(Chest. 2003;123:348S-355S.)
© 2003
American College of Chest Physicians
Contribution of the Distal Lung to the Pathologic and Physiologic Changes in Asthma*
Potential Therapeutic Target Roger S. Mitchell Lecture
Meri K. Tuli
, PhD and
Qutayba Hamid, MD
* From the Meakins-Christie Laboratories, McGill University, Montreal, PQ, Canada.
Correspondence to: Qutayba Hamid, MD, PhD, Professor of Medicine, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain St, Montreal, PQ, Canada H2X 2P2; e-mail: qutayba.hamid{at}mcgill.ca
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Abstract
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Pathologic and physiologic evidence has emerged in the last few years suggesting that the airway inflammation and remodeling that characterize asthma occur not only in the central airways but extend to the distal lung and the lung parenchyma. The distal airways are capable of producing T helper (Th) type 2 cytokines and chemokines, and, more recently, they have been recognized as a predominant site of airflow obstruction in asthmatic patients. In the lung parenchyma, a similar Th2 cytokine profile and infiltration of inflammatory cells also has been reported. The inflammation at this distal site has been described as being more severe when compared to the large amount of airway inflammation, and evidence of remodeling in the lung periphery is emerging. The recognition of asthma as a disease of the entire respiratory tract has an important clinical significance highlighting the need to also consider the distal lung as a target in any therapeutic strategy for effective treatment of this disease.
Key Words: allergic inflammation • asthma • distal airways • small airways
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Introduction
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Asthma is a chronic inflammatory disease that is characterized by episodic airway obstruction and increased bronchial responsiveness. The major pathologic and structural features of asthma include epithelial shedding, airway smooth muscle hypertrophy and hyperplasia, mucous gland hyperplasia, subepithelial fibrosis, and infiltration of the bronchial wall with inflammatory cells. The concept that inflammation is a major component of asthmatic pathology was established > 100 years ago. These studies have used autopsy specimens to study the macroscopic, morphologic, and histologic changes within the large asthmatic airways. That the distal airways and the lung parenchyma play a role in asthma has been suggested by experiments in which the physiologic behavior of the lung has been investigated. These early studies conducted from the Meakins-Christie laboratories1
2
focused attention on the role of the distal airways in asthma; however, investigation in this area lagged because of the difficulties in examining these peripheral structures directly. Since then, the development of new techniques with which to measure lung physiology has demonstrated the distal site to be recognized as a predominant site of airflow obstruction in asthmatic patients.3
4
5
6
The introduction of fiberoptic bronchoscopy techniques has enabled us to obtain small human endobronchial biopsy specimens from the large airways of asthmatic patients and, together with the recent applications of molecular pathology techniques, to advance our understanding of the pathogenesis of bronchial asthma. Studies utilizing these approaches in surgically resected lung tissue,7
8
postmortem lung specimens,9
10
11
12
and transbronchial biopsy specimens13
14
have demonstrated that similar but more severe inflammatory and structural changes also occur in the distal lung and lung parenchyma of asthmatic patients. It is now accepted that in asthmatic patients, the recruitment of inflammatory cells, in particular eosinophils and T cells, also occurs in the distal lung7
8
and the lung parenchyma.13
In asthmatic patients there is also an abundance of T helper type 2 cytokines present at this distal site.8
These pathologic findings may prove to be extremely important as the total volume and the combined surface area of the distal airways are much greater than the combined volume and surface area of the large airways. These data suggest that any changes developing in the distal lung and the parenchyma in patients with asthma will have a dramatic effect on the pathogenesis and treatment of this disease. Currently, the therapeutic challenge is to develop better inhalation technologies to improve the delivery of antiinflammatory agents to the distal lung. This may have been a neglected site of treatment in asthmatic patients in the past. This study aimed to evaluate the pathologic and the physiologic evidence presented in the literature to date outlining the contribution of the distal lung to asthma pathophysiology. We will also explore some of the new technologies of drug delivery, the efficacy and safety of these new formulations for asthmatic patients, and address the pertinent questions that remain to be answered regarding the distal airways and the future directions in treatment of this disabling disease.
