulation of airway resistance in asthma is unclear. In this study, we aimed to evaluate the therapeutic potential of KyoT2 in preventing asthma-associated airway remodeling and AHR. BALB/c mice were used to generate a mouse model of asthma. Additionally, the expression of Hes1 and Notch1 in airway was analyzed using Immunofluorescence examination. The asthmatic mice were intranasally administered adenovirus expressing KyoT2 and were compared to control groups. Furthermore, subepithelial fibrosis and other airway remodeling features were analyzed using hematoxylin and eosin staining, Van Gieson’s staining and Masson’s trichrome staining. AHR was also evaluated. This study revealed that KyoT2 downregulated the expression of Hes1, repressed airway remodeling, and alleviated AHR in asthmatic mice. It is reasonable to assume that KyoT2 downregulates airway remodeling and resistance in asthmatic mice through a Hes1-dependent mechanism. Therefore, KyoT2 is a potential clinical treatment strategy for asthma.     

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.     

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.     

Adam 33 and its association with airway remodeling and hyperresponsiveness in asthma

Asthma is known to be a Th2 inflammatory syndrome that leads to intermittent airway obstruction. However, the mechanisms involved in development of the clinical features remain enigmatic, although genetic elements clearly are involved. Recently, based on a large genome wide screen involving families in the United Kingdom and the United States with at least two siblings with asthma, a locus was identified that encoded for a family of proteases. This group of proteins is now known as the ADAM superfamily. In this review, we discuss the ADAM superfamily and, in particular, ADAM 33, a member of a family of genes which encode a subgroup of zinc dependent metalloproteinase (metzincin). The potential for therapeutic intervention with ADAM 33 is extremely attractive and further work will not only focus on the specific domains of ADAM 33, but also the mechanisms by which they lead to bronchial hyperreactivity.     

Persistent peripheral airway obstruction in children with severe asthma

We reviewed pulmonary function data on 447 children with the diagnosis of asthma, who were studied in our laboratory over a 6-year interval. We found 19 with evidence of consistent airway obstruction. Two patients who had obvious causes for persistent obstruction were excluded. Seven of the remaining 17 patients consented to further studies. In six of the seven patients studied, flow rates at low lung volumes were severely depressed and remained unchanged after 2 weeks of vigorous "inpatient" therapy. No clinical benefit was apparent. One patient had relentlessly worse disease and died of his asthma. The autopsy revealed changes characteristic of asthma. We conclude that some children with severe asthma have persistent and severe peripheral airway obstruction. These findings challenge the current paradigm that asthma in children is a completely "reversible" illness. Long-term follow-up of children with persistent chronic obstruction may clarify the question of childhood origin of adult lung disease.     

Airway remodeling is correlated with obstruction in children with severe asthma

Background: Severe asthma may involve an irreversible obstructive pattern, and structural changes in bronchial airways are believed to play a key role in this context. The aim of the present study was to compare airway remodeling in severe asthmatic children with or without obstructive pattern. Methods: Two groups of children with severe asthma and persistent symptoms, 5–14 years old were included, 15 with persistent obstructive pattern (group O) and 10 without obstructive pattern (group N). Persistent obstructive pattern was defined as a forced expiratory volume in 1 s (FEV₁) less than 80% of the predicted value after a course of systemic corticosteroids and no significant improvement after bronchodilator. We examined bronchial biopsies by pathological and immunochemical methods and quantified airway smooth muscle (ASM) and mucus gland areas, reticular basement membrane (RBM) thickening, distance between ASM and RBM, muscle light chain kinase (MLCK) expression and number of vessels (CD31 expression). Results: Surface area of ASM (P = 0.009), MLCK expression (P = 0.03) and number of vessels (P = 0.0008) were increased in group O compared with group N. Distance of RBM–ASM was shorter in group O (P = 0.007). FEV₁ negatively correlated with ASM area (r = ?0.6; P = 0.002), MLCK expression (r = ?0.45; P = 0.02) and CD31 expression (r = ?0.7; P = 0.0003), and positively correlated with the distance of RBM–ASM (r = 0.5; P = 0.007). Conclusions: Structural abnormalities of airway remodeling are present in children with severe asthma. Only an increase in surface area of ASM and the density of the vascular network are more pronounced in children with persistent obstructive pattern, while RBM thickening is similar. These results are concordant with longitudinal studies which emphasize the precocity of bronchial obstruction.     

Lung damage and airway remodelling in severe asthma

Severe asthma is a heterogeneous disease with substantial unmet clinical need. Airway damage and remodelling is a consequence of complex host-environment interactions and is considered to be the cardinal feature leading onto the development and persistence of airflow obstruction. In this review, we shall bring together recent insights into the causes of airway damage and remodelling that propose key roles for pathogens and mechanical damage in addition to allergens, underlying genetic susceptibility, inflammatory and structural cell interactions, and impaired resolution of damage. We shall consider the consequences of airway remodelling in terms of airway geometry, mechanics and clinical expression of disease. Understanding the causes and consequences of airway damage and remodelling will shed light upon the structure-function relationships required to begin to unravel the complexity of severe asthma and will enable us to target current and novel therapies as we begin to move towards realizing personalized medicine.