Airway Structural Changes Research Articles

Airway remodelling in asthma: models and supermodels?

Although currently anti-inflammatory treatments are effective for most of the 5 million patients treated in the UK they do not completely control symptoms, and a minority of asthmatics continue to experience severe debilitating disease [1]. Of note, although inhaled corticosteroids reduce the Th2type eosinophilic airway inflammation and airway hyperresponsiveness (AHR) that characterize asthma, they do not restore either variable to normal [2]. For this reason attention has been focused on structural changes in the asthmatic airway termed airway remodelling. These changes include epithelial damage and goblet cell hyperplasia [3], increased airway smooth muscle [4] and recruitment and activation of myofibroblasts [5]. Increased deposition of collagens and other extracellular matrix proteins such as tenascin and fibronectin occurs both in the reticular basement membrane (RBM) [6] and throughout the bronchial mucosa and this structural remodelling is accompanied by new blood vessel formation [7]. The clinical consequences of airway remodelling in asthma remain uncertain but contributions to AHR and fixed airflow obstruction have been suggested. Mathematical modelling predicts that airways with increased smooth muscle narrow to a much greater extent than airways with less smooth muscle volume for a given degree of circumferential smooth muscle shortening [8]. Asthmatic subjects show accelerated decline in lung function over time compared with non-asthmatic subjects, and this loss of lung function is more marked in asthmatic smokers [9, 10]. Although duration and severity of asthma are the most important risk factors for development of fixed obstruction the highest rate of loss of lung function is seen during the early course of the illness. Interestingly, remodelling changes are seen early in childhood and may even pre-date the onset of symptoms [11]. The impact of current anti-inflammatory treatment on remodelling is controversial. Although partial reversal of remodelling has been reported with inhaled corticosteroid treatment, responses are seen after prolonged therapy [12] and are not confirmed in all studies. The initial rapid improvement in AHR in asthma with inhaled corticosteroid treatment may be explained by reduction in airway inflammation [13], but additional improvements over many months may reflect changes in remodelling. Important questions about airway remodelling in asthma remain unanswered (see Fig. 1). These include:

A critical role for eosinophils in allergic airways remodeling.

Features of chronic asthma include airway hyperresponsiveness, inflammatory infiltrates, and structural changes in the airways, termed remodeling. The contribution of eosinophils, cells associated with asthma and allergy, remains to be established. We show that in mice with a total ablation of the eosinophil lineage, increases in airway hyperresponsiveness and mucus secretion were similar to those observed in wild-type mice, but eosinophil-deficient mice were significantly protected from peribronchiolar collagen deposition and increases in airway smooth muscle. These data suggest that eosinophils contribute substantially to airway remodeling but are not obligatory for allergen-induced lung dysfunction, and support an important role for eosinophil-targeted therapies in chronic asthma.

The Effect of Upper Airway Structural Changes on Central Chemosensitivity in Obstructive Sleep Apnea-Hypopnea

The Effect of Upper Airway Structural Changes on Central Chemosensitivity in Obstructive Sleep Apnea-Hypopnea

The effect of upper airway structural changes on central chemosensitivity in obstructive sleep apnea-hypopnea.

We examined the efficiency of upper airway structural changes in uvulopalatopharyngoplasty and/or tonsillectomy on central chemosensitivity, and whether the outcome of such surgeries can be predicted by the central chemosensitivity in obstructive sleep apnea-hypopnea syndrome (OSAHS) patients. In 11 patients with OSAHS group, the average of the hypercapnic ventilatory response (HCVR) slope was 1.93 +/- 0.20 L/min/mm Hg preoperatively and 1.78 +/- 0.22 L/min/mm Hg postoperatively. The average of the mouth occlusion pressure at 0.1 second after the onset of inspiration (P (0.1)) slope was 0.47 +/- 0.06 cm H (2)O/mm Hg and 0.44 +/- 0.08 cm H (2)O/mm Hg, before and after surgery, respectively. There were no significant differences before and after treatment, although OSAHS was improved by these surgeries. In control group with 5 patients, the HCVR slope and P (0.1) slope also showed no significant difference before and after the procedure. When we divided the 11 OSAHS patients into 7 responders (apnea-hypopnea index < 20 events/h and > 50% reduction) and 4 poor responders, there was a significant difference between the average HCVR slope of responders (1.59 +/- 0.21 L/min/mm Hg) and that of poor responders (2.52 +/- 0.20 L/min/mm Hg). We saw no significant difference in physiologic (age, body mass index, one-piece tonsil weight), blood gas values, cephalometric, spirometric, or sleep parameters.

