Reduced apoptosis of memory T-cells in the inner airway wall of mild and severe asthma.

Effector memory T-cells (CD45RO+) may provide pro-inflammatory signals that contribute to the persistent airway inflammation that is characteristic of asthma, and reduced apoptosis of these cells may prolong their effects. The present authors compared apoptosis of CD45RO+ T-cells in the inner airway wall in nonfatal asthma (n = 7), fatal asthma (n = 7) and control (n = 8) cases. Apoptotic cells were identified using both the terminal deoxynucleotidyl transferase dNTP nick end-labelling (TUNEL) technique and cell morphology. The percentage of CD45RO+ T-cells that were apoptotic was significantly greater in control cases compared with nonfatal and fatal cases of asthma, respectively, in small (42+/-19, 16+/-9, 7+/-6%), medium (40+/-12, 15+/-11, 12+/-8%) and large airways (42+/-15, 23+/-18, 18+/-12%). The reduction in the percentage of apoptotic CD45RO+ cells in the cases of asthma was observed in both blood vessels and the interstitium in large airways. In conclusion, these data suggest that reduced apoptosis may prolong the active life of effector memory T-cells in the airways. It is possible that survival signals may be received before cells migrate into the interstitium of the inner airway wall.     

Airway remodeling: a comparison between fatal and nonfatal asthma.

BACKGROUND: Airway remodeling has been recently one of the main goals in asthma research because it has been implicated to influence airway behavior and evolution of asthma; hence, important in long-term followup of asthmatic patients. METHODS: Airways of fatal asthma (n=3), non-fatal asthma (n=3) and control cases (n=4) were studied using morphometry and immunohistochemical and H&E staining. RESULTS: The basement membrane was thicker in the cartilaginous and membranous airways of fatal and non-fatal asthma groups compared to the control group (p<0.05). Smooth muscle shortening was greater in airways of fatal asthma cases while submucosal gland area and mucus plug occupying ratio were greater in fatal asthma large airways compared to the two other groups (p<0.01). Increased intact and degranulated mast cells were observed in smooth muscle and in submucosal gland of fatal asthma airways (p<0.01) and were associated with greater degree of smooth muscle shortening and larger submucosal gland area, respectively. Eosinophil and EG2+ cell infiltrations were greatest in lamina propria of airways of fatal asthma than in nonfatal and control cases (p<0.01), but were not associated with any airway structural change. CONCLUSION: Increased infiltration of eosinophils in the lamina propria and mast cells in smooth muscle and submucosal glands may have a role in airway remodeling of fatal asthma airways but needs further investigation. Moreover, mast cells in cartilaginous airways may participate in the regulation of smooth muscle tone and mucous gland secretion and hyperplasia.     

Characterization of airway plugging in fatal asthma

PURPOSE: Case reports suggest that deaths due to asthma can occur without airway plugging. In this study, we examined the hypothesis that obstruction of the airway lumen by an exudate containing mucus and cells is a key feature of fatal asthma attacks. METHODS: We quantified airway narrowing and lumenal content in 275 airways from 93 patients with fatal asthma aged 10 to 49 years (59 white subjects and 34 Polynesian subjects, including 19 children), compared with airways from control patients who died suddenly without pulmonary diseases. RESULTS: The severity of lumenal occlusion ranged from 4% to 100% in these cases, but only five airways showed less than 20% occlusion. Compared with controls, patients with asthma had more lumenal occlusion (mean [+/- SD] open lumen, 42% +/- 23% vs. 93% +/- 8%), greater mucus occlusion (28% +/- 13% vs. 5% +/- 6%), and more occlusion by cells (30% +/- 17% vs. 3% +/- 2%, all P<0.0001). Airway narrowing was greater in larger airways (P<0.0001) and older patients (P = 0.009). Greater lumen content was associated with a higher proportion of cells (P = 0.003), and cells made up a higher proportion of the exudate in the small airways (P<0.0001). Lumenal mucus was greater in younger patients with asthma (P = 0.0007) and in Polynesian patients with asthma (P = 0.04). CONCLUSION: Airway lumenal obstruction by an exudate composed of mucus and cells is a major contributing cause of fatal asthma in most patients.     