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Pathologic Evidence
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Asthma is characterized by inflammatory cell infiltration into the airways and an up-regulation of T helper type 2 cytokines. The majority of these observations have been made from studies that sampled central airways, as bronchoscopic sampling was largely limited to proximal airway sites only. For this reason, the pathologic process that occurs in the distal airways has been less well-defined. The early studies looking at the role of the distal airways in the pathophysiology of asthma originated from autopsy studies9
11
and have demonstrated that the entire length of the airway is involved in asthma, not only the central airways as originally was proposed. Carroll and colleagues9
have examined the distribution of inflammatory cells throughout the bronchial trees of patients who experienced both fatal and nonfatal asthma and have shown increased numbers of lymphocytes and eosinophils to be uniformly distributed throughout the large and distal airways of asthmatic patients with mild and severe disease when compared to those in control subjects.
Similarly, we have demonstrated,7
using resected lung specimens from asthmatic and nonasthmatic patients, that the inflammatory response in asthma is not restricted to the proximal airways. We reported increased numbers of T cells (CD3+ cells), total eosinophils (MBP+ cells), and activated eosinophils (EG2+ cells) in both the large and distal airways of asthmatic patients when compared to those in control subjects (Fig 1
). Comparing the large and distal airways directly, a greater number of activated eosinophils (EG2+) was seen in airways of < 2 mm internal diameter (Fig 1)
, suggesting that a similar but more severe inflammatory process is present in the distal airways.15
In these patients, we have also shown increased numbers of interleukin (IL)-5 and IL-4 messenger RNA-positive cells in the distal airways of asthmatic subjects compared to those in nonasthmatic control subjects, and, more importantly, the expression of IL-5 messenger RNA was increased in the distal airways compared with the large airways (Fig 2
).8
Using simultaneous in situ hybridization and immunocytochemistry, we were able to demonstrate that 85% of the IL-5 messenger RNA-positive cells in the distal airways were CD3+ T cells, similar to the proportion found in the large airways.8
The increased expression of eotaxin and monocyte chemotactic protein-4 messenger RNA also has been reported to be present in the epithelial cells layer and in the airway wall of the distal airways of asthmatic patients compared to that in nonasthmatic control subjects.16
In that study, the number of chemokine-positive cells in the distal airways correlated with the number of MBP+ eosinophils at the same site.16
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Figure 1.. Identification of T cells (CD3), total eosinophils (MBP), activated eosinophils (EG2), and mast cells (tryptase) in airways that are < 2 mm in diameter (top) and in airways that are > 2 mm in diameter (bottom) from patients with asthma using immunocytochemistry. The results are given as the average data of 6 airways (< 2 mm) or 10 airways (> 2 mm) from 4 to 6 asthmatic patients and of 13 airways (< 2 mm) or 31 airways (> 2 mm) airways from 6 to 10 control subjects. * = p < 0.05 vs nonasthmatic subjects; ** = p < 0.001 vs nonasthmatic subjects; Pi = internal perimeter of the airways. Adapted from Hamid and colleagues.7
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In patients who died of asthma, inflammation extends beyond the airway smooth muscle and is still significant around the pulmonary arterioles. Kraft and colleagues13
have shown alveolar inflammation in patients with nocturnal asthma (NA), which is not the case in those with non-NA (NNA). Patients with NA had increased numbers of eosinophils per lung volume in their lung parenchyma at 4:00 AM compared to patients without NA, and the NA patients had a greater number of eosinophils and macrophages in their alveolar tissue at 4:00 AM than at 4:00 PM. In addition, in NA patients, only alveolar (and not central airway) eosinophilia correlated with an overnight reduction in lung function.13
Those same investigators14
have shown increased numbers of CD4+ cells in the alveolar tissue of NA patients at 4:00 AM compared to those found in NNA patients. Although the number of CD4+ cells in the endobronchial lamina propria was higher than that in the alveolar tissue, once again, only the alveolar tissue CD4+ lymphocytes correlated with the predicted lung function (ie, FEV1) at 4:00 AM (r = -0.68) and with the number of activated alveolar eosinophils (r = 0.66).14
In this same patient cohort, NA was associated with reduced glucocorticoid receptor (GR)-binding affinity, reduced proliferation of blood mononuclear cells, and decreased responsiveness to steroids at 4:00 AM compared to those in NNA patients.17
Those studies have proposed that the increased numbers of CD4+ cells in the alveolar tissue of NA patients, the reduced GR-binding affinity, and the reduced steroid responsiveness may be responsible for orchestrating eosinophil influx and exacerbations of symptoms in patients with NA. One of the mechanisms that may be responsible for this phenomenon is an up-regulation of GRß, which has been reported previously12
in the peripheral airways of steroid-insensitive subjects with severe asthma. The main cells expressing GRß were CD3+ T lymphocytes and, to a lesser extent, eosinophils, neutrophils, and macrophages.12
Those results suggested that the increased number of GRß-positive cells in the distal airways of patients with fatal asthma may be associated with steroid resistance, contributing to asthma mortality.