Airway Remodeling: A Comparison Between Fatal and Nonfatal Asthma

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

Ovalbumin-Induced Airway Inflammation and Fibrosis in Mice Also Exposed to Ultrafine Particles

A murine model of allergen-induced airway inflammation was used to examine the effects of exposure to ultrafine particles (PM2.5) on airway inflammation and remodeling. Lung inflammation was measured by quantitative differential evaluation of lung lavage cells. Alterations in lung structure (airway remodeling and fibrosis) were evaluated by quantitative biochemical analysis of microdissected airways and by histological evaluation of stained lung sections. The same total number of cells was observed in lavage fluid from animals exposed for 4 wk to ovalbumin alone or to ovalbumin for 4 wk immediately before or after 6 exposures over a period of 2 wk to 235 ug/m3 of PM2.5. Mice exposed to ovalbumin for 6 wk with concurrent exposure to PM2.5 during wk 5–6 had a significant decrease in the total number of cells recovered by lavage as compared with the group exposed to ovalbumin alone. There were no significant differences in the cell differential counts in the lavage fluid from mice exposed to ovalbumin alone as compared with values from mice exposed to ovalbumin and PM2.5 under the protocols studied. Airway structural changes (remodeling) were examined by three different quantitative methods. None of the groups exposed to ovalbumin and PM had a significant increase in airway collagen content evaluated biochemically (i.e., total airway collagen) as compared to the matched groups of mice exposed to ovalbumin alone. Airway collagen content evaluated histologically by sirius red staining showed significant increases in all of the animals exposed to ovalbumin, with or without PM, and no apparent difference between the ovalbumin group and mice exposed to PM with ovalbumin. The findings were consistent with an additive, or less than additive, response of mice to exposure to PM and ovalbumin. Air or PM exposure alone for 2 wk did not result in observable goblet cells in the airways, while mice exposed to ovalbumin aerosol alone for 4 wk had about 20–25% goblet cells in their conducting airways. Sequential exposure to ovalbumin and PM (or vice versa) caused significant increases in goblet cells (to about 35% of total cells) in the conducting airways of the exposed mice. We conclude that when mice with allergen-induced airway inflammation induced by ovalbumin are also exposed to PM2.5, the lung inflammatory response and airway remodeling may be modified, but that this altered response is dependent upon the sequence of exposure and the duration of exposure to ovalbumin aerosol. At the concentrations of PM tested, we did not see changes in airway fibrosis or airway reactivity for animals exposed to ovalbumin and PM2.5 as compared with animals exposed only to ovalbumin aerosol. However, goblet-cell hyperplasia was significantly increased in mice exposed concurrently to ovalbumin and PM2.5 as compared with mice exposed to ovalbumin alone.

Effects of chronic intermittent asphyxia on haematocrit, pulmonary arterial pressure and skeletal muscle structure in rats.