Distribution and degranulation of airway mast cells in normal and asthmatic subjects.

It was hypothesized that the distribution and activation of mast cells across the airway wall may reflect their function in asthma. The density of mast cells (intact and degranulated) within airway compartments in cartilaginous and membranous airways, obtained from autopsies on patients with fatal asthma, nonfatal asthma, and nonasthmatic control cases have been examined. In cartilaginous airways, the mean+/-SE density of mast cells in control cases was 27+/-9 cells x mm(-2). It was similar in nonfatal asthma (24+/-2 cells x mm(-2)) but reduced (p<0.05) in fatal asthma cases (16+/-2 cells x mm(-2)). In membranous airways, the density of mast cells in control cases was 155+/-21 cells x mm(-2) and was higher (p<0.05) in cases of nonfatal (270+/-51 cells x mm(-2)) and fatal asthma (219+/-26 cells x mm(-2)). Mast-cell density was greatest on the smooth muscle and mucous glands in cartilaginous airways and on the smooth muscle and outer airway wall in membranous airways. The percentage of degranulated mast cells was higher (p<0.05) in cases of asthma, related to disease severity, and was higher in cartilaginous than membranous airways. Degranulation was greatest on the smooth muscle in fatal asthma cases. Mast-cell distribution and degranulation varies between cartilaginous and membranous airways and across the airway wall. Degranulation of mast cells is related to asthma severity. The increased degranulation in proximal airways may reflect stimulation via the inhaled route.     

Peripheral airways in asthma

The peripheral, or small, airways are usually defined as conducting airways that are less than 2 mm in internal diameter and extend from the noncartilaginous bronchioles to the alveolar ducts. Noninvasively measuring the function of the small airways in isolation is difficult since they make up only about 10% of total airway resistance. Quantitative pathologic studies have shown that both the small and large airways are involved in inflammation and remodeling in asthma. Recent studies also have shown that inflammation involves the alveoli surrounding small airways in asthma and that the distribution of different inflammatory cells across the airway wall varies in both large and small airways. Inhaled treatment that targets the small airways may be more effective than treatment that is deposited more proximally and suggests that treatments in the future need to address the variable distribution of pathology in the bronchial tree in asthma.     

Airway Dimensions in Fatal Asthma and Fatal COPD: Overlap in Older Patients

Abstract

In some patients with chronic asthma clinical and physiological similarities with COPD may exist, such as partial reversibility to bronchodilators and persistent expiratory airflow obstruction. However, pathological data comparing both diseases in patients of similar age and disease severity are scarce. We compared large and small airway dimensions in 12 younger (mean age 32 yrs) and 15 older (mean age 65 yrs) non-smoker adult fatal asthma patients with 14 chronic smokers with severe, fatal COPD (mean age 71 yrs). Using H&E, Movat pentachrome staining and image analysis, we quantified large airway basement membrane (BM) thickness (μm), submucosal gland area and large and small airway inner wall, smooth muscle and outer wall areas. Areas were normalized by BM perimeter (μm²/μm).

Younger adult fatal asthma patients had thicker BM, smooth muscle, and outer wall areas in both small and large airways when compared to COPD patients. In older asthmatics there was an overlap in BM thickness and airway structure in small airways. Inner wall layer in large and small airway level and submucosal gland areas were similar among groups. In conclusion, there are airway histological structural similarities between fatal asthma and fatal COPD. Older fatal asthmatics present overlapping airway structural features with younger adult fatal asthmatics and severe COPD patients. Our data contributes to a better understanding of asthma pathology in the elderly.     

Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers.

Interleukin (IL)-10 is a potent regulatory cytokine that decreases inflammatory responses. This study investigated whether IL-10 levels in the airway are decreased in chronic airway inflammation associated with asthma or chronic obstructive pulmonary disease (COPD). Sputum was obtained from 12 healthy nonsmokers, 10 healthy smokers, 16 asthmatic patients and seven patients with COPD by means of the sputum-induction method. The IL-10 level was measured via enzyme-linked immunosorbent assay and immunocytochemical analysis. The IL-10 level in sputum was significantly lower in asthma and COPD patients and healthy smokers compared with that in healthy nonsmokers (nonsmokers, 68.0+/-11.3; smokers, 45.3+/-7.8; asthma, 26.7+/-4.0; COPD, 18.0+/-2.3 pg x mL(-1); p<0.05 for nonsmokers versus the other groups). The percentage of IL-10-positive cells in the sputum was also significantly lower in asthma and COPD and in smokers (nonsmokers, 13.2+/-1.7; smokers, 6.4+/-1.8; asthma, 5.4+/-3.5; COPD, 3.5+/-1.6%; p<0.05 for nonsmokers versus the other groups). The IL-10-positive cell appeared morphologically to be the macrophage. These data suggest that the reduced level of interleukin-10 within the airways plays a role in the pathogenesis of chronic airway inflammation in asthma and chronic obstructive pulmonary disease.     

The mechanics of airway narrowing in asthma

This study was designed to determine the potential importance of airway wall thickening in the pathogenesis of the excess airways narrowing of asthma. The airways in postmortem specimens of lung obtained from 18 patients who suffered from asthma were compared to similar airways from 23 patients without asthma. Each airway was projected onto a digitizing board of a microcomputer to trace the internal and external perimeter of the airway and to calculate the submucosal and mucosal thicknesses. The relaxed length of the airway smooth muscle and the shortening required to occlude the airway lumen were calculated. These data show that the wall area was greater (p less than 0.001) in the membranous and cartilaginous airways of asthmatic patients and the airway smooth muscle shortening required to occlude the lumen was less in asthmatic than nonasthmatic airways (p less than 0.001). The increased wall area was due to increased areas of epithelium, muscle, and submucosa. We conclude that the walls of the airways of patients with asthma are thickened by chronic inflammation and that this thickening could be as important as smooth muscle shortening in determining the airway responsiveness of these patients.     

Reduced apoptosis of CD8+ T-lymphocytes in the airways of smokers with mild/moderate COPD

Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation in airways and lung parenchyma. CD8+ T-lymphocytes, crucial effector and regulatory cells in inflammation, are increased in the central and peripheral airways in COPD. The aim of this study was to assess the role of apoptosis in the accumulation of CD8+ T-lymphocytes within the airway wall in COPD. We examined the submucosa of transverse sections of central and peripheral airways from post-operative tissues from non-smokers (n?=?16), smokers with normal lung function (n?=?16), smokers with mild/moderate COPD (n?=?16), and smokers with severe/very severe COPD (n?=?9). TUNEL and immunohistochemistry techniques were used to identify apoptosis and cell phenotype, respectively. The percentage of apoptotic CD8+ T-lymphocytes was significantly lower (p?相似文献   

Intraluminal airway inflammation in chronic bronchitis. Characterization and correlation with clinical parameters

In order to characterize intraluminal airway inflammation in subjects with chronic bronchitis, bronchoscopy and bronchoalveolar lavage were performed in 28 subjects with chronic bronchitis with fixed airway obstruction and, for comparison, 15 asymptomatic smokers and 25 normal nonsmoking volunteers. The chronic bronchitics had a cough productive of sputum on most days of the month for 6 months in the preceding 2 yr, had at least one exacerbation requiring medical intervention in each of the previous 2 yr, and had an FEV1 less than 76% of predicted without response to bronchodilator. During bronchoscopy the airways were assessed for visual evidence of inflammation by assigning them a score, the bronchitis index, that graded the airways according to the apparent severity of airway edema, erythema, friability, and secretions. Bronchoalveolar lavage was performed by sequentially instilling and retrieving with gentle suction five 20-ml aliquots of sterile normal saline into each of three separate lobes. The first aliquots, the "bronchial" sample, were pooled and processed separately from the final four aliquots, the "distal" sample. Cell counts, cell differentials, and albumin were determined for both the bronchial and distal samples. In order to correlate inflammation with clinical parameters, sputum was collected for 24 h prior to bronchoscopy; spirometry was performed just prior to bronchoscopy, and smoking histories were obtained. Visual inspection of the airways, as quantified by the bronchitis index, demonstrated significantly more evidence for inflammation in the chronic bronchitics than in either the asymptomatic smokers or the normal subjects. The bronchial sample lavage fluids from the chronic bronchitics tended to contain more cells (6.1 +/- 2.2 x 10(6) cells) than the bronchial sample fluids from the asymptomatic smokers (3.6 +/- 0.6 x 10(6) cells) or normal subjects (3.7 +/- 0.5 x 10(6) cells). Furthermore, the chronic bronchitics had a higher percentage of neutrophils in their bronchial lavage fluid (35.8 +/- 5.6%) than did either the asymptomatic smokers (20.7 +/- 2.6%, p = 0.0001) or the normal subjects (10.3 +/- 5.6%). The distal sample lavage fluid also recovered more neutrophils from both the chronic bronchitics (15.0 +/- 4.2%, p = 0.0012) and asymptomatic smokers (5.7 +/- 1.3%, p = 0.002) than from the normal subjects (2.8 +/- 0.4%). The chronic bronchitics were divided into two groups: those with low (less than 20%) and those with high (greater than 20%) bronchial sample neutrophils. Those with higher bronchial sample neutrophils had significantly more sputum production and lower FEV1, FEV1/FVC, and FEF25-75 than did the subjects with lower bronchial sample neutrophils.(ABSTRACT TRUNCATED AT 400 WORDS)     

The airway longitudinal elastic fiber network and mucosal folding in patients with asthma

A submucosal network of elastic fibers in a collagen and myofibroblast matrix form discrete longitudinal bundles (LB) in the bronchial tree. The LB may affect airway function by altering the mechanical properties of the airway wall or by changing the folding behavior of the airway mucosa. The area and number of LB were quantified from 12 cases each of fatal asthma (FA), nonfatal asthma (NF), and nonasthmatic (NA) control cases on elastic-trichrome stained airways. The effects of group, sex, age, and smoking were examined using multiple linear regression. The area fraction of LB increased (p < 0.05) approximately twofold in cases of FA compared with NA control cases in both large and small airways. The areas of LB were increased in smokers, older subjects, and men (p < 0.05). The number of mucosal folds was related to the number of longitudinal bundles in asthmatics and nonasthmatics and was not different between groups. Collagen and myofibroblasts were increased (p < 0.05) in LB of FA and NF cases compared with NA control cases. The increased size and altered composition of LB in asthma may influence airway function; however, excessive airway narrowing in asthma is not due to altered numbers of mucosal folds.     

Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma

IgE plays an important role in allergic asthma. We hypothesized that reducing IgE in the airway mucosa would reduce airway inflammation. Forty-five patients with mild to moderate persistent asthma with sputum eosinophilia of 2% or more were treated with humanized monoclonal antibody against IgE (omalizumab) (n = 22) or placebo (n = 23) for 16 weeks. Outcomes included inflammatory cells in induced sputum and bronchial biopsies, and methacholine responsiveness. Treatment with omalizumab resulted in marked reduction of serum IgE and a reduction of IgE+ cells in the airway mucosa. The mean percentage sputum eosinophil count decreased significantly (p < 0.001) from 6.6 to 1.7% in the omalizumab group, a reduction significantly (p = 0.05) greater than with placebo (8.5 to 7.0%). This was associated with a significant reduction in tissue eosinophils; cells positive for the high-affinity Fc receptor for IgE; CD3+, CD4+, and CD8+ T lymphocytes; B lymphocytes; and cells staining for interleukin-4, but not with improvement in airway hyperresponsiveness to methacholine. This study shows antiinflammatory effects of omalizumab treatment and provides clues for mechanisms whereby omalizumab reduces asthma exacerbations and other asthma outcomes in more severe asthma. The lack of effect of omalizumab on methacholine responsiveness suggests that IgE or eosinophils may not be causally linked to airway hyperresponsiveness to methacholine in mild to moderate asthma.     

Fractal geometry of airway remodeling in human asthma

RATIONALE: Airway wall remodeling is an important aspect of asthma. It has proven difficult to assess quantitatively as it involves changes in several components of the airway wall. OBJECTIVE: To develop a simple method for quantifying the overall severity of airway wall remodeling in asthmatic airways using fractal geometry. METHODS: Negative-pressure silicone rubber casts of lungs were made using autopsy material from three groups: fatal asthma, nonfatal asthma, and nonasthma control. All subjects were lifelong nonsmokers. A fractal dimension was calculated on two-dimensional digital images of each cast. RESULTS: Nonasthma control casts had smooth walls and dichotomous branching patterns with nontapering segments. Asthmatic casts showed many abnormalities, including airway truncation from mucous plugs, longitudinal ridges, and horizontal corrugations corresponding to elastic bundles and smooth muscle hypertrophy, respectively, and surface projections associated with ectatic mucous gland ducts. Fractal dimensions were calculated from digitized images using an information method. The average fractal dimensions of the airways of both the fatal asthma (1.72) and nonfatal asthma (1.76) groups were significantly (p<0.01 and p=0.032, respectively) lower than that of the nonasthma control group (1.83). The lower fractal dimension of asthmatic airways correlated with a decreased overall structural complexity and pathologic severity of disease. CONCLUSION: Fractal analysis is a simple and useful technique for quantifying the chronic structural changes of airway remodeling in asthma.     

Quantitative analysis of bronchial wall vascularity in the medium and small airways of patients with asthma and COPD

BACKGROUND: Submucosal hypervascularity is part of airway remodeling in patients with asthma; however, its existence in the small airways and its contribution to airflow limitation remain controversial. METHODS: We investigated bronchial wall vascularity and angiogenic cells between medium airways (inner diameter, 2 to 5 mm) and small airways (inner diameter, < 2 mm) in patients with asthma (n = 9) and COPD (n = 11), and in 8 control subjects. The lung specimens obtained during surgery were immunostained to detect CD31, CD34, vascular endothelial growth factor, and basic fibroblast growth factor. RESULTS: The number of vessels in both the medium and small airways in patients with asthma was significantly (p < 0.01) increased compared to those in patients with COPD and control subjects, and the percentage of vascularity was significantly (p < 0.01) increased in the medium airways in asthma patients and in the small airways in COPD patients. Patients with moderate asthma showed a greater increase in vascularity than those with mild asthma (p < 0.01), and the number of angiogenic factor-positive cells increased in asthma patients compared with control subjects. In asthmatic subjects, inverse correlations were found between FEV(1) percentage of predicted and the number of vessels (r = -0.85; p < 0.01), or the percentage of vascularity (r = -0.72; p < 0.03) in the inner area of the medium airways, but they were not found for the small airways. In COPD patients, no correlations were demonstrated. CONCLUSIONS: The number of vessels in the medium and small airways in asthma patients shows a greater increase than those in COPD patients, and the vascular area in the small airways is increased in COPD patients but not in asthma patients. Enhanced vascularity in the inner area of the medium airways, but not in the small airways, might contribute to airflow limitation in asthma patients.     

Asthma and smoking: an unfortunate combination

Asthma is an inflammatory disease of the airways in which a key role is played by certain cells and mediators (T-helper 2 cells, mast cells, eosinophils, interleukin 4 and 5). In certain disorders such as irritant-induced asthma, reactive airways dysfunction syndrome, and asthma due to toluene diisocyanate, inflammation is mediated predominantly by T-helper 1 cells, macrophages and neutrophils. Smoking also produces bronchial inflammation, in this case mediated primarily by macrophages and neutrophils although eosinophil predominance has also been observed in some smokers (an allergic response to certain antigens). The remodeling of the airway wall that accompanies the chronic inflammatory cascade may alter the cell response profile making it difficult to determine which type of inflammatory infiltrate is predominant. The association of asthma and smoking is a reality in our society, and it is a combination that substantially modifies pathogenic mechanisms and gives rise to a more severe clinical picture. Resistance to some of the pharmacotherapies used routinely in the treatment of asthma (corticosteroids) has also been observed and this has favored the use of other drugs (antileukotrienes). One of the preventative measures that should be used more energetically is to encourage patients to stop smoking, paying particular attention to asthmatic smokers.     

Airway reactivity to inhaled mannitol in cigarette smokers: a longitudinal study

Smoking induces airway hyperresponsiveness (AHR). Bronchial provocation with mannitol is used to identify AHR in subjects with asthma. This study aimed to determine the prevalence of airway hyperresponsiveness to mannitol in asymptomatic smokers compared to non-smokers and to assess if airway responsiveness to mannitol changes after smoking cessation. Airway responsiveness to inhaled mannitol was measured in smokers (n=42), and non-smokers (n=45). In smokers, the mannitol test was repeated 3 months after smoking cessation. Demographics including age, lung function and atopy status were similar for smokers and non-smokers (p=ns). Compared with non-smokers (2.2%), AHR to mannitol expressed by 15%> or = fall in FEV(1) was significantly more common in smokers (26.2%) (p=0.001). The provoking dose to induce a 15%> or = fall in FEV(1) (PD(15)), a measure of sensitivity, was median [IQR] 291 mg [207-377] in the 11 positive smokers. The response-dose ratio (RDR) (% fall in FEV(1)/cumulative dose), a measure of reactivity, was significantly higher in smokers (0.013 [0.006-0.029]) compared with non-smokers (0.004 [0.002-0.007]), (p<0.0001). After successful smoking cessation, the RDR decreased in most cases (p=0.01) and only one patient still recorded a 15% fall in FEV(1). None of the patients with a negative mannitol test turned positive, irrespective of the outcome of smoking cessation. AHR to mannitol is quite common in smokers compared to non-smokers and decreases significantly after smoking cessation. Thus, the mannitol test may be sensitive to non-asthmatic inflammation of the airways.     

Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers

To evaluate the possible pulmonary effects of habitual marijuana smoking with and without tobacco, we administered a detailed respiratory and drug use questionnaire and/or lung function tests to young, habitual, heavy smokers of marijuana alone (n = 144) or with tobacco (n = 135) and control subjects of similar age who smoked tobacco alone (n = 70) or were nonsmokers (n = 97). Mean amounts of marijuana and/or tobacco smoked were 49 to 57 joint-years marijuana (average daily number of joints times number of years smoked) and 16 to 22 pack-years of tobacco. Among the smokers of marijuana and/or tobacco, prevalence of chronic cough (18 to 24%), sputum production (20 to 26%), wheeze (25 to 37%) and greater than 1 prolonged acute bronchitic episode during the previous 3 yr (10 to 14%) was significantly higher than in the nonsmokers (p less than 0.05, chi square). No difference in prevalence of chronic cough, sputum production, or wheeze was noted between the marijuana and tobacco smokers, nor were there additive effects of marijuana and tobacco on symptom prevalence. We noted significant worsening effects of marijuana but not to tobacco on specific airway conductance and airway resistance (tests of mainly large airways function) in men and of tobacco but not of marijuana on carbon monoxide diffusing capacity and on closing volume, closing capacity, and the slope of Phase III of the single-breath nitrogen washout curve (tests reflecting mainly small airways function) (p less than 0.03, two-way ANCOVA). No adverse interactive effects of marijuana and tobacco on lung function were found.     

Airway smooth muscle in health and disease; methods of measurement and relation to function.

Smooth muscle is present and probably functional in the airways in utero and increases in absolute area during growth with little further change during adulthood. It encircles the entire airway below the level of the main bronchus, in a roughly circular orientation, except at high lung volumes. It occupies relatively more of the airway wall in the peripheral airways, reaching a maximum in the membranous bronchioles. Measurement of smooth muscle area in the airway wall is confounded by clinical classification of cases, methods of tissue retrieval and preparation, staining and orientation of sections, magnification, image analysis and statistical methods of comparison between groups. Airway smooth muscle area is pathologically increased in inflammatory conditions of the airways such as chronic obstructive pulmonary disease, in relation to airways obstruction, and asthma, in relation to severity and airway size (between 25 and 250% compared with control cases). It is increased in sudden infant death syndrome, but there are few studies in other conditions such as bronchiectasis. In asthma, smooth muscle must shorten (not necessarily to an abnormal degree) for the structural abnormalities of the airway to manifest as excessive airway narrowing. Not surprisingly there is renewed interest in the relationships between the mechanical and contractile properties of smooth muscle, parenchymal properties and lung volume and how these interact to determine smooth muscle length. The relative importance of smooth muscle area and mechanical properties, altered airway structure and airway inflammation in disease are yet to be determined.     

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.