Similar distal airway inflammation has been reported in symptomatic, steroid-dependent asthmatic patients with severe disease. Using endobronchial and transbronchial biopsies, Wenzel and colleagues18
reported persistent proximal and distal airway inflammation. Although the number of eosinophils was similar between severe asthmatic patients and healthy control subjects, asthmatic patients with severe disease had high numbers and percentages of neutrophils in their BAL fluid, and endobronchial and transbronchial biopsy specimens when compared with asthmatic patients with mild-to-moderate disease, despite their receiving aggressive treatment with steroids.18
It has been speculated that the inflammatory cell density in the distal airways in patients with severe asthma may relate to the peripheral airway obstruction that is characteristic of this disease. The distal airway inflammation may cause an uncoupling of the parenchyma and airways due to the mechanical interdependence between these two compartments, leading to changes in the overall lung mechanics in asthmatic patients. These results have therapeutic as well as diagnostic implications.
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Physiologic Evidence
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Most of our knowledge of lung function in asthmatic patients comes from spirometric and plethysmographic measurements made during bronchoprovocation, and these are dominated by large airway responsiveness. Since the volume and surface area of the lungs increases with increasing airway generations, the contribution of peripheral resistance to total lung resistance was originally thought to be minimal. Research conducted > 3 decades ago in animals,19
using a retrograde catheter technique, demonstrated the distal airways to be pathways of small resistance, contributing to < 10% of the total resistance to airflow in the lung models, and for this reason the distal airways were originally described as the "quiet zone" of the lungs. Since then, more sophisticated measurements of the peripheral airways have been developed. Invasive studies in mongrel dogs using alveolar capsules20
21
or the forced oscillation technique in rodents22
23
have demonstrated that both airway and parenchymal compartments contribute to airway hyperresponsiveness. Invasive studies4
also have been carried out in patients with asymptomatic asthma using a catheter-tipped micromanometer wedged into the lower lobe of the bronchus in order to partition central and peripheral airway resistance. In that study, the investigators showed a dose-dependent increase in both central and peripheral airway resistance in response to inhaled methacholine (MCh) in all patients studied.
The nature of airway wall remodeling has been reasonably well described in the large airways; however, relatively little is known about structural remodeling of the distal airways. Subepithelial fibrosis and thickening have been reported due to the excess deposition of collagen, laminin, fibronectin, and proteoglycans in the airway wall of asthmatic patients, and changes in these structural proteins have been positively correlated with airway responsiveness to MCh.24
In a modeling study, Wiggs and coworkers25
have shown that a moderate increase in distal airway wall thickness, which has little effect on baseline resistance, can profoundly affect the airway narrowing caused by airway smooth muscle shortening. The combination of peripheral airway wall thickening and a loss of lung recoil are additive in their effect on enhanced airway responsiveness. In patients with chronic obstructive lung disease, distal airway resistance has been shown to contribute to 50 to 90% of total lung resistance.26
In that study, the investigators concluded that the contribution of the distal airways to total lung resistance has been, thus far, grossly underestimated and that the physiologic outcome is largely dependent on the frequency used to measure the peripheral lung mechanics. They26
argued that the reason for this is because with high-frequency, low-amplitude oscillations the contribution of the distal airways to total lung resistance is minimized, whereas with low-frequency, high-amplitude oscillations their contribution is maximized.