Sleep-disordered breathing in humans is a common condition associated with serious cardiovascular and other abnormalities. The prevalence and pathogenesis of increased haematocrit and pulmonary hypertension is controversial and it has been suggested that these changes only occur in patients who also have daytime continuous hypoxaemia. The hypothesis tested here is that the chronic intermittent hypoxia and asphyxia associated with sleep-disordered breathing causes erythropoiesis and pulmonary hypertension and that this occurs in the absence of periods of continuous hypoxia. In humans and animals with obstructive sleep apnoea, there are abnormalities of upper airway muscle structure that have been ascribed to increased load placed on these muscles. An alternative hypothesis is that chronic intermittent hypoxia and asphyxia cause changes in upper airway muscle structure and function. To test these hypotheses, rats were exposed to intermittent hypoxia and asphyxia for 8 h per day for 5 weeks. This caused an increase in haematocrit, right ventricular weight and pulmonary arterial pressure. There were only slight changes in diaphragm, upper airway and limb muscle structure and force production but in general, muscle fatigability was increased. In conclusion chronic intermittent hypoxia and asphyxia cause an increase in haematocrit and pulmonary arterial pressure in the absence of periods of continuous hypoxia. Chronic intermittent hypoxia and asphyxia have little effect on skeletal muscle structure and force production but increase muscle fatigue. Increased upper airway muscle fatigue could lead to a vicious cycle of further compromise in upper airway patency and further hypoxia and asphyxia.

Evaluation of airway wall thickness and air trapping by HRCT in asymptomatic asthma

The aim of this study was to examine the relationship between the structural changes in large and small airways in asymptomatic asthmatics quantified by high-resolution computed tomography (HRCT) and airflow obstruction. The bronchial wall thickness at the trunk of the apical bronchus (B1) of the right upper lobe was used for assessment of the large airways. Air trapping, evaluated by the ratio of the average CT-determined values for the bilateral upper and lower lung segments at full expiration to that at full inspiration (E/I ratio), was used for assessment of the small airways. Measurements were obtained with a helical HRCT in 24 asymptomatic asthmatics followed by optimal treatment with inhaled and/or oral corticosteroids for >6 months. Prior (20-30 min) to the HRCT examination, all patients were given an inhaled bronchodilator. The ratio of airway wall thickness to outer diameter (T/D) and the percentage wall area (WA%) at the B1 bronchus and the E/I ratio were significantly greater for the 14 asthmatics with deficient reversible airflow obstruction (forced expiratory volume in one second (FEV1) <80% prediced or FEV1/forced vital capacity <70% after bronchodilator inhalation) than for the 10 asthmatics with normal spirometry and seven normal subjects. T/D, WA%, and E/I ratio showed significant negative correlations with FEV1 % pred after bronchodilator inhalation. The E/I ratio also showed significant positive correlations with T/D, WA%, and residual volume/total lung capacity. These findings suggest that, in spite of optimal treatment, structural changes in both large and small airways may simultaneously occur in asthmatics with deficient reversible airflow obstruction.

Expression of matrix metalloproteinases MMP-9 within the airways in asthma

The matrix metalloproteinase (MMP) enzymes MMP-9, have relevance to chronic structural airway changes in asthma, which can be generated by structural and inflammatory cells, and have the ability to degrade proteoglycans and thus potentially enhance airway fibrosis and smooth muscle proliferation through their ability to release and activate latent, matrix-bound growth factors. Immunostaining for MMP-9 was undertaken in acetone-fixed and glycolmethacrylate-embedded endobronchial biopsy specimens obtained by fibreoptic bronchoscopy under local anaesthesia. The findings from 30 asthmatic subjects were compared with those from 18 chronic obstructive pulmonary disease (COPD) subjects and 10 healthy controls. Meanwhile, pulmonary function test and airway responsiveness were performed. Immunoreactivity for MMP-9 was assessed by an image analysis system. The biopsy specimens from asthmatic subjects contained significantly more eosinophils ( P<0·001) than those from COPD subjects, and healthy control did not contain eosinophils. MMP-9 immunoreactivity could be identified in endobronchial biopsy specimens from all the asthmatic subjects and 40% of the COPD subjects, but could not be identified in healthy controls. Gelatinase B (MMP-9) immunoreactivity was located in bronchial epithelium and extracellular matrix in submucosa, prominent in denuded epithelium. The immunohistochemical score for MMP-9 was significantly correlated with eosinophilic number in bronchial mucosa. FEV 1% predicted FEV 1/FVC (%) ( r = 0·52, 0·41, 0·37, respectively P<0·01), did not correlate with PD 20 FEV 1 from asthmatic subjects. MMP-9 is expressed by bronchial epithelium and may be a important factor for eosinophil infiltraed into airway from asthma subjects.

