Maximal Airway Narrowing Research Articles

Heterogeneity of airway wall dimensions in humans: a critical determinant of lung function in asthmatics and nonasthmatics.

Airway remodeling, a key feature of asthma, alters every layer of the airway wall but most strikingly the airway smooth muscle (ASM) layer. Airway remodeling in asthmatics contributes to fixed airflow obstruction and can amplify airway narrowing caused by ASM activation. Previous modeling studies have shown that the increase in ASM mass has the largest effect on increasing maximal airway narrowing. Simulated heterogeneity in the dimensions and properties of the airway wall can further amplify airway narrowing. Using measurements made on histological sections from donor lungs, we show for the first time that there is profound heterogeneity of ASM area and wall area in both nonasthmatics and asthmatics. Using a mathematical model, we found that this heterogeneity, together with changes in the mean values, contributes to an increased baseline resistance and elastance in asthmatics as well as a leftward shift in the responsiveness of the airways to a simulated agonist in both nonasthmatics and asthmatics. The ability of heterogeneous wall dimensions to shift the dose-response curve is largely due to an increased susceptibility for the small airways to close. This research confirms that heterogeneity of airway wall dimensions can contribute to exaggerated airway narrowing and provides an actual assessment of the magnitude of these effects.

Thoracic Oncology HERMES syllabus: setting the basis for thoracic oncology training in Europe

Background: The mechanism of exaggerated airway narrowing in asthma is unclear and there is little to no biological data on whether increased airway smooth muscle (ASM) increases narrowing capacity. Objective: Determine whether increased airway narrowing in asthma is related to increased ASM mass. Methods: Bronchial segments were acquired from subjects undergoing surgery, mostly to remove pulmonary neoplasms. Subjects reported doctor-diagnosed asthma (n=5) or had no history of asthma (n=8). In vitro airway narrowing in response to acetylcholine (3x10-6M to 3x10-3M) was assessed to determine maximal bronchoconstriction and sensitivity. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the ASM layer. Results: Airways from the asthma group had increased ASM (P=0.014), greater maximal airway narrowing (P=0.003) but no change in sensitivity. Maximal airway narrowing was positively correlated with the area of the ASM layer (r=0.58, P=0.039) but was not related to any other morphological parameter including inner and outer wall dimensions. Conclusions: Results suggest that greater ASM mass in asthma contributes to increased maximal airway narrowing in vivo. In contrast, properties of the ASM may not determine increased airway sensitivity.

Airway narrowing and bronchodilation to deep inspiration in bronchial segments from subjects with and without reported asthma

The present study presents preliminary findings on how structural/functional abnormalities of the airway wall relate to excessive airway narrowing and reduced bronchodilatory response to deep inspiration (DI) in subjects with a history of asthma. Bronchial segments were acquired from subjects undergoing surgery, mostly to remove pulmonary neoplasms. Subjects reported prior doctor-diagnosed asthma (n = 5) or had no history of asthma (n = 8). In vitro airway narrowing in response to acetylcholine was assessed to determine maximal bronchoconstriction and sensitivity, under static conditions and during simulated tidal and DI maneuvers. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the airway smooth muscle (ASM) layer. Airways from subjects with a history of asthma had increased ASM (P = 0.014), greater maximal airway narrowing under static conditions (P = 0.003), but no change in sensitivity. Maximal airway narrowing was positively correlated with the area of the ASM layer (r = 0.58, P = 0.039). In tidally oscillating airways, DI produced bronchodilation in airways from the control group (P = 0.0001) and the group with a history of asthma (P = 0.001). While bronchodilation to DI was reduced with increased airway narrowing (P = 0.02; r = -0.64)), when the level of airway narrowing was matched, there was no difference in magnitude of bronchodilation to DI between groups. Results suggest that greater ASM mass in asthma contributes to exaggerated airway narrowing in vivo. In comparison, the airway wall in asthma may have a normal response to mechanical stretch during DI. We propose that increased maximal airway narrowing and the reduced bronchodilatory response to DI in asthma are independent.

