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.     

Effect of inhaled corticosteroids on small airways in asthma: Investigation using impulse oscillometry

BackgroundSmall airways appear to have an important role in asthma. Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) has ultrafine particles and accordingly greater deposition in the small airways than chlorofluorocarbon (CFC)-BDP. Impulse oscillometry systems (IOS), a new and non-invasive measure of pulmonary function, can examine the resistance of total (R5), large (R20), and small airways (R5–R20) separately, and low-frequency reactance area (AX), also considered a measure of small airways dysfunction.MethodsMild-to-moderate asthmatics who were inhaled corticosteroid naïve were randomized to receive 200 mcg HFA-BDP bid (n = 26) or 400 mcg CFC-BDP bid (n = 12) for 12 weeks in an open-label manner. Following baseline measurements, IOS and spirometry were repeated every 4 weeks, and methacholine challenge to separately assess airway sensitivity and airway reactivity and lung volumes at 12 weeks.ResultsModerate correlations were found between R5–R20 or AX and spirometry and lung volume indices of small airways, and between R20 and peak expiratory flow at baseline. The two groups did not significantly differ in baseline clinical or functional parameters. At 12 weeks, all IOS indices improved in the HFA-BDP group, whereas all but R5–R20 improved with CFC-BDP. R5–R20 and AX progressively improved with HFA-BDP; these changes achieved statistical significance at 12 weeks versus the CFC-BDP group. Other IOS and spirometry indices failed to show such trends. HFA-BDP significantly attenuated methacholine airway sensitivity; the degree of this attenuation strongly correlated with R5–R20 and AX baseline values, and with improvement of AX with treatment.ConclusionHFA-BDP is an effective treatment of small airways in asthma. Prolonged treatment provides a progressive effect over time, which is associated with an attenuation of airway responsiveness.     

Bronchial thermoplasty failure in severe persistent asthma: a case report

Abstract

Introduction: Bronchial thermoplasty (BT) is an emerging therapy for patients with severe persistent asthma who remain poorly controlled despite standard maximal medical therapy. Thermoplasty elicits asthma control over time by applying thermal radiofrequency energy to airways to ablate underlying smooth muscle. While this therapy is suggested to eliminate such smooth muscle permanently, no human studies have examined the possibility of treatment failure. Case report: We present a 62-year-old female with severe, refractory asthma symptoms who underwent BT without apparent complications. However, severe symptoms including multiple clinical exacerbations persisted despite BT treatment. Repeat endobronchial biopsy done six months after BT treatment demonstrated persistent smooth muscle hyperplasia in multiple airways that previously had been treated. The patient continued to have uncontrolled, refractory asthma despite multiple therapies. Conclusion: This case is the first to describe a failure of BT to reduce or eliminate airway smooth muscle in a patient with severe persistent asthma. It suggests the potential for treatment failure in the management of these patients after BT and highlights the need for further study of potential BT-refractory patients.     

Effect of Bronchial Thermoplasty on Air Trapping Assessed by Xenon Ventilation Computed Tomography

Objective Bronchial thermoplasty (BT) is a bronchoscopic procedure for patients with severe asthma. Although it has been suggested that BT works by reducing airway smooth muscle, the detailed mechanism underlying its effects is still unknown. Methods We performed xenon ventilation computed tomography (Xe-CT) before each BT procedure and six weeks after the third treatment to assess the improvement in lung ventilation at each separate lung region. The air trapping index in each lobe was defined as the mean trapping value (0: none, 1: mild, 2: moderate, and 3: severe) of the included segments. Patients and Materials Four patients were included. Results Asthma symptoms were improved after BT. The comparison of the scores at baseline with those after the third treatment showed that the air trapping index was improved in both the treated and untreated regions. However, neither the pulmonary function nor the exhaled nitric oxide was improved. Conclusion Using Xe-CT, we successfully evaluated the air trapping in patients who underwent BT. The improvement in asthma symptoms by BT may be related to the amelioration of peripheral lung ventilation in both the treated and untreated regions.     

Comparison of the effects of budesonide/formoterol maintenance and reliever therapy with fluticasone/salmeterol fixed-dose treatment on airway inflammation and small airway impairment in patients who need to step-up from inhaled corticosteroid monotherapy

BackgroundIf asthma patients fail to achieve symptom control using a medium dose of inhaled corticosteroid (ICS) alone, adding a long-acting β₂ agonist (LABA) is the preferred treatment. We aimed to compare the effect of two widely available ICS/LABA combinations in these patients in real-life conditions: budesonide/formoterol (BUD/FM; Symbicort^®) for maintenance and reliever therapy (SMART) and a fixed dose of fluticasone propionate/salmeterol (FP/SM).MethodsInadequately controlled asthma patients treated with a medium dose of ICS alone, with an Asthma Control Questionnaire (ACQ) score >0.75 and using a short-acting β₂-agonist (SABA) 2–6 occasions/week, were enrolled. Patients were randomized into two groups and treated with two inhalation twice-daily BUD/FM 160/4.5 μg plus as-needed BUD/FM (SMART group, n = 15) or one inhalation twice-daily FP/SM 250/50 μg plus as-needed procaterol (FP/SM group, n = 15) for 8 weeks.ResultsBoth groups showed significant improvement in airway inflammation, pulmonary functions and symptoms from baseline. The SMART group showed significant improvement in the fraction of nitric oxide, ACQ score, rescue medication use and small airway parameter R5–R20 measured by impulse oscillometry compared with the FP/SM group.ConclusionFor stepping up treatment from ICS alone to an ICS/LABA combination, SMART is preferable for controlling asthma symptoms by suppressing airway inflammation and improving small airway impairment compared with a fixed dose of FP/SM. It may be achieved by the property of BUD/FM itself and as-needed use, but the degree of each contribution must be investigated further.     

Bronchial thermoplasty for asthma

RATIONALE: Bronchial thermoplasty (BT) reduces the potential for smooth muscle-mediated bronchoconstriction by reducing the mass of smooth muscle in the walls of conducting airways. OBJECTIVES: This study was conducted to examine the safety and impact on lung function and airway responsiveness of BT over 2 yr. METHODS: The safety of BT was studied in 16 subjects with mild to moderate asthma. Baseline and 12-wk post-treatment measurements included spirometry, methacholine challenge, daily diary recordings of peak flow, symptoms, and medication usage. Subjects completed follow-up evaluations at 12 wk, 1 yr, and 2 yr. MEASUREMENTS AND MAIN RESULTS: The procedure was well tolerated; side effects were transient and typical of what is commonly observed after bronchoscopy. All subjects demonstrated improvement in airway responsiveness. The mean PC(20) increased by 2.37 +/- 1.72 (p < 0.001), 2.77 +/- 1.53 (p = 0.007), and 2.64 +/- 1.52 doublings (p < 0.001), at 12 wk, 1 yr, and 2 yr post-procedure, respectively. Data from daily diaries collected for 12 wk indicated significant improvements over baseline in symptom-free days (p = 0.015), morning peak flow (p = 0.01), and evening peak flow (p < or = 0.007). Spirometry measurements remained stable throughout the study period. CONCLUSIONS: BT is well tolerated in patients with asthma and results in decreased airway hyperresponsiveness that persists for at least 2 yr.     

Comparison of budesonide/formoterol Turbuhaler with fluticasone/salmeterol Diskus for treatment effects on small airway impairment and airway inflammation in patients with asthma

Background

A course of combination therapy with an inhaled corticosteroid (ICS) and a long-acting β₂ agonist (LABA) for asthma can improve lung function, asthma symptoms and reduce exacerbations. Because both medicinal substance and inhalation devices are associated with clinical efficacy, each ICS/LABA combination may have different features. This study aimed to compare the effects of two widely available formulations, budesonide/formoterol (BUD/FM) delivered by a Turbuhaler^®, and fluticasone/salmeterol (FP/SM) delivered by a Diskus^®, on small airway function and airway inflammation.

Methods

Asthmatic patients (n = 40) treated twice daily with FP/SM 250/50 μg with forced expiratory volume in 1 s values controlled above 80% of the predicted normal but with suspected persistent airway inflammation and small airway impairment were enrolled in the study. Patients were randomized into two groups, receiving either twice daily BUD/FM 320/9 μg or FP/SM 250/50 μg, and treatment efficacy was compared after 4 weeks. Outcomes included impulse oscillometry (IOS), fractional exhaled nitric oxide (FeNO), spirometry and Asthma Control Questionnaire (ACQ) scores.