Physiopathology of airway hyperresponsiveness.

Airway hyperresponsiveness (AHR), the tendency of the airways to narrow too much and too easily in response to various stimuli, is a universal feature of asthma, although it is not exclusive to this disease. Airway responsiveness shows a unimodal distribution in the general population and might vary with time, increasing after exposure to allergens, industrial substances, or infectious agents in predisposed individuals, or decreasing for variable time periods after environmental or pharmacologic interventions. Airway inflammation and structural airway changes can lead to this heightened airway response, but the mechanisms by which they modify airway function are still unclear. They might be associated with increased contractile properties of the airways--from an increase in contractile elements, a change in smooth muscle mechanical properties, or a reduction of forces opposing bronchoconstriction, such as reduced airway-parenchymal interdependence. Other factors, such as neurohumoral influences and "geometric factors" (eg, airway caliber), can modulate the degree of AHR.

Clinical Assessment of Airway Function in Health and Disease

After completing this article, readers should be able to: 1. Describe which pulmonary function tests can be used to measure tidal lung mechanics and forces of expiratory flow. 2. Describe the airway conditions that can be assessed radiographically. 3. Delineate clinical methods of diagnosing central airway collapse and quantifying airway wall stiffness. Clinical assessment of pulmonary function is a valuable tool in the identification and treatment of neonatal disease. As shown in the Table⇓, a multitude of tests is available to identify and measure airway function clinically in pediatric populations. These tests often identify functional abnormalities in the airways of preterm infants exposed to mechanical ventilation, including elevated resistance, decreased forced expiratory flow, airway hyperreactivity, and excessive central airway collapsibility. In addition to aiding in diagnosis, these procedures help predict the effects of early injury on future airway growth and function and can be used to evaluate the effectiveness of newer therapies. Serial evaluation of airway function is especially useful for infants who fail to improve as expected; who have frequent severe exacerbations of pulmonary dysfunction; or who demonstrate stridor, chronic wheezing, or focal areas of chronic atelectasis or hyperinflation. View this table: Table Clinical Evaluation of Airway Function With the simultaneous measurement of respiratory pressures, volumes, and air flow, pulmonary mechanics can be monitored relatively noninvasively. Pulmonary function profiles can be determined to assess initial disease etiology, the response to therapy, and disease sequelae during follow-up. For example, the pressure-volume relationship of a preterm infant can identify the degree of respiratory function and monitor the response following surfactant administration (Fig. 1). The evaluation of tidal breath pressure-volume relationships serves as a tool to optimize the parameters of mechanical ventilation (Fig. 2). Over time, sequential pulmonary mechanics can be used to monitor the progression and improvement in both lung and airway abnormalities (Fig. 3). Dynamic …

Effect of age on allergen-induced structural airway changes in brown Norway rats.

It remains to be fully established whether allergen-induced airway inflammation and remodeling are influenced by age. The aim of the present study was to compare allergen-induced airway changes in young and adult rats. Brown Norway rats were sensitized at 4 weeks of age (young) or 13 weeks of age (adult) and exposed to aerosolized ovalbumin (OA) or phosphate-buffered saline for 2 weeks. In both age groups OA exposure induced an increase in OA-specific Immunoglobulin E and in the number of peribronchial eosinophils. OA-challenged animals also developed an increase in total airway wall area, enhanced fibronectin deposition, and goblet cell hyperplasia. Both inflammatory and structural alterations were more pronounced in the airways of young compared with adult OA-exposed rats. The number of peribronchial eosinophils was increased in young animals (685.4 +/- 75.0 versus 389.9 +/- 37.8/mm2 in adult rats; p < 0.001). A higher degree of goblet cell hyperplasia was observed in young rats (65.37 +/- 4.68 versus 34.74 +/- 3.68/mm basement membrane in adult rats; p < 0.001) and area of fibronectin deposition in the airway wall was higher in young compared with adult animals (5.08 +/- 0.46 versus 3.62 +/- 0.29 microm2/microm basement membrane; p < 0.005). In conclusion, in young rats airways are more susceptible to allergen-induced inflammatory and structural airway changes.

