Corticosteroid and long-acting ß-agonist therapy reduces epithelial goblet cell metaplasia.

BACKGROUND: Bronchial epithelial goblet cell metaplasia (GCM) with hyperplasia is a prominent feature of asthma, but the effects of treatment with corticosteroids alone or in combination with a long-acting ß2 -adrenergic receptor agonist (LABA) on GCM in the bronchial epithelium are unknown. OBJECTIVES: To determine whether corticosteroid alone or in combination with a LABA alters protein and gene expression pathways associated with IL-13-induced goblet cell metaplasia. RESULTS: We evaluated the effects of fluticasone propionate (FP) and of salmeterol (SM), on the response of well-differentiated cultured bronchial epithelial cells to interleukin-13 (IL-13). Outcome measures included gene expression of SPDEF/FOXa2, gene expression and protein production of MUC5AC/MUC5B and morphologic appearance of cultured epithelial cell sheets. We additionally analysed expression of these genes in bronchial epithelial brushings from healthy, steroid-naïve asthmatic and steroid-treated asthmatic subjects. In cultured airway epithelial cells, FP treatment inhibited IL-13-induced suppression of FOXa2 gene expression and up-regulation of SPDEF, alterations in gene and protein measures of MUC5AC and MUC5B and induction of GCM. The addition of SM synergistically modified the effects of FP modestly-only for gel-forming mucin MUC5AC. In bronchial epithelial cells recovered from asthmatic vs healthy human subjects, we found FOXa2 and MUC5B gene expression to be reduced and SPDEF and MUC5AC gene expression to be increased; these alterations were not observed in bronchial epithelial cells recovered after treatment with inhaled corticosteroids. CONCLUSION AND CLINICAL RELEVANCE: Corticosteroid treatment inhibits IL-13-induced GCM of the airways in asthma, possibly through its effects on SPDEF and FOXa2 regulation of mucin gene expression. These effects are modestly augmented by the addition of a long-acting ß-agonist. As we found evidence for drug treatment counteracting the effects of IL-13 on the epithelium, we conclude that further exploration into the mechanisms by which corticosteroids and long-acting ß2 -adrenergic agonists confer protection against pathologic airway changes is warranted.

Genetic association between human chitinases and lung function in COPD.

Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.

A protective role for periostin and TGF-ß in IgE-mediated allergy and airway hyperresponsiveness.

BACKGROUND: The pathophysiology of asthma involves allergic inflammation and remodelling in the airway and airway hyperresponsiveness (AHR) to cholinergic stimuli, but many details of the specific underlying cellular and molecular mechanisms remain unknown. Periostin is a matricellular protein with roles in tissue repair following injury in both the skin and heart. It has recently been shown to be up-regulated in the airway epithelium of asthmatics and to increase active TGF-ß. Though one might expect periostin to play a deleterious role in asthma pathogenesis, to date its biological role in the airway is unknown. OBJECTIVE: To determine the effect of periostin deficiency on airway responses to inhaled allergen. METHODS: In vivo measures of airway responsiveness, inflammation, and remodelling were made in periostin deficient mice and wild-type controls following repeated intranasal challenge with Aspergillus fumigatus antigen. In vitro studies of the effects of epithelial cell-derived periostin on murine T cells were also performed. RESULTS: Surprisingly, compared with wild-type controls, periostin deficient mice developed increased AHR and serum IgE levels following allergen challenge without differences in two outcomes of airway remodelling (mucus metaplasia and peribronchial fibrosis). These changes were associated with decreased expression of TGF-ß1 and Foxp3 in the lungs of periostin deficient mice. Airway epithelial cell-derived periostin-induced conversion of CD4(+) CD25(-) cells into CD25(+) , Foxp3(+) T cells in vitro in a TGF-ß dependent manner. CONCLUSIONS AND CLINICAL RELEVANCE: Allergen-induced increases in serum IgE and bronchial hyperresponsiveness are exaggerated in periostin deficient mice challenged with inhaled aeroallergen. The mechanism of periostin's effect as a brake on allergen-induced responses may involve augmentation of TGF-ß-induced T regulatory cell differentiation.