Results

Patients in the BUD/FM group showed significant improvements in their IOS and spirometry parameters of small airway function, FeNO values and ACQ scores, compared with the FP/SM group. There were good correlations between IOS parameters, FeNO and ACQ score changes over the course of the treatment.

Conclusions

BUD/FM twice daily significantly improved small airway impairment and airway inflammation in asthmatic patients, leading to a reduction in asthma symptoms and achievement of good asthma control. In addition, improvement of small airway function may improve airway inflammation and/or lead to better controlled asthma.     

Forced Vital Capacity and Low Frequency Reactance Area Measurements Are Associated with Asthma Control and Exacerbations

Introduction

Forced vital capacity (FVC) is often preserved in severe asthma unless there is evidence of either airway remodelling or air trapping. Area under the reactance curve (AX) can be used to assess small airways dysfunction related lung stiffness and is related to disease control in severe asthma.

Methods

We explore if there may be a potential synergistic interaction between FVC and AX in terms of impaired asthma control as ACQ and exacerbations requiring oral corticosteroids (OCS). We pragmatically defined?<?100% and?≥?1.0 kPa/L/s as impaired FVC or AX, respectively.

Results

Patients with combined impairment of FVC and AX had significantly worse asthma control as higher ACQ, more severe exacerbations requiring OCS and worse spirometry (FEV₁ and FEF_25–75) than those with impaired FVC but preserved AX.

Conclusion

This in turn supports using both spirometry and oscillometry to characterise airway physiology more comprehensively in patients with more severe asthma.

     

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.     

Abstracts

Increase in Alveolar Nitric Oxide in the Presence of Symptoms in Childhood Asthma; Mahut, B., Delacourt, C., Zerah-Lancner, F., et al. Chest 2004; 125:1012–1018.

Background. Asthma is defined as an inflammation encompassing both the proximal and distal pulmonary airways. Exhaled nitric oxide is regarded as a non-invasive surrogate of airway inflammation. There is evidence of cellular inflammation in the very small airways and alveoli that result in an increase in nitric oxide (Q_no) output. There is documentation using bronchial alveolar lavage of cytokine expression, eosinophil presence, and nitric oxide synthetase expression in the distal airways. The authors hypothesized that increased nitric oxide output could result from distal airways and/or alveoli in asthmatic individuals.

Objective. The objective was to assess the contributions of alveolar and proximal airway compartments in exhaled nitric oxide (NO) output (Q_no) in children with asthma and to determine their correlation with mild symptoms of bronchial obstruction.

Methods. The subjects in this study included 15 children with asthma with recent onset of mild symptoms, 30 asymptomatic asthmatic children and 15 healthy children. The investigators measured exhaled nitric oxide concentration at multiple expiratory flow rates (V) allowing the determination of alveolar and proximal airway contributions in Q_no. Spirometric measurements and flow volume curves were obtained, as well.

Results. The asymptomatic and recently symptomatic individuals were not significantly different with regard to spirometry measurements. The maximal airway nitric oxide output was more elevated in recently symptomatic versus asymptomatic asthmatics, and in asymptomatic asthmatics versus healthy children. Variables that impacted airway nitric oxide output were symptoms and distal airway obstruction as assessed by MEF (25-75). The nitric oxide determination from the distal airways was significantly higher in individuals with MEF (25-75) less than 50% of predicted as compared with children whose MEF (25-75) was greater than 50% of predicted. Alveolar nitric oxide was significantly elevated in recently symptomatic children as compared with children who were asymptomatic, whereas it was not significantly different between asymptomatic and healthy children.

Conclusions. An increase in alveolar nitric oxide concentration was observed in correlation with increased symptoms of asthma and proximal airway nitric oxide was correlated with distal obstruction during asthma.

Reviewer's Comment. This is a useful prospective study, having healthy children as control subjects, which indicates the increased sensitivity and specificity of nitric oxide determination in the assessment of airway inflammation and correlating with the results of pulmonary function tests. It further extends our knowledge of airway inflammation to include the smallest airways and alveoli and indicates that even with mild or no symptoms, airway inflammation can be present distally as detected by nitric oxide, although it is not detected by conventional pulmonary function testing. It would be of interest to determine the correlation of nitric oxide with increasing levels of symptoms to provide parameters that might parallel the NHLBI Guidelines for mild, moderate, and severe asthma. Nitric oxide determination, particularly of the distal airway, may be useful as a marker of recent symptoms and of increasing loss of asthma control.

Christopher Randolph, M.D.

Waterbury, CT     

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.     

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.     

Reduction of eosinophils in small airways by inhaled steroids is insufficient in patients with adult asthma.

BACKGROUND: Recent reports suggest that small airway as well as large airway involvement in asthma is important. We investigate the therapeutic effects of a meter-dose inhaler of chrolofluorocarbon-beclomethasone dipropionate (CFC-BDP) and dry-powder fluticasone (DP-FP). METHODS: Lung specimens obtained at operation due for small size lung cancer in 16 asthmatic patients and 16 controls were evaluated immunohistochemically using antibodies of EG2 (eosinophil), AA1 (mast cell), CD68 (macrophage), and CD34 (pluripotent hematopoietic stem cell). We calculated the number of each cell type in 5 fields in the inner and outer areas of large airways (luminal diameter; > or =2 mm) and small airways (<2 mm) using computer software. RESULTS: In asthmatic patients eosinophils were significantly increased in both inner and outer areas of small airways and the number of CD34+ cells was significantly elevated in inner areas as compared with controls. Although the density of eosinophils in the inner area of large airways was significantly suppressed (p < 0.02), there was no such suppression in the inner areas of small airways in asthmatic patients treated with CFC-BDP or DP-FP. CONCLUSIONS: It was speculated that inhaled CFC-BDP and DP-FP might deposit mainly in large airways and fail to fully reach small airways, consequently allowing eosinophilic inflammation to continue in small airways.     

Substance P immunoreactive nerves in airways from asthmatics and nonasthmatics.

Substance P has been localized to nerves supplying smooth muscle, blood vessels and glands in the human lung and may play a major role in the pathophysiology of asthma. We performed a morphological study, using the avidin biotin peroxidase immunostaining technique, to examine sections of airway wall from subjects with and without asthma for the presence of substance P immunoreactive nerve fibres. Airways of 200 microns-12 mm were obtained from autopsy, lobectomy and bronchoscopy. Quantitative morphological analysis was performed on 3 mm diameter airways from three asthmatic and three nonasthmatic subjects collected at autopsy, and on biopsies of 10 mm diameter airways from eight asthmatic and thirteen nonasthematic subjects. There was an increase in both the number and the length of substance P immunoreactive nerve fibres, in airways from subjects with asthma when compared with airways from subjects without asthma. Fibres were found in the lamina propria and surrounding vessels and glands. The fibres were commonly seen as bundles rather than as single fibres. There was no difference in the number of substance P nerves between normal subjects and subjects with chronic airflow limitation (CAL). The difference in the number, length and morphological characteristics of the substance P immunoreactive nerves between asthmatic and nonasthmatic subjects were striking.     

A sensory neuronal ion channel essential for airway inflammation and hyperreactivity in asthma

Asthma is an inflammatory disorder caused by airway exposures to allergens and chemical irritants. Studies focusing on immune, smooth muscle, and airway epithelial function revealed many aspects of the disease mechanism of asthma. However, the limited efficacies of immune-directed therapies suggest the involvement of additional mechanisms in asthmatic airway inflammation. TRPA1 is an irritant-sensing ion channel expressed in airway chemosensory nerves. TRPA1-activating stimuli such as cigarette smoke, chlorine, aldehydes, and scents are among the most prevalent triggers of asthma. Endogenous TRPA1 agonists, including reactive oxygen species and lipid peroxidation products, are potent drivers of allergen-induced airway inflammation in asthma. Here, we examined the role of TRPA1 in allergic asthma in the murine ovalbumin model. Strikingly, genetic ablation of TRPA1 inhibited allergen-induced leukocyte infiltration in the airways, reduced cytokine and mucus production, and almost completely abolished airway hyperreactivity to contractile stimuli. This phenotype is recapitulated by treatment of wild-type mice with HC-030031, a TRPA1 antagonist. HC-030031, when administered during airway allergen challenge, inhibited eosinophil infiltration and prevented the development of airway hyperreactivity. Trpa1^−/− mice displayed deficiencies in chemically and allergen-induced neuropeptide release in the airways, providing a potential explanation for the impaired inflammatory response. Our data suggest that TRPA1 is a key integrator of interactions between the immune and nervous systems in the airways, driving asthmatic airway inflammation following inhaled allergen challenge. TRPA1 may represent a promising pharmacological target for the treatment of asthma and other allergic inflammatory conditions.     