Autocrine regulation of asthmatic airway inflammation: role of airway smooth muscle

Chronic airway inflammation is one of the main features of asthma. Release of mediators from infiltrating inflammatory cells in the airway mucosa has been proposed to contribute directly or indirectly to changes in airway structure and function. The airway smooth muscle, which has been regarded as a contractile component of the airways responding to various mediators and neurotransmitters, has recently been recognised as a rich source of pro-inflammatory cytokines, chemokines and growth factors. In this review, we discuss the role of airway smooth muscle cells in the regulation and perpetuation of airway inflammation that contribute to the pathogenesis of asthma.

Anti-remodelling drugs for the treatment of asthma: requirement for animal models of airway wall remodelling.

1. Airway wall remodelling (AWR), the structural change induced by acute and chronic inflammation in the airways, may be one of the most significant and difficult to reverse components of progressive asthma. 2. The mechanisms underlying the development of AWR are not known. Studies of only the most superficial wall structures of large airways can be conducted in living humans because of the degree of invasiveness required to measure airway structural changes. These studies reveal that currently available agents do not fully prevent or reverse AWR. Thus, animal models of asthma pathology may be used to assess the contribution of particular mediators and cells to the development of remodelling and may also prove to be useful in the initial screening of potential anti-remodelling agents. 3. Airway hyperresponsiveness and AWR stimulated by chronic antigen challenge in previously disease-free animals is the most popular of the currently used models of remodelling. Other animal models include the use of specially bred strains with intrinsic airway hyperresponsiveness or animals that have a naturally occurring asthma-like disease, such as cats with feline asthma or horses with heaves. The further development of animal models of AWR will facilitate the development of novel anti-asthma therapies.

Fluticasone inhibits but does not reverse allergen-induced structural airway changes.

Ethical and technical reasons limit the possibility of evaluating the effects of inhaled corticosteroids on structural changes in airways of humans with asthma. We therefore evaluated whether fluticasone propionate (FP) modifies airway remodeling, induced by repeated allergen exposure in rats. Sensitized BN rats were exposed to aerosolized ovalbumin (OA) for 2 wk. To assess the effect of FP on the development of or on established airway remodeling, animals were treated with aerosolized FP or placebo during allergen exposure or for 2 wk afterward. Compared with animals exposed to phosphate-buffered saline (PBS), OA-challenged animals developed an increase in total airway wall area, enhanced fibronectin deposition, epithelial cell proliferation, goblet cell hyperplasia, and airway hyperresponsiveness. Concomitant treatment with FP decreased all allergen-induced structural changes without being able to reverse them to normal. Initiating FP treatment after the allergen exposure had no effect on any of the OA-induced structural airway changes. The increase in total airway wall area, enhanced fibronectin deposition, and epithelial cell proliferation persisted. The goblet cell hyperplasia disappeared spontaneously. In conclusion, concomitant treatment with FP partly inhibits structural airway changes as well as hyperresponsiveness induced by OA exposure. Post hoc treatment fails to reverse established airway remodeling.

Functional polymorphism in the gelatinase B gene and asthma.

AllergyVolume 55, Issue 9 p. 900-900 Functional polymorphism in the gelatinase B gene and asthma L. I. Hollá, L. I. Hollá Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this authorA. Vašků, A. Vašků Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this authorA. Stejskalová, A. Stejskalová Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this authorV. Znojil, V. Znojil Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this author L. I. Hollá, L. I. Hollá Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this authorA. Vašků, A. Vašků Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this authorA. Stejskalová, A. Stejskalová Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this authorV. Znojil, V. Znojil Institute of Pathological PhysiologyMedical Faculty, Masaryk UniversityKom. nám 2, CZ 662 43 BrnoCzech RepublicTel. +420 5 47121314Fax:+ 420 5 47121300E-mail: holla@med.muni.czSearch for more papers by this author First published: 05 April 2002 https://doi.org/10.1034/j.1398-9995.2000.00736.xCitations: 10Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume55, Issue9September 2000Pages 900-900 RelatedInformation

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.