Long-term asthma remission during adolescence

Asthma is a heterogeneous disorder with a variable course, characterized by episodes of cough, wheezing and shortness of breath, reversible airflow limitation, and bronchial hyperresponsiveness (BHR). It begins early in life in many subjects, and it is well recognized that over 50% of asthmatic children go into long-term clinical remission, defined as the complete absence of asthmatic symptoms and no asthma medication for at least 24 months, during adolescence. Several studies have shown spirometric abnormalities and BHR during clinical remission. It is unknown whether these functional abnormalities, which are supposed to be indicative of asthma severity with respect to symptomatic asthma, reflect persistent airway inflammation or merely indicate residual airway damage or are related to another mechanism such as a familial predisposition. It is likely that the nature of BHR in asthma remission is not same as that in symptomatic asthma. We have shown that the former condition is associated with lower levels of blood eosinophils and eosinophilic cationic protein, a lower degree of bronchial responsiveness to exercise, and a more common formation of plateau on the dose-response curve to high-dose inhaled methacholine (i.e., limited maximal airway narrowing), compared to the latter condition. It is still controversial whether BHR in adolescents with asthma remission is reduced by inhaled corticosteroids. Better understanding of the mechanisms that lead to asthma remission, especially that seen during adolescence, is likely to lead to significant advances in our understanding of asthma pathogenesis, and should provide insights into how remission might be induced with therapy. We still have minimal understanding of the mechanism underlying BHR in adolescents with asthma remission. Elucidation of this mechanism would be an important step towards new perspectives that see remission as the next therapeutic frontier in asthma. (Allergy Asthma Respir Dis 1(1):11-19, 2013)

Counterpoint: Alterations in airway smooth muscle phenotype do not cause airway hyperresponsiveness in asthma

We have been assigned the task of showing that “alterations in airway smooth muscle phenotype DO NOT cause the airways hyperresponsiveness of asthma.” In the following paragraphs we will briefly review the overwhelming lack of evidence that any fundamental change in the intrinsic properties of

Therapeutic Effects of Mycobacterial Secretory Proteins Against Established Asthma in BALB/c Mice

PurposeLive/killed mycobacteria and culture supernatants can suppress asthmatic reactions. This study investigated whether mycobacterial secretory proteins have therapeutic effects on asthma.MethodsMycobacterium bovis bacille Calmette-Guérin (BCG; 2×105 CFUs) and mycobacterial secretory proteins (Ag85 complex, 38-kDa protein or MPB70; 4 or 20 µg) were administered intraperitoneally to female BALB/c mice with established airway hyperresponsiveness. One week after treatment, the mice underwent a methacholine challenge test, and then inflammatory cell numbers in bronchoalveolar lavage fluid (BAL) and around bronchi (<500 µm), and cytokine levels in splenocyte supernatants, were assessed.ResultsBCG and all of the tested secretory proteins significantly improved airway sensitivity compared to baseline values (P<0.05). The secretory protein Ag85 complex significantly suppressed airway reactivity also (P<0.05), while 38-kDa protein significantly suppressed reactivity and maximal narrowing (P<0.05). The number of eosinophils in BAL and around bronchi, and the goblet cell proportion, were also significantly reduced in mice in both the BCG and secretory protein groups compared to the asthma control group. IFN-γ/IL-5 ratios were significantly higher in mice treated with BCG, 4 µg MPB70 or 4 µg 38-kDa protein than in asthma control mice (P<0.05), and were negatively associated with airway hyperresponsiveness, peribronchial eosinophil numbers and goblet cell proportion (all P<0.05). IL-17A was positively correlated with IL-5 (r=0.379, P<0.001), maximal airway narrowing, peribronchial eosinophil numbers and goblet cell proportion (all P<0.05).ConclusionsSecretory proteins from BCG and M. tuberculosis and live BCG were effective against established asthma, their effects being accompanied by increased IFN-γ/IL-5 ratios. Thus, allergic asthma could be effectively treated with mycobacterial secretory proteins.

Rhinovirus infection in nonasthmatic subjects: effects on intrapulmonary airways.

The common cold is a highly prevalent, uncomplicated upper airway disease. However, rhinovirus (RV) infection can lead to exacerbation of asthma, with worsening in airway hyperresponsiveness and bronchial inflammation. The current authors questioned whether such involvement of the intrapulmonary airways is disease specific. Twelve nonatopic, healthy subjects (forced expiratory volume in one second (FEV1) >80% predicted, provocation concentration causing a 20% fall in FEV1 (PC20) >8 mg x mL(-1)) were experimentally infected with RV16. Next to PC20 and the maximal response to methacholine (MFEV1 and MV'40p), the numbers of mucosal inflammatory cells and epithelial intercellular adhesion molecule (ICAM)-1 expression in bronchial biopsies were assessed before and 6 days after RV16 inoculation. RV16 infection induced a small but consistent increase in maximal airway narrowing, without a change in PC20. There was a significant increase in bronchial epithelial ICAM-1 expression after RV16, whereas inflammatory cell counts did not change. Nevertheless, the change in the number of submucosal CD3+ cells was correlated with the change in MV'40p. In conclusion, rhinovirus infection in normal subjects induces a limited, but significant increase in maximal airway narrowing, which is associated with changes in bronchial T-cell numbers. Together with the upregulation of bronchial epithelial intercellular adhesion molecule-1, these findings indicate that, even in healthy subjects, rhinovirus infection affects the intrapulmonary airways.