More recently, peripheral airways have been recognized as a predominant site of airflow obstruction in asthmatic patients.3
6
In partitioning the central and peripheral airway resistance in awake humans, Yanai and colleagues3
demonstrated a dramatically increased contribution of the distal airways to total lung resistance in patients with moderate-to-severe asthma when compared to healthy subjects or to patients with mild asthma (Fig 3
). Furthermore, Wagner and colleagues27
have shown that in asthmatic patients with mild disease who have normal spirometry findings, distal airway resistance was increased up to sevenfold when compared to that in control subjects and that these measurements correlated with responsiveness to MCh. Computational analyses25
based on quantitative histology have shown that the peripheral airways account for the majority of airway hyperresponsiveness among asthmatic patients. Noninvasive methodologies for separating airway and parenchymal mechanics recently have been developed using the low-frequency forced oscillation technique in animals and in humans. With this technique, Hall and colleagues28
demonstrated that inhaled MCh altered both the central and peripheral airway mechanics in infants. They have shown that infants with a history of wheeze have significantly increased responses to MCh in their peripheral airways and parenchyma compared to those in healthy control subjects,28
further consolidating the important contribution of the distal airways to total lung responsiveness in vivo.
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Figure 3.. Contribution of distal airway resistance to total lung resistance in healthy subjects (5 subjects), in patients with mild asthma (10 patients), and in patients with moderate-to-severe asthma (10 patients), showing absolute values of total pulmonary resistance (black), central airway resistance (white), and distal airway resistance (gray) during expiration. The results are given as the mean ± SEM. * = p < 0.01 vs healthy subjects. Adapted from Yanai and colleagues.3
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The Distal Airways as a Therapeutic Target in Asthma
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The physiologic and pathologic evidence presented in this article unquestionably suggests that the distal airways and the lung parenchyma are clearly implicated in the pathogenesis of asthma. However, damage in the distal airways often goes undetected. What is unclear at the moment is whether therapy with inhaled corticosteroids, the mainstay of asthma treatment, effectively treats this compartment of the lung. Although therapy with inhaled corticosteroids reduces airway inflammation in asthmatic patients with mild-to-moderate disease, prolonged courses of inhaled steroids do not normalize hyperresponsiveness. Furthermore, it has been demonstrated in deposition studies29
that most of the currently used inhaled corticosteroids are predominantly deposited in the central airways and not in the lung periphery.
Metered-dose inhalers (MDIs), pressurized inhalers, or dry-powder inhalers are not very efficient in depositing medication in the more peripheral airways of the lung. These delivery systems typically deliver 
15% of the inhaled dose to the distal sites of the lungs,30
and for this reason the challenge for the pharmaceutical companies is to improve the technology of aerosol delivery systems to allow the delivery of drugs to the peripheral inflammatory sites as well as to the central inflammatory sites, thus enabling inflammation to be treated uniformly throughout the airways.