The contribution of airway smooth muscle to airway narrowing and airway hyperresponsiveness in disease

Airway hyperresponsiveness (AHR), the exaggerated response to constrictor agonists in asthmatic subjects, is incompletely understood. Changes in either the quantity or properties of airway smooth muscle (ASM) are possible explanations for AHR. Morphometric analyses demonstrate structural changes in asthmatic airways, including subepithelial fibrosis, gland hyperplasia/hypertrophy, neovascularization and an increase in ASM mass. Mathematical modelling of airway narrowing suggests that, of all the changes in structure, the increase in ASM mass is the most probable cause of AHR. An increase in ASM mass in the large airways is more closely associated with a greater likelihood of dying from asthma than increases in ASM mass in other locations within the airway tree. ASM contraction is opposed by the elastic recoil of the lungs and airways, which appears to limit the degree of bronchoconstriction in vivo. The cyclical nature of tidal breathing applies stresses to the airway wall that enhance the bronchodilating influence of the lung tissues on the contracting ASM, in all probability by disrupting cross-bridges. However, the increase in ASM mass in asthma may overcome the limitation resulting from the impedances to ASM shortening imposed by the lung parenchyma and airway wall tissues. Additionally, ASM with the capacity to shorten rapidly may achieve shorter lengths and cause a greater degree of bronchoconstriction when stimulated to contract than slower ASM. Changes in ASM properties are induced by the process of sensitization and allergen-exposure such as enhancement of phospholipase C activity and inositol phosphate turnover, and increases in myosin light chain kinase activity. Whether changes in ASM mass or biochemical/biomechanical properties form the basis for asthma remains to be determined.

Prolonged allergen exposure induces structural airway changes in sensitized rats.

The pathogenesis and functional consequences of airway remodeling in asthma remain to be fully established. In the present study we evaluated the effect of prolonged allergen exposure on airway function and structure in rats. Sensitized Brown Norway rats were repeatedly exposed for periods of 2, 4, or 12 wk to aerosolized ovalbumin (OA) or phosphate-buffered saline (PBS). OA exposure induced a persistent increase in OA-specific serum IgE and in the number of peribronchial eosinophils. After 2 wk of OA exposure, airway histology revealed goblet-cell hyperplasia, an increase in bromodeoxyuridine-positive cells in airway epithelium, increased fibronectin deposition, and a thickening of the airway inner wall area. This coincided with airway hyperresponsiveness (AHR) to aerosolized carbachol. After OA exposure for 12 wk, increased fibronectin (p < 0.05 versus PBS) and collagen deposition (p < 0.05 versus PBS) were observed in the submucosa. After 12 wk of exposure, neither total nor inner wall area or airway responsiveness to carbachol were any longer significantly different from those of PBS-exposed animals. In conclusion, prolonged OA exposure in rats induces structural airway changes that bear similarities to airway remodeling in asthma. The study data further indicate that depending on the extent and distribution of remodeling, changes in the extracellular matrix can enhance or protect against AHR.

The distal airways: are they important in asthma?

Although the airways of <2 mm in diameter have been dubbed the "quiet zone", they do not appear to be so in asthma. Physiological and pathological evidence suggests that the small airways and lung parenchyma participate in asthma pathogenesis, and may explain many of the clinical observations noted. This review presents this evidence, beginning with physiological evidence, followed by pathology and last by imaging studies that evaluate the distal lung. Seminal physiological studies date back to the 1960s, with significant progress in the area of airway smooth muscle and its contribution to airways responsiveness noted over the last several years. The use of bronchoscopy in clinical studies has complemented the autopsy studies in advancing knowledge about airway structural changes appreciated in asthma in the small airways and lung parenchyma. These pathological studies have allowed validation of the physiological, and more recently the imaging studies performed to evaluate this compartment of the lung in asthma. Thus, the evidence suggests that the small airways and parenchyma contribute significantly to asthma pathogenesis. The challenge now lies in evaluating this compartment in the context of its value as a therapeutic target in asthma.