Computational model of airway narrowing: mature vs. immature rabbit

Immature rabbits have greater maximal airway narrowing and greater maximal fold increases in airway resistance during bronchoconstriction than mature animals. We have previously demonstrated that excised immature rabbit lungs have more distensible airways, a lower shear modulus, and structural differences in the relative composition and thickness of anatomically similar airways. In the present study, we incorporated anatomic and physiological data for mature and immature rabbits into a computational model of airway narrowing. We then investigated the relative importance of maturational differences in these factors as determinants of the greater airway narrowing that occurs in the immature animal. The immature model demonstrated greater sensitivity to agonist, as well as a greater maximal fold increase in airway resistance. Exchanging values for airway compliance between the mature and immature models resulted in the mature model exhibiting a greater maximal airway response than the immature model. In contrast, exchanging the shear moduli or the composition of the airway wall relative to the airway size produced relatively small changes in airway reactivity. Our results strongly suggest that the mechanical properties of the airway, i.e., greater compliance of the immature airway, can be an important factor contributing to the greater airway narrowing of the immature animal.

Early phase bronchoconstriction in the mouse requires allergen-specific IgG.

Allergen provocation of allergic asthma patients is often characterized by an initial period of bronchoconstriction, or early phase reaction (EPR), that leads to maximal airway narrowing within 15-30 min, followed by a recovery period returning airway function to baseline within 1-2 h. In this study, we used a defined OVA provocation model and mice deficient for specific leukocyte populations to investigate the cellular/molecular origins of the EPR. OVA-sensitized/challenged wild-type (C57BL/6J) mice displayed an EPR following OVA provocation. However, this response was absent in gene knockout animals deficient of either B or T cells. Moreover, transfer of OVA-specific IgG, but not IgE, before the OVA provocation, was capable of inducing the EPR in both strains of lymphocyte-deficient mice. Interestingly, an EPR was also observed in sensitized/challenged mast cell-deficient mice following an OVA provocation. These data show that the EPR in the mouse is an immunologically based pathophysiological response that requires allergen-specific IgG but occurs independent of mast cell activities. Thus, in the mouse the initial period of bronchoconstriction following allergen exposure may involve neither mast cells nor IgE-mediated events.

Effect of apocynin on ozone-induced airway hyperresponsiveness to methacholine in asthmatics

Apocynin is an inhibitor of NADPH oxidase present in inflammatory cells such as eosinophils and neutrophils. We investigated the effect of inhaled apocynin on ozone-induced bronchial hyperresponsiveness in vivo. Seven mild atopic asthmatics participated in a placebo-controlled, cross-over study with two exposures to O 3 at 2-week intervals. Apocynin (3 ml of 0.5 mg/ml) was inhaled 2 times before and 6 times after O 3 exposure at hourly intervals. At 36 h before and 16 h after O 3 exposure, methacholine inhalation challenge tests (Mch) were performed, and PC 20 and maximal % fall from baseline (MFEV 1) were calculated from dose-response curves. O 3-induced change in PC 20 (ΔPC 20) after placebo treatment was −1.94 ± 0.39 DD (mean ± SEM doubling dose Mch) ( p = .001) and apocynin was −0.6 ± 0.33 DD ( p = .17). The difference between apocynin and placebo treatment was 1.3 DD ± 0.42 ( p = .02). O 3-induced ΔMFEV 1 was 11.9 ± 1.5% ( p = .008) during placebo inhalation and 3.85 ± 1.8% during apocynin ( p = .47). Apocynin reduced the ΔMFEV 1 by 8.05% compared to placebo ( p = .025). We conclude that apocynin markedly reduced O 3-induced hyperreactivity for Mch as well as maximal airway narrowing. The results suggest that apocynin may have a role in preventing ozone-induced exacerbations of asthma.

Molecular mechanisms of corticosteroids in allergic diseases.

Molecular mechanisms of corticosteroids in allergic diseases.

Gene knockout models of asthma.