Negative methacholine challenge tests in subjects who report physician-diagnosed asthma.

BACKGROUND: The frequency of adults reporting a history of asthma is rising. However, it is unclear whether this increased prevalence accurately demonstrates a rising trend or if it reflects an overall increase in asthma awareness. OBJECTIVE: To determine the frequency of negative methacholine bronchoprovocation tests in adults who report physician-diagnosed asthma and to explore the clinical characteristics of subjects with negative tests. METHODS: Data from methacholine challenge, spirometry, and physician assessment were analysed from 304 adults who reported physician-diagnosed asthma and responded to community-based advertising for asthma research studies. The clinical characteristics of methacholine-positive and -negative subjects were compared and a predictive model was tested to identify those characteristics associated with a negative test. RESULTS: Of the 304 subjects tested, 83 (27%) had a negative methacholine test. A negative test was positively associated with an adult-onset of symptoms (P<0.001), normal forced expiratory volume in 1 s (P<0.001), and having no history of exacerbation requiring oral steroids (P=0.03). Over half (60%) of those with a negative test reported weekly asthma-like symptoms (cough, dyspnoea, chest tightness, or wheeze), while 39% reported emergency department visits for asthma-like symptoms. CONCLUSIONS AND CLINICAL RELEVANCE: A sizeable percentage of subjects who report physician-diagnosed asthma have a negative methacholine challenge test. These subjects are characterized by diagnosis of asthma as an adult and by normal or near normal spirometry. Caution should be exercised in the assessment and diagnosis of adults presenting with asthma-like symptoms, because they may not have asthma. Further diagnostic studies, including bronchoprovocation testing, are warranted in this patient group, especially if their spirometry is normal.

Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype.

Asthma is a highly prevalent chronic respiratory disease affecting 300 million people world-wide. A significant fraction of the cost and morbidity of asthma derives from acute care for asthma exacerbations. In the United States alone, there are approximately 15 million outpatient visits, 2 million emergency room visits, and 500,000 hospitalizations each year for management of acute asthma. Common respiratory viruses, especially rhinoviruses, cause the majority of exacerbations in children and adults. Infection of airway epithelial cells with rhinovirus causes the release of pro-inflammatory cytokines and chemokines, as well as recruitment of inflammatory cells, particularly neutrophils, lymphocytes, and eosinophils. The host response to viral infection is likely to influence susceptibility to asthma exacerbation. Having had at least one exacerbation is an important risk factor for recurrent exacerbations suggesting an 'exacerbation-prone' subset of asthmatics. Factors underlying the 'exacerbation-prone' phenotype are incompletely understood but include extrinsic factors: cigarette smoking, medication non-compliance, psychosocial factors, and co-morbidities such as gastroesophageal reflux disease, rhinosinusitis, obesity, and intolerance to non-steroidal anti-inflammatory medications; as well as intrinsic factors such as deficient epithelial cell production of the anti-viral type I interferons (IFN-alpha and IFN-beta). A better understanding of the biologic mechanisms of host susceptibility to recurrent exacerbations will be important for developing more effective preventions and treatments aimed at reducing the significant cost and morbidity associated with this important global health problem.

A Design of Experiment (DoE) approach to optimise spray drying process conditions for the production of trehalose/leucine formulations with application in pulmonary delivery.

The present study evaluates the effect of L-leucine concentration and operating parameters of a laboratory spray dryer on characteristics of trehalose dry powders, with the goal of optimizing production of these powders for inhaled drug delivery. Trehalose/L-leucine mixtures were spray dried from aqueous solution using a laboratory spray dryer. A factorial design of experiment (DoE) was undertaken and process parameters adjusted were: inlet temperature, gas flow rate, feed solution flow rate (pump setting), aspiration setting and L-leucine concentration. Resulting powders were characterised in terms of particle size, yield, residual moisture content, and glass transition temperature. Particle size was mainly influenced by gas flow rate, whereas product yield and residual moisture content were found to be primarily affected by inlet temperature and spray solution feed rate respectively. Interactions between a number of different process parameters were elucidated, as were relationships between different responses. The leucine mