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.     

Mast cells in COPD airways: relationship to bronchodilator responsiveness and angiogenesis

We have investigated whether mast cells are associated with bronchodilator responsiveness and airway vascular changes in chronic obstructive pulmonary disease (COPD) airways. We have previously shown that the reticular basement membrane is hypervascular and the lamina propria is hypovascular in COPD. Bronchial biopsies from 32 COPD subjects, 15 smokers with normal lung function and 17 controls, were immunostained for factor VIII, mast cell tryptase and chymase antibodies. Mast cells in the airway smooth muscle, the reticular basement membrane and the underlying lamina propria were quantitated. 41% of COPD subjects had significant bronchodilator responsiveness, but this was not related to smooth muscle mast cell numbers. The reticular basement membrane had greater mast cell density in all groups compared with controls (p<0.01). In this compartment, perivascular mast cell density was related to hypervascularity. Lamina propria mast cell density was increased only in COPD (p<0.05). Perivascular mast cell density in the lamina propria was not related to its decreased vessel density. Bronchodilator responsiveness in COPD is not related to large airway smooth muscle mast cells of either type; both reticular basement membrane and lamina propria mast cells are increased in COPD patients, and perivascular mast cells may be involved in increased angiogenesis in the reticular basement membrane.     

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.     

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.     

Airway smooth muscle growth in asthma: proliferation, hypertrophy, and migration

Increased airway smooth muscle mass is present in fatal and non-fatal asthma. However, little information is available regarding the cellular mechanism (i.e., hyperplasia vs. hypertrophy). Even less information exists regarding the functional consequences of airway smooth muscle remodeling. It would appear that increased airway smooth muscle mass would tend to increase airway narrowing and airflow obstruction. However, the precise effects of increased airway smooth muscle mass on airway narrowing are not known. This review will consider the evidence for airway smooth muscle cell proliferation and hypertrophy in asthma, potential functional effects, and biochemical mechanisms.     

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.     

Time to death and mast cell degranulation in fatal asthma

Background and objective:   Attacks of fatal asthma have been shown to be either of short duration or long duration and associated with differing degrees of smooth muscle contraction, luminal mucus deposition and ratios of eosinophils to neutrophils in the airway wall. We hypothesized that this bimodal distribution might be related to airway mast cell degranulation.
Methods:   Airway sections from cases of fatal asthma in the second Victorian asthma mortality study and from cases coming to coronial autopsy in Perth were examined. Tryptase-positive mast cells, numbers of intact and degranulated mast cells, post-mortem blood salbutamol levels and airway dimensions were measured.
Results:   Although the total number of mast cells were similar, the ratio of degranulated to intact mast cells (D/I) was significantly increased in the smooth muscle ( P  < 0.05) and outer airway wall ( P  < 0.001), in short-duration cases compared with long-duration cases. Proportional muscle shortening was significantly increased ( P  < 0.05) in short-duration cases (17 ± 7%) compared with long-duration cases (11 ± 7%). Blood salbutamol levels were related to the total airway wall mast cell D/I ratio for all cases combined ( r  = 0.57, P  = 0.01).
Conclusions:   The duration of a fatal attack of asthma may be partly determined by the degranulation of mast cells.     

Aggregations of lymphoid cells in the airways of nonsmokers, smokers, and subjects with asthma

Persistent airway inflammation is present in cases with asthma and in smokers with airflow obstruction. Isolated aggregations of lymphoid cells (IALC) may be sites of localized inflammatory cell activation. Their distribution and characteristics in cartilaginous airways were assessed in postmortem tissue from nonsmokers (n=10), smokers (n=9), and cases of nonfatal (n=10) and fatal asthma (n=10). IALC were present in 70-100% of cases, were more often in proximal than distal airways, and 80% were confined to the outer airway wall. IALC with area greater than 0.1 mm2 were more frequent in both asthma groups (p<0.001). Airways with IALC had increased airway dimensions and greater numbers of eosinophils and lymphomononuclear cells. Within IALC, T and B lymphocytes were segregated and comprised more than 90% of all cells. Proliferating, apoptotic, and antigen-presenting cells (Rel B+ and HLA-DR+) were less than 5%, 30-40%, and less than 1% of all cells, respectively, and were similar in each case group. Vascular structures were increased (p < 0.01) in cases of fatal asthma. These findings show that, even in nonsmoking cases and cases without asthma, IALC are common, show cellular organization, and are associated with airway wall inflammation and remodeling. It remains to be determined if IALC contribute to or result from persistent airway inflammation in asthma.     

Airway remodeling in asthma and irreversible airflow limitation-ECM deposition in airway and possible therapy for remodeling-.

Airway remodeling in asthma is characterized by goblet cell hyperplasia, subepithelial fibrosis, and hyperplasia and hypertrophy of airway smooth muscle cells. The airway wall thickness increases because of subepithelial fibrosis, and hyperplasia and hypertrophy of the airway smooth muscle cells and submucosal glands. Airway remodeling, therefore, can often cause irreversible airflow limitation and an increase of airway hyperresponsiveness. Recent studies have described the molecular and cellular mechanisms of collagen deposition in the airway wall such as subepithelial fibrosis. Fibroblasts or myofibroblasts play a critical role in the exaggerated deposition of collagen in asthmatic airways. Bone marrow derived fibroblasts may play a role in fibrotic remodeling in asthmatic airways. Airway remodeling is induced by cytokines and mediators produced in chronic allergic airway inflammation. Since, once formed, remodeling is resistant to asthma therapy, early intervention with inhaled corticosteroid should be considered to prevent the progress of airway remodeling.     

The role of airway smooth muscle in the pathogenesis of airway wall remodeling in chronic obstructive pulmonary disease

Airway wall remodeling processes are present in the small airways of patients with chronic obstructive pulmonary disease, consisting of tissue repair and epithelial metaplasia that contribute to airway wall thickening and airflow obstruction. With increasing disease severity, there is also increased mucous metaplasia and submucosal gland hypertrophy, peribronchial fibrosis, and an increase in airway smooth muscle mass. Apart from its contractile properties, airway smooth muscle produces inflammatory cytokines, proteases, and growth factors, which may contribute to the remodeling process and induce phenotypic changes of the muscle. Airflow limitation responds minimally to beta-agonists and corticosteroid therapy, unlike asthma, perhaps because of alterations in beta-receptor or glucocorticoid receptor numbers, alterations in receptor signaling, or the constrictive limitation imposed by peribronchial fibrosis. Better response is observed with the combination of inhaled long-acting beta-agonists and corticosteroids. This could result from effects at the level of airway smooth muscle. Airway wall remodeling may involve the release of growth factors from inflammatory or resident cells. The influence of smoking cessation or of current therapies on airway wall remodeling is unknown. Specific therapies for airway wall remodeling may be necessary, together with noninvasive methods of imaging small airway wall remodeling to assess responses.     

Endobronchial Biopsy: A Guide for Asthma Therapy Selection in the Era of Bronchial Thermoplasty

Objective. Bronchial thermoplasty (BT) reduces airway smooth muscle in patients with severe asthma. We developed a novel standardized histologic grading system assessing inflammation and structural remodeling on endobronchial biopsy (EBBx) in severe persistent asthma and evaluated airway structure before and after BT. In addition, we correlated invasive and non-invasive inflammatory markers in severe persistent asthma. Methods. Thirty-three patients with severe persistent asthma underwent bronchoscopy, including bronchoalveolar lavage (BAL) and diagnostic EBBx. The control group (N = 41) underwent EBBx for other clinical indications. Biopsies were graded for airway inflammation and epithelial and submucosal structural features. We also evaluated airway histology in three patients before and after BT. Results. Compared to the control group, patients with severe persistent asthma more often had intraepithelial eosinophils and lymphocytes (67% vs. 17% and 61% vs. 27%; p < .001 and p = .005, respectively) and prominent smooth muscle and goblet cell hyperplasia (88% vs. 29% and 47% vs. 22%, p < .001 and p = .004, respectively). Other features including epithelial denudation and basement membrane thickening were not significantly different. Following BT, airway smooth muscle was no longer prominent due to partial replacement by fibrosis. Increased submucosal eosinophilic inflammation and BAL eosinophilia correlated with exhaled nitric oxide (eNO, p = .05 for both). Conclusions. We developed a clinically applicable standardized histologic grading system which identified structural but not inflammatory changes before and after BT in severe persistent asthmatics. Additionally, we demonstrated that eNO is representative of submucosal eosinophilia in this population. This semi-quantitative assessment will be useful for practicing pathologists assessing EBBx from severe persistent asthma patients for diagnostic and clinical research purposes.     

Airway inflammation and remodeling in asthma

An important advance in our understanding of the pathophysiology of asthma has been the discovery that airway inflammation is not confined to severe asthma but also characterizes mild and moderate asthma. Inflammation in asthma may be the result of a peculiar type of lymphocytic inflammation whereby Th2 lymphocytes secrete cytokines that orchestrate cellular inflammation and promote airway hyperresponsiveness. The term "airway remodeling" in 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. The consequences of airway remodeling in asthma may include incompletely reversible airway narrowing, bronchial hyperresponsivenesss, airway edema, and mucus hypersecretion. Airway remodeling in asthma thus may predispose persons with asthma to asthma exacerbations and even death from airway obstruction caused by smooth muscle contraction, airway edema, and mucus plugging. Although much has been learned in the past 25 years about the pathophysiology of airway inflammation and airway remodeling in asthma, important questions remain about the relation between airway inflammation and remodeling, the natural history of airway remodeling, and the effects of current asthma treatments on remodeled airways.     

Airway remodeling in asthma

Airway remodeling is a summary term for the pathological changes that occur in airway structure in allergic or suppurative airway diseases. Characteristic changes of airway remodeling in asthma include goblet cell hyperplasia, deposition of collagens in the basement membrane zone, increased size and number of microvessels in the submucosa, hyperplasia and hypertrophy of airway smooth muscle, and hypertrophy of submucosal glands. Some of these changes, such as goblet cell hyperplasia and subepithelial collagen deposition, are present even in mild asthma; other changes such as increases in airway smooth muscle and gland volume appear to be more characteristic of severe asthma. Airway narrowing, airway hyperresponsiveness, and mucus hypersecretion are all functional consequences of airway remodeling leading to clinical manifestations such as dyspnea, wheeze, sputum production, and susceptibility to asthma exacerbations. Noninvasive measures of remodeling are lacking, and monitoring the effects of treatment on remodeling has been difficult. For this reason relatively little is known about the effects of current asthma treatments on airway remodeling. As mechanisms of airway remodeling are developed, it is hoped that novel therapeutic targets will be identified. Treatments specifically targeting mediators of remodeling hold promise as treatments that could modify disease progression in asthma.     

Neural control of human airways in health and disease

Several aspects of airway function are under autonomic control: airway smooth muscle tone, submucosal gland secretion, epithelial cell function, bronchial vascular tone and permeability, and probably secretion from mast cells and other inflammatory cells. Neural control of human airways is more complex than previously recognized. In addition to afferent nerves and cholinergic adrenergic mechanisms (including circulating catecholamines), there are nonadrenergic, noncholinergic nerves that may be both excitatory and inhibitory. The neurotransmitters of this third nervous system are uncertain, but there is some evidence that neuropeptides may be involved. Several neuropeptides have recently been identified in human airways and, although they have potent effects, their pathophysiologic role is uncertain. There is much evidence that autonomic control of the airways may be abnormal in airway disease, particularly in asthma, but the precise role of neural mechanisms in the pathogenesis of air-flow obstruction and bronchial hyperresponsiveness remains to be defined.     

Understanding asthma pathophysiology.

Asthma is best described as a chronic disease that involves inflammation of the pulmonary airways and bronchial hyperresponsiveness that results in the clinical expression of a lower airway obstruction that usually is reversible. Physiologically, bronchial hyperresponsiveness is documented by decreased bronchial airflow after bronchoprovocation with methacholine or histamine. Other triggers that provoke airway obstruction include cold air, exercise, viral upper respiratory infection, cigarette smoke, and respiratory allergens. Bronchial provocation with allergen induces a prompt early phase immunoglobulin E (IgE)-mediated decrease in bronchial airflow (forced expiratory volume in 1 second) followed in many patients by a late-phase IgE-mediated reaction with a decrease in bronchial airflow for 4-8 hours. The gross pathology of asthmatic airways displays lung hyperinflation, smooth muscle hypertrophy, lamina reticularis thickening, mucosal edema, epithelial cell sloughing, cilia cell disruption, and mucus gland hypersecretion. Microscopically, asthma is characterized by the presence of increased numbers of eosinophils, neutrophils, lymphocytes, and plasma cells in the bronchial tissues, bronchial secretions, and mucus. Initially, there is recruitment of leukocytes from the bloodstream to the airway by activated CD4 T-lymphocytes. The activated T-lymphocytes also direct the release of inflammatory mediators from eosinophils, mast cells, and lymphocytes. In addition, the subclass 2 helper T-lymphocytes subset of activated T-lymphocytes produces interleukin (IL)-4, IL-5, and IL-13. IL-4 in conjunction with IL-13 signals the switch from IgM to IgE antibodies. The cross-linkage of two IgE molecules by allergen causes mast cells to degranulate, releasing histamine, leukotrienes, and other mediators that perpetuate the airway inflammation. IL-5 activates the recruitment and activation of eosinophils. The activated mast cells and eosinophils also generate their cytokines that help to perpetuate the inflammation. Regardless of the triggers of asthma, the repeated cycles of inflammation in the lungs with injury to the pulmonary tissues followed by repair may produce long-term structural changes ("remodeling") of the airways. This review will discuss in greater detail the relationships of inflammation and airway hyperresponsiveness to the pathophysiology of asthma.     

Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma.

There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling, such as the increased subepithelial airway vascularity in patients with asthma. We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids (ICS) (range 200-500 microg twice a day) and 28 normal subjects without asthma as a control population. Subjects underwent bronchoscopy with airway biopsy and subjects with asthma were then randomized to receive supplementary inhaled salmeterol 50 microg twice a day, fluticasone propionate 100 microg twice a day, or placebo for 3 mo in addition to their baseline ICS. Biopsy of the airway was then repeated. The biopsies were analyzed for vascular structures in the subepithelial lamina propria. Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects. We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects (524 +/- 137 vessels/mm2, n = 34 versus 425 +/- 130 vessels/mm2, n = 28; p = 0.004). There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline (before, 535 +/- 153 vessels/mm2 versus after, 400 +/- 142 vessels/mm2; n = 12; p = 0.04). There was no significant change within the fluticasone (n = 11) or placebo (n = 11) treatment groups, but also no significant differences between the groups. Notably, no treatment was associated with increased airway wall vascularity. The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study, which is complementary to the action of ICS on airway vascularity.     

Protective effects of tiotropium bromide in the progression of airway smooth muscle remodeling

RATIONALE: Recent findings have demonstrated that muscarinic M(3) receptor stimulation enhances airway smooth muscle proliferation to peptide growth factors in vitro. Because both peptide growth factor expression and acetylcholine release are known to be augmented in allergic airway inflammation, it is possible that anticholinergics protect against allergen-induced airway smooth muscle remodeling in vivo. OBJECTIVE: We investigated the effects of treatment with the long-acting muscarinic receptor antagonist tiotropium on airway smooth muscle changes in a guinea pig model of ongoing allergic asthma. RESULTS: Twelve weekly repeated allergen challenges induced an increase in airway smooth muscle mass in the noncartilaginous airways. This increase was not accompanied by alterations in cell size, indicating that the allergen-induced changes were entirely from increased airway smooth muscle cell number. Morphometric analysis showed no allergen-induced changes in airway smooth muscle area in the cartilaginous airways. However, repeated ovalbumin challenge enhanced maximal contraction of open tracheal ring preparations ex vivo. This was associated with an increase in smooth muscle-specific myosin expression in the lung. Treatment with inhaled tiotropium considerably inhibited the increase in airway smooth muscle mass, myosin expression, and contractility. CONCLUSIONS: These results indicate a prominent role for acetylcholine in allergen-induced airway smooth muscle remodeling in vivo, a process that has been thus far considered to be primarily caused by growth factors and other mediators of inflammation. Therefore, muscarinic receptor antagonists, like the long-acting anticholinergic tiotropium bromide, could be beneficial in preventing chronic airway hyperresponsiveness and decline in lung function in allergic asthma.     

Airway size and structure in the normal fetal and infant lung and the effect of premature delivery and artificial ventilation

Light microscopic morphometric techniques were used to study the inflated airways of 17 normal infants from 22 wk of gestation to 8 months postnatal age, plus three young adults. In addition, the lungs of four premature and seven mechanically ventilated infants were studied. A computer-assisted digitizer was used to measure airway diameter and to determine the area of cartilage, gland, and muscle in each type of airway. Epithelial height was also measured, and goblet cell number was counted. Using histochemical stains, types of glycoprotein were identified in goblet cells and submucosal glands. Between 22 wk of gestation and 8 months of age, the normal infant showed a linear increase with age in airway diameter. With age the area of muscle and submucosal gland increased in total amount and showed a significant linear increase when related to the size of the airways, except the submucosal gland in hilar airways. By contrast, the increase in cartilage was only commensurate with the increase in size of intrapulmonary airways, but showed a linear size-related increase in the main bronchus. Epithelial height and goblet cell number increased with age in the bronchi, but not more peripherally. Premature infants had for their postconceptional age normal-sized airways with an increase in amount of bronchial smooth muscle and an increase in number of goblet cells. Ventilated infants had a greater increase in smooth muscle (p less than 0.05 to p less than 0.002) and goblet cells (p less than 0.05) and an increase in submucosal gland area (p less than 0.04) whether or not the infant had had hyaline membrane disease.     

Bronchial inflammation and airway responses to deep inspiration in asthma and chronic obstructive pulmonary disease

RATIONALE: Deep inspirations provide physiologic protection against airway narrowing in healthy subjects, which is impaired in asthma and chronic obstructive pulmonary disease (COPD). Airway inflammation has been suggested to alter airway mechanics during deep inspiration. OBJECTIVES: We tested the hypothesis that the number of bronchial inflammatory cells is related to deep inspiration-induced bronchodilation in asthma and COPD. METHODS: In a cross-sectional study, three modified methacholine challenges were performed in 13 patients with mild, persistent asthma, 12 patients with mild to moderate COPD, and 12 healthy control subjects. MEASUREMENTS AND MAIN RESULTS: After a 20-minute period of deep inspiration avoidance, inhalation of methacholine was followed by either one or five deep inspirations, or preceded by five deep inspirations. The response to deep inspiration was measured by forced oscillation technique. Inflammatory cells were counted within the lamina propria and airway smooth muscle area in bronchial biopsies of patients with asthma and COPD. The reduction in expiratory resistance by one and five deep inspirations was significantly less in asthma (mean change+/-SD: -0.5+/-0.8 and -0.9+/-1.0 cm H2O/L/s, respectively) and COPD (+0.2+/-1.1 and +0.4+/-1.0 cm H2O/L/s, respectively) as compared with healthy subjects (-1.5+/-1.3 and -2.0+/-1.2 cm H2O/L/s, respectively; p=0.05 and p=0.001, respectively). In asthma, this was related to an increase in mast cell numbers within the airway smooth muscle area (r=0.73; p=0.03), and in CD4+ lymphocytes in the lamina propria (r=0.61; p=0.04). CONCLUSIONS: Inflammation in the airway smooth muscle bundles and submucosa of bronchial biopsies is positively associated with impaired airway mechanics during deep inspiration in asthma, but not in COPD. Clinical trial registered with www.clinicaltrials.gov (NCT OO279136).     

Consequences of long-term inflammation. Airway remodeling

Airway inflammation may not account for all the clinical manifestations of asthma. Airway remodeling, which is thought to be a result of airway chronic inflammation, may help fill this void. Remodeling is described for fatal and nonfatal asthmatics including changes in smooth muscle, collagen deposition, noncollagenous matrix, and mucus glands. This article also reviews the correlation of airway remodeling with clinical, physiologic and biologic data, experimental models of airways remodeling, and effect of therapy on airway remodeling. Throughout, it is emphasized that the concept of airway remodeling is a dynamic process that is active and potentially progressive in asthmatic patients but that may be prevented by appropriate therapy.