Airway morphology in asthma is characterized not only by features of an acute allergic inflammation, but also by structural airway changes including subepithelial fibrosis or smooth muscle hypertrophy and/or hyperplasia (1). The key functional abnormality of asthma is the presence of nonspecific bronchial hyperresponsiveness (BHR). This is reflected by an increase both in sensitivity and reactivity of the airways (2, 3). Hypersensitivity is characterized by a leftward shift of the dose–response curve of a bronchoconstrictor agonist, whereas hyperreactivity is reflected in a steeper slope of the dose– response curve and increased maximal airway narrowing. These morphological and functional characteristics are not fully mimicked in the currently developed murine models of allergic airway inflammation. First, no “gold standard” lung function index has been invariably accepted in mice. The indices used include lung resistance, based on the principles described by Amdur and Mead, overflow of insufflation pressure as described by Konzett and Rossler, and sometimes expressed as the airway pressure over time index (APTI), or the enhanced pause (Penh) value (4–7). These various indices reflect to a variable and ill-defined degree changes in airway sensitivity and reactivity. In the vast majority of murine models, these two components of bronchial hyperresponsiveness are not specifically examined. In addition, the overall increase in airway responsiveness obtained in murine models is smaller than the difference in airway responsiveness that exists between healthy subjects and subjects with asthma. This presumably relates, at least in part, to the differences observed at a morphological level. In most of the murine models of allergen exposure, only acute inflammatory changes are induced, without any concomitant structural change that might affect responsiveness to a larger degree. The distribution of the inflammation is also different from that of human asthma. In animal models, the inflammatory changes not only concentrate in or around the airways, but frequently also include lung parenchymal, mainly perivascular, changes. A serious limitation of the currently available knockout models is that most of these consist of constitutional deletions, precluding the evaluation of the gene of interest in a specific phase of the disease process. As the technology further improves, the possibilities for conditional deletions increase, thus allowing investigators to time the switching off of the gene of interest (8–10). This will, for example, allow an evaluation in adult life of the role of gene products that are essential during the early stage of development. In addition, conditional deletions will also enable researchers to dissect the role of gene products specifically during the primary antigen sensitization, or during the secondary antigen exposure to memory cells. Finally, it must be borne in mind that important differences exist between different mouse strains, both in the functional role of components of the immune system and the baseline degree of airway responsiveness (11–14). Moreover, the sensitization and exposure procedures used in the different models also vary greatly. These different issues must be taken into account, not only when comparing results from different experiments, but especially when trying to extrapolate data from murine models to human asthma.

Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing.

Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated. We selected 31 mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5 levels were measured in the entire sputum supernatant. Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found. Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.

Immune mechanisms of smooth muscle hyperreactivity in asthma

Asthma is characterized by bronchial hyperresponsiveness to a variety of bronchospasmogenic stimuli. To study the pathophysiologic mechanisms underlying the increased sensitivity and degree of maximal airway narrowing, various in vivo and in vitro models have been developed with methods of active and passive sensitization. These studies indicated a major role for alterations in the smooth muscle itself rather than neural dysfunction or airway inflammation as the underlying cause for the development of bronchial hyperresponsiveness. During the last years smooth muscle cells were found to exhibit not only the “classical” contractile phenotype but also a proliferative-synthetic phenotype, which is capable of producing proinflammatory cytokines, chemotaxins, and growth factors. Allergic sensitization can alter both contractile and secretory functions, thereby indicating that the smooth muscle cell could contribute directly to the persistence of airway inflammation in asthma. A better understanding of the changes within the smooth muscle cells and of the mechanisms that lead to their induction could contribute to the development of novel therapeutic approaches for the treatment of asthma. (J Allergy Clin Immunol 2000;105:673-82.)

Airway smooth muscle in asthma. Perturbed equilibria of myosin binding.