The improved lung deposition of steroids may be achieved by the modification of propellants to produce finer and slower moving aerosols. The latest development is the introduction of chlorinated fluorocarbon (CFC)-free hydrofluoroalkane (HFA) propellants, which exhibit improved airway targeting when compared to the CFC propellants.31
32
33
HFA formulations deliver extra-fine particles (only 1.1 µm in diameter), are deposited in both the central and distal airways, and produce equivalent control of the disease and improvement in lung function.32
Leach and colleagues31
have directly compared steroid airway targeting in asthmatic patients using a novel HFA MDI with a conventional CFC MDI. By radiolabeling beclomethasone dipropionate (BDP), they31
have been able to show that HFA propellant deposits 55 to 60% of BDP into the lungs and 29 to 30% into the oropharynx. However, using the CFC propellant only 4 to 7% of BDP was deposited in the lungs, and the remainder was deposited into the oropharynx.31
With the HFA-BDP formulation, these investigators31
demonstrated equivalent control of the disease at half the daily dose required for the CFC-BDP formulation. Similar lung deposition results have been reported by Busse and colleagues32
in asthmatic patients who had deterioration in asthma control after the discontinuation of therapy with inhaled corticosteroids. These investigators calculated that these patients would require 2.6 times as much of the CFC-BDP formulation to achieve the same improvement in lung function as that obtained with the HFA-BDP formulation.32
The primary concern with HFA formulations, however, is the safety of the inhaled steroids and their potentially adverse systemic effects in asthmatic patients. These safety concerns have been addressed in a number of studies. Lipworth34
reported that even up to the highest recommended maximum dose of HFA-BDP (ie, 800 µg/d) there appear to be no clinically relevant systemic side effects associated with the HFA-BDP formulation. Another study32
reported that > 96% of patients (347 patients) had plasma cortisol levels within the normal range following 12 weeks of therapy with HFA-delivered steroids. Furthermore, after 12 months of treatment with HFA-BDP, the patients’ morning plasma cortisol levels were similar to those of the group of patients treated with a CFC-BDP formulation, and in this study cohort < 1% of patients treated with HFA-delivered steroids had abnormal responses to cosyntropin stimulation.35
Thompson and colleagues36
have summarized the incidence of adverse events in five large, phase III clinical trials and have shown that the number of patients reporting at least one adverse event was significantly lower in patients treated with an HFA-BDP formulation than in those treated with a CFC-BDP formulation. These studies have provided reassurance that the increased deposition of steroids in the lungs with the new formulation does not adversely affect adrenal function or compromise the safety of the patient.
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Conclusion
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A large body of literature has suggested that airway inflammation occurs throughout the airway. Although the clinical significance of the distal airways and the lung parenchyma in asthma is not yet known, it is possible that poorly controlled inflammation in peripheral airways, which are not penetrated by conventional inhaled steroids, may contribute to accelerated decline in lung function and airway remodeling. We have learned a great deal about the peripheral airways with the help of new physiologic and biochemical technologies; however, there are many questions that still remain unanswered in this important area of research. There is a need to assess distal lung and parenchymal inflammation in all degrees of asthma. Critical questions to be answered are whether mild-to-moderate disease can be eliminated or reversed, and whether the situation is very different in asthmatic patients with mild disease compared to those with severe disease. The accurate detection and early diagnosis of distal airway dysfunction is important, as treatment during early stages of the disease may be able to effectively reverse airway remodeling and progression to airway fibrosis and irreversible airway damage in asthmatic patients with mild-to-moderate disease.
There is also a need to identify an accurate way to assess distal airway inflammation noninvasively. The introduction of high-resolution CT allows the assessment of morphologic changes in the distal airways that are associated with dysfunction that is too subtle to be identified with lung function testing alone. This novel, noninvasive imaging technique allows us to study the relationships among airway structure, function, and therapeutic efficacy, and may prove to be important not only in the diagnosis of distal airway inflammation, but also in helping us toward a better understanding of the role of the distal airways in the pathogenesis of allergic asthma. Another emerging technology is the laser capture microdissection. Laser capture microdissection is an easy, extremely fast, and versatile method for the isolation of morphologically defined cell populations from complex primary tissues for molecular analyses. With this sensitive technique, once the inflammatory cells or the area of interest in the distal airway and parenchyma have been isolated and captured with a laser, further studies such as DNA application, and reverse transcriptase and real-time polymerase chain reaction can be performed. Together, these novel tools offer great promise in unraveling some of the pertinent questions centering on the role of the distal lung in asthma. One of the most important questions is whether the improved delivery of corticosteroids to the central and peripheral airways is associated with added benefits to the patients and whether this results in clinically reduced inflammation. Importantly, further studies are needed using a larger number of adults and children with asthma of varying severity to assess the benefits and safety of targeting the distal lung and the parenchyma in the future treatment of asthma.
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Figure 2.. The expression of IL-4 messenger RNA and IL-5 messenger RNA in distal airways (ie, those < 2 mm in diameter) and large airways (ie, those < 2 mm in diameter) of asthmatic subjects and control subjects. For airways < 2 mm in diameter, the results are expressed as the mean of 10 airways from 4 asthmatic patients and the mean 14 airways from 10 control subjects. For airways > 2 mm in diameter, the results are expressed as the mean of 10 airways from 6 asthmatic patients and the mean of 10 airways from 10 control subjects. * = p < 0.05 vs control subjects. See legend of Figure 1
for abbreviations not used in the text. Adapted from Minshall and colleagues.8
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Acknowledgements
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We thank J.C. Hogg and M.W. Elliott for the supply of biopsy samples as well as R. Taha and E.M. Minshall who have performed distal airway studies in our laboratories.
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Footnotes
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Abbreviations: BDP = beclomethasone dipropionate; CFC = chlorofluorocarbon; GR = glucocorticoid receptor; HFA = hy-drofluoroalkane; IL = interleukin; MCh = methacholine; MDI = metered-dose inhalers; NA = nocturnal asthma; NNA = nonnoc-turnal asthma
The authors would like to acknowledge MRC Canada, GlaxoSmithKline and 3M Pharmaceuticals for their support. Dr. Tulic is a Ludwig-Engel Post-Doctoral Fellow, and Dr. Hamid is a recipient of the Senior Fonds de la Recherche en Santé du Quebec Chercheur-Boursier Award.
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References
|
|---|
- Despas, PJ, Leroux, M, Macklem, PT (1972) Site of airway obstruction in asthma as determined by measuring maximal expiratory flow breathing: air and helium oxygen mixture. J Clin Invest 51,3235-3243[ISI][Medline]
- Levine, G, Housley, E, MacLeod, P, et al Gas exchange abnormalities in mild bronchitis and asymptomatic asthma. N Engl J Med 1970;282,1277-1282[ISI][Medline]
- Yanai, M, Sekizawa, K, Ohrui, T, et al Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol 1992;72,1016-1023[Abstract/Free Full Text]
- Ohrui, T, Sekizawa, K, Yanai, M, et al Partitioning of pulmonary responses to inhaled methacholine in subjects with asymptomatic asthma. Am Rev Respir Dis 1992;146,1501-1505[Medline]
- Kuwano, K, Bosken, CH, Pare, PD, et al Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148,1220-1225[ISI][Medline]
- Wagner, EM, Bleecker, ER, Permutt, S, et al Direct assessment of small airways reactivity in human subjects. Am J Respir Crit Care Med 1998;157,447-452
- Hamid, Q, Song, Y, Kotsimbos, TC, et al Inflammation of small airways in asthma. J Allergy Clin Immunol 1997;100,44-51[CrossRef][ISI][Medline]
- Minshall, EM, Hogg, JC, Hamid, QA Cytokine mRNA expression in asthma is not restricted to the large airways. J Allergy Clin Immunol 1998;101,386-390[CrossRef][ISI][Medline]
- Carroll, N, Cooke, C, James, A The distribution of eosinophils and lymphocytes in the large and small airways of asthmatics. Eur Respir J 1997;10,292-300[Abstract]
- Carroll, N, Carello, S, Cooke, C, et al Airway structure and inflammatory cells in fatal attacks of asthma. Eur Respir J 1996;9,709-715[Abstract]
- Faul, JL, Tormey, VJ, Leonard, C, et al Lung immunopathology in cases of sudden asthma death. Eur Respir J 1997;10,301-307[Abstract]
- Christodoulopoulos, P, Leung, DY, Elliott, MW, et al Increased number of glucocorticoid receptor-beta-expressing cells in the airways in fatal asthma. J Allergy Clin Immunol 2000;106,479-484[CrossRef][ISI][Medline]
- Kraft, M, Djukanovic, R, Wilson, S, et al Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154,1505-1510[Abstract]
- Kraft, M, Martin, RJ, Wilson, S, et al Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999;159,228-234[Abstract/Free Full Text]
- Hamid, QA Peripheral inflammation is more important than central inflammation. Respir Med 1997;91,11-12
- Taha, RA, Minshall, EM, Miotto, D, et al Eotaxin and monocyte chemotactic protein-4 mRNA expression in small airways of asthmatic and nonasthmatic individuals. J Allergy Clin Immunol 1999;103,476-483[CrossRef][ISI][Medline]
- Kraft, M, Vianna, E, Martin, RJ, et al Nocturnal asthma is associated with reduced glucocorticoid receptor binding affinity and decreased steroid responsiveness at night. J Allergy Clin Immunol 1999;103,66-71[CrossRef][ISI][Medline]
- Wenzel, SE, Szefler, SJ, Leung, DY, et al Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156,737-743[Abstract/Free Full Text]
- Macklem, PT, Mead, J Resistance of central and peripheral airways measured by a retrograde catheter. J Appl Physiol 1967;22,395-401[Free Full Text]
- Sly, PD, Willet, KE, Kano, S, et al Pirenzepine blunts the pulmonary parenchymal response to inhaled methacholine. Pulm Pharmacol 1995;8,123-129[CrossRef][ISI][Medline]
- Ludwig, MS, Romero, PV, Bates, JH A comparison of the dose-response behavior of canine airways and parenchyma. J Appl Physiol 1989;67,1220-1225[Abstract/Free Full Text]
- Peták, F, Hantos, Z, Adamicza, Á, et al Methacholine-induced bronchoconstriction in rats: effects of intravenous vs. aerosol delivery. J Appl Physiol 1997;82,1479-1487[Abstract/Free Full Text]
- Tulic, MK, Wale, JL, Petak, F, et al Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats. Thorax 1999;54,531-537[Abstract/Free Full Text]
- Boulet, LP, Laviolette, M, Turcotte, H, et al Bronchial subepithelial fibrosis correlates with airway responsiveness to methacholine. Chest 1997;112,45-52[Abstract/Free Full Text]
- Wiggs, BR, Bosken, C, Pare, PD, et al A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1992;145,1251-1258[ISI][Medline]
- Van, Brabandt H, Cauberghs, M, Verbeken, E, et al Partitioning of pulmonary impedance in excised human and canine lungs. J Appl Physiol 1983;55,1733-1742[Abstract/Free Full Text]
- Wagner, EM, Liu, MC, Weinmann, GG, et al Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141,584-588[ISI][Medline]
- Hall, GL, Hantos, Z, Petak, F, et al Airway and respiratory tissue mechanics in normal infants. Am J Respir Crit Care Med 2000;162,1397-1402[Abstract/Free Full Text]
- Esmailpour, N, Hogger, P, Rabe, KF, et al Distribution of inhaled fluticasone propionate between human lung tissue and serum in vivo. Eur Respir J 1997;10,1496-1499[Abstract]
- Dolovich, MB, Rhem, R, Gerrard, L, et al Lung deposition of coarse CFC vs fine HFA pMDI aerosols of beclomethasone dipropionate (BDP) in asthma [abstract]. Am J Respir Crit Care Med 2000;161,A33
- Leach, CL, Davidson, PJ, Boudreau, RJ Improved airway targeting with the CFC-free HFA-beclomethasone metered-dose inhaler compared with CFC-beclomethasone. Eur Respir J 1998;12,1346-1353[Abstract]
- Busse, WW, Brazinsky, S, Jacobson, K, et al Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 1999;104,1215-1222[CrossRef][ISI][Medline]
- Vanden, Burgt JA, Busse, WW, Martin, RJ, et al Efficacy and safety overview of a new inhaled corticosteroid, QVAR (hydrofluoroalkane-beclomethasone extrafine inhalation aerosol), in asthma. J Allergy Clin Immunol 2000;106,1209-1226[CrossRef][Medline]
- Lipworth, BJ The comparative safety/efficacy ratio of HFA-BDP. Respir Med 2000;94(suppl),S21-S26
- Cohen, R, Fireman, P, Windom, H Long-term safety of beclomethasone dipropionate extrafine aerosol (HFA-BDP) [abstract]. Am J Respir Crit Care Med 1999;159,A631
- Thompson, PJ, Davies, RJ, Young, WF, et al Safety of hydrofluoroalkane-134a beclomethasone dipropionate extrafine aerosol. Respir Med 1998;92,33-39
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Abstract
Introduction