Association of airway pentosidine levels with bronchodilator response mediated by salbutamol administration in asthmatic patients

BackgroundRecently, increased levels of pentosidine, an intermolecular cross-linking type of advanced glycation end products, are observed in the airways of asthmatic patients. This study was designed to determine whether differences in bronchodilator response among individuals with asthma are attributable to pentosidine levels in their airways.MethodsFifty-six asthmatic patients (21 with airway obstruction, 35 without airway obstruction) and 10 normal controls were included in this study. For asthmatic patients, we evaluated the spontaneous reversibility of airway obstruction or the reversibility that can be obtained after methacholine provocation. And we also measured pentosidine levels and percentage of sputum eosinophils in induced sputum, and exhaled nitric oxide (NO) levels.ResultsThe pentosidine levels did not significantly differ between the two asthmatic subgroups with and without airway obstruction. In asthmatic patients without airway obstruction, airway hyperresponsiveness to methacholine (PC20 methacholine) was significantly correlated with sputum eosinophils and exhaled NO levels. In contrast, PC20 methacholine was not significantly correlated with pentosidine levels. In asthmatic patients with or without airway obstruction, bronchodilator response was not significantly correlated with sputum eosinophils and exhaled NO levels. However, bronchodilator response was closely correlated with pentosidine levels (asthmatics without airway obstruction: r = ?0.54, p = 0.002; asthmatics with airway obstruction: r = ?0.48, p = 0.03).ConclusionsOur results showed that pentosidine might be a potential biomarker reflecting the reduced bronchodilator response in asthma. This study will provide new insights into the mechanisms underlying persistent airway obstruction.     

Association of Tumor Necrosis Factor-α and Neutrophilic Inflammation in Severe Asthma

BackgroundThere is evidence that neutrophils are increased in the airway of severe disease or acute exacerbations of asthma. The mechanisms by which neutrophils are recruited to the airways and contribute to the pathophysiology of asthma remain to be elucidated. Tumor necrosis factor (TNF-α), which can induce both tissue accumulation and activation of neutrophils and eosinophils, has been shown to be increased in the airways of severe asthma. The objective of this study is to evaluate whether TNF-α is associated with neutrophilic inflammation in asthma.MethodsFollowing an inhalation of hypertonic saline, induced sputum was obtained from 9 healthy controls, 9 mild persistent asthma patients who were treated with low-dose inhaled corticosteroids; and 7 severe persistent asthma patients who were treated with combinations of drugs including high-dose inhaled corticosteroids, oral prednisolone, bronchodilators, and leukotriene receptor antagonist. After 0.1% dithiothreitol (DTT) homog- enization, they were examined for total cell count, cellular differentiation, and the concentrations of TNF-α and myeloperoxidase (MPO).ResultsThe concentration of TNF-α was not correlated with neutrophils in healthy controls or mild asthma patients. In sputum from severe asthma patients, however, the concentration of TNF-α is significantly correlated with both the percentage of neutrophils and the concentration of MPO. The concentration of TNF-α is not correlated with the percentage of eosinophils in healthy controls, mild asthma patients, or severe asthma patients.ConclusionsTNF-α may be a contributing molecule for both accumulation and activation of neutrophils in the airways of severe asthma.     

The role of small airway inflammation in asthma.

Although inflammation in the large central airways has been the subject of numerous asthma studies, inflammation in the small distal airways remained largely unexamined because of the relative inaccessibility of these structures. However, fiberoptic bronchoscopy, combining endobronchial and transbronchial biopsy, now allows specimens to be obtained from both proximal and distal areas of the lung. Newly refined morphometric and immunocytochemical techniques have been applied to both autopsy and lung biopsy specimens. Together, these technological changes have had a profound impact on the study of small airway inflammation. Now, it is understood that the asthma-associated inflammation evident in the large airways occurs in the distal airways as well. The inflammatory process in the two regions has related features: infiltrates contain activated T lymphocytes and eosinophils, increased mucus plugging, and smooth muscle hyperplasia can be observed. Although the similarities are pronounced, inflammation in the small airways differs in important ways from large airway inflammation. The eosinophilic infiltration that occurs throughout the asthmatic lung also is active in the small airways. The contribution of small airway inflammation to deficits in pulmonary function has been clarified by thoracic high-resolution computed tomography imaging. Results of such imaging suggest that the distal airways are a major site of airway obstruction in patients with asthma and may play a significant role in airway hyperresponsiveness; both disorders are cardinal features of asthma. In addition, functional bronchoscopic studies of the small airways in asthma patients have found high peripheral airflow resistance, even when lung function appears normal. Current formulations of inhaled anti-inflammatory medications, particularly corticosteroids administered by metered dose inhalers using chlorofluorocarbon propellants, treat the proximal airways more effectively than the distal airways. However, some new formulations of inhaled steroids that utilize hydrofluoroalkane propellants produce aerosols of smaller average particle size, with greater penetration into the peripheral airways. Their potential to treat inflammation at peripheral sites may account for the significant improvements in asthma outcomes that have been reported in clinical trials of these new formulations.     

Control of airway caliber by autonomic nerves in asthma and in chronic obstructive pulmonary disease

Autonomic nerves can influence airway caliber via their effects on airway smooth muscle, bronchial vessels, and mucous glands and may therefore contribute to airway narrowing in asthma or in chronic obstructive pulmonary disease (COPD). Human lungs receive cholinergic, noradrenergic, and peptidergic efferents and several types of afferents. Cholinergic nerve activity contributes to airway narrowing both in asthma and in COPD. Reflex vagal activity may be enhanced because of epithelial damage and exposition of sensory nerve endings to nonspecific irritants. Other possible mechanisms include defects in prejunctional receptors that inhibit acetylcholine release, several postjunctional factors that nonspecifically enhance the effect of a given degree of cholinergic muscle contraction on airway caliber, and interactions between inflammatory mediators and the cholinergic system. The main direct bronchodilating nerve activity in human lungs is nonadrenergic, and scanty data suggest that nonadrenergic inhibitory nerve activity may be variably reduced in asthmatics. Human airway muscle virtually lacks adrenergic innervation, but adrenergic nerves may influence airway caliber by acting on bronchial vessels, mucous glands, and parasympathetic nerves and ganglia. The response of asthmatic airways to beta-agonists seems intrinsically normal, but it may be reduced during severe asthma attacks. There are no convincing data that abnormal adrenergic control is present in the airways of patients with COPD. The physiologic relevance of excitatory neuropeptides in sensory nerves in human airways is uncertain. Tachykinins have proinflammatory and spasmogenic properties and are therefore of potential interest as a factor in the pathogenesis of obstructive airway disease. In conclusion, the data presently available support an abnormal autonomic control of the airways in asthma but not in COPD.     

Reduced airway distensibility, fixed airflow limitation, and airway wall remodeling in asthma.

The airways of individuals with asthma are less distensible than normal and it has been assumed that this may be due to airway remodeling associated with chronic inflammation, although there are currently no available data directly relating these two aspects of asthma. We have therefore carried out a study of the relationship between airway distensibility (DeltaVD) and subepithelial reticular basement membrane (RBM) thickening as an index of airway remodeling, in a group of patients with relatively mild but symptomatic asthma. Our methods included a cross-sectional study of DeltaVD in patients with mild to moderate atopic asthma, with matched airway biopsy for structural components. We confirmed that DeltaVD was lower in patients with asthma than in normal individuals (19.8 +/- 1.1 versus 24.1 +/- 1.5; p < 0.05) and that RBM thickness was increased in patients with asthma (9.1 +/- 2.2 versus 7.7 +/- 1.2 microm; p < 0.01). There was a negative correlation between DeltaVD and RBM thickness in asthma (r = -0.37, p = 0.03) and positive correlations between percent predicted postbronchodilator large and small airway function (for percent predicted FEV(1 )versus DeltaVD, r = 0.59, p < 0.001). We conclude that, cross-sectionally, DeltaVD was related to airway remodeling (RBM thickening) and airflow limitation (percent predicted large and small airway function). Our findings support the hypothesis that DeltaVD is a physiologic test that is reflective of airway remodeling.