The classic theory of airway lumen narrowing was developed to explain the determinants of airway narrowing, and why that narrowing can become excessive in asthma. The classic theory emphasizes that muscle length and airway caliber are set by a force balance in which the active force generated by airway smooth muscle statically is in mechanical equilibrium with the passive reaction force developed by the elastic load against which that muscle has shortened. Since both forces depend on muscle length, the muscle accommodates itself to the length at which these opposing forces come into static balance (1, 2). If the external load should change in time, as would occur with lung inflation, for example, then the activated muscle is believed to accommodate itself to a sequence of states lying along its static force–length characteristic (3–6). The isometric forcegenerating capacity of airway smooth muscle is set principally by muscle mass, muscle contractility, and muscle position on its static force–length characteristic (2, 7). Taken together, evidence available in the literature suggests that there is no systematic difference in force-generating capacity between muscle from the normal versus the asthmatic lung, although this evidence is equivocal (8, 9). Moreover, animal studies now suggest that the force-generating capacity of normal airway smooth muscle is, in any event, more than sufficient to close all airways in the lung (10, 11). The passive reaction force against which the muscle shortens is set principally by the elasticity and geometry of the airway wall, tethering of the airway to the lung parenchyma, and the state of lung inflation (5, 11, 12). Each of these factors, in turn, has its own determinants that are known to be modified with chronic airway inflammation (13, 14). This classic framework explained much of what needed to be explained, but our understanding of the causality linking airway inflammation to its ultimate mechanical consequence— excessive airway narrowing—remains fragmentary. For example, for reasons that remain poorly understood the plateau of the dose–response curve is elevated in asthma, or abolished altogether, suggesting that those factors that limit maximal airway narrowing in the normal lung, whatever they are, have somehow been attenuated in the asthmatic lung. And no less important than the mystery of the plateau is the perplexing role of deep inspirations (3, 15–18). Deep inspirations that are attendant to spontaneous breathing may be the most potent of all known bronchodilating agencies, and they comprise the first line of defense against bronchospasm. But in the spontaneous asthmatic attack this potent bronchodilating mechanism fails. Indeed, Fish and colleagues (16) suggested that it may be the failure of this very defense mechanism that is the most telling end effect of the inflammatory cascade and, therefore, the proximal cause of excessive airway narrowing in asthma. Moreover, there is ample evidence from the work of Ingram and colleagues (17–19) to show that, if anything, in an asthmatic attack deep inspirations only make matters worse. The inability of deep inspirations to relax airway smooth muscle during episodes of spontaneous asthmatic obstruction remains unexplained.

The Effect of Regular Salbutamol on Lung Function and Bronchial Responsiveness in Patients with Primary Ciliary Dyskinesia

There is growing evidence that regular beta(2)-agonist use in patients with asthma is associated with decreased airway caliber and increased bronchial responsiveness. The aim of this study was to determine whether regular treatment with beta(2)-agonists induces changes in lung function and bronchial responsiveness in patients with primary ciliary dyskinesia. A randomized, double-blind, placebo-controlled, crossover study. Nineteen children with primary ciliary dyskinesia. Subjects received inhaled salbutamol or identical placebo (2 x 100 microg qid) for periods of 6 weeks with a wash-out period of 4 weeks. FEV(1) was measured before and 3 weeks and 6 weeks after salbutamol or placebo treatment. High-dose methacholine inhalation tests were performed before and 6 weeks after each treatment. The provocative concentration of methacholine producing a 20% fall in FEV(1) (PC(20)) and maximal airway narrowing (MDeltaFFEV(1)) was measured. No significant change in FEV(1) was observed during the salbutamol or placebo periods. No significant differences in the parameters of bronchial responsiveness (PC(20) and MDeltaFFEV(1)) were noted as the result of either salbutamol or placebo treatment. Our data have shown that salbutamol, inhaled regularly for 6 weeks, did not cause either a decline in lung function or an increase in bronchial responsiveness in subjects with primary ciliary dyskinesia.

Relation between exhaled nitric oxide and bronchial reactivity during induced maximal airway narrowing in asthma

Relation between exhaled nitric oxide and bronchial reactivity during induced maximal airway narrowing in asthma

Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo.

Interaction between airway edema and lung inflation on responsiveness of individual airways in vivo. J. Appl. Physiol. 83(2): 366-370, 1997.-Inflammatory changes and airway wall thickening are suggested to cause increased airway responsiveness in patients with asthma. In five sheep, the dose-response relationships of individual airways were measured at different lung volumes to methacholine (MCh) before and after wall thickening caused by the inflammatory mediator bradykinin via the bronchial artery. At 4 cmH2O transpulmonary pressure (Ptp), 5 microg/ml MCh constricted the airways to a maximum of 18 +/- 3%. At 30 cmH2O Ptp, MCh resulted in less constriction (to 31 +/- 5%). Bradykinin increased airway wall area at 4 and 30 cmH2O Ptp (159 +/- 6 and 152 +/- 4%, respectively; P < 0.0001). At 4 cmH2O Ptp, bradykinin decreased airway luminal area (13 +/- 2%; P < 0.01), and the dose-response curve was significantly lower (P = 0.02). At 30 cmH2O, postbradykinin, the maximal airway narrowing was not significantly different (26 +/- 5%; P = 0.76). Bradykinin produced substantial airway wall thickening and slight potentiation of the MCh-induced airway constriction at low lung volume. At high lung volume, bradykinin increased wall thickness but had no effect on the MCh-induced airway constriction. We conclude that inflammatory fluid leakage in the airways cannot be a primary cause of airway hyperresponsiveness.

Protective effect of inhaled budesonide against unlimited airway narrowing to methacholine in atopic patients with asthma

Background: Patients with asthma who have moderate to severe airway hyperresponsiveness often demonstrate progressive, unlimited airway narrowing in response to inhaled bronchoconstrictor stimuli, which is likely to be due to inflammatory changes within the airway wall. It is unknown whether regular therapy with inhaled steroids can limit this excessive response. Objective: We investigated the effect of inhaled budesonide on the development of a plateau on the dose-response curve to methacholine in patients with asthma who did not show such a plateau before the study. Methods: Thirty-one atopic patients with asthma (age, 19 to 31 years; FEV 1 > 70% of predicted value; PC 20 < 8 mg/ml) with documented absence of a maximal-response plateau to methacholine on two occasions during the run-in period, participated in a double-blind, placebo-controlled, parallel study. Standardized methacholine challenges were performed at –1, 0, 4, 8, and 12 weeks of treatment with inhaled budesonide, 800 μg two times a day, or corresponding placebo, and after a 2-week washout period. Airway response was measured by FEV 1 (percent fall from baseline). A maximal-response plateau was considered if three or more consecutive data points fell within a 5% response range. Results: Thirty patients completed the study. There was a steady increase in the number of budesonide-treated patients exhibiting a maximal-response plateau on the dose-response curve from zero of 15 patients at run-in to nine of 14 patients at week 12, as compared with four of 16 patients in the placebo group ( p = 0.03, chi square test). This was accompanied by a significant improvement in PC 20 in the budesonide group as compared with the placebo group ( p < 0.01 at week 12), whereas the changes in FEV 1 were not significantly different between the groups ( p = 0.77 at week 12). Conclusion: Regular treatment with the inhaled corticosteroid budesonide limits maximal airway narrowing in response to methacholine by introducing a plateau on the dose-response curve in patients with asthma, who were initially characterized by the absence of a plateau. This indicates that inhaled steroids are likely to reduce the hazard of unlimited airway narrowing in asthma. (J Allergy Clin Immunol 1997;99:330–7.)

Relationship between loss in parenchymal elastic recoil pressure and maximal airway narrowing in subjects with alpha1-antitrypsin deficiency.

Airway hyperresponsiveness is characterized by an increase in sensitivity and excessive airway narrowing to inhaled bronchoconstrictor stimuli. There is experimental evidence that maximal airway narrowing is related to lung elasticity in normal and asthmatic subjects. We hypothesized that reduced lung elasticity by parenchymal destruction increases the level of maximal airway narrowing in subjects with alpha1-antitrypsin deficiency. To that end, we measured complete dose-response curves to methacholine, quasistatic pressure-volume (P-V) curves, diffusion capacity for carbon monoxide per unit lung volume (DLCO/VA), and mean lung density by spirometrically controlled computed tomography (CT) scan in eight non- or ex-smoking subjects with alpha1-antitrypsin deficiency. Methacholine dose-response curves were expressed as the provocative concentration causing 20% fall in FEV1 (PC20). A maximal response plateau was considered if > or = 3 highest doses fell within a 5% response range, the maximal response (MFEV1) being the average value on the plateau. The P-V curves were characterized by an index of compliance (exponent K), and elastic recoil pressures at 90, and 100% of TLC (PL90 and PLmax). In all subjects a complete dose-response curve to methacholine could be recorded. MFEV1 was significantly correlated with logPC20 (r = -0.94, p < 0.001), but not with baseline FEV1 (r = -0.53, p > 0.15). There was a significant relationship between MFEV1 and PL90 (r = -0.79, p < 0.02), PLmax (r = -0.87, p < 0.005), and K (r = 0.79, p < 0.02). Furthermore MFEV1 was significantly correlated with DLCO/VA (r = -0.76, p < 0.03) and with lung density (r = 0.78, p < 0.04). We conclude that in subjects with alpha1-antitrypsin deficiency the level of maximal airway narrowing increases with loss in lung elasticity, with reduction in diffusing capacity, and with lowered mean lung density. This suggests that loss in elastic recoil pressure secondary to parenchymal destruction contributes to excessive airway narrowing in humans in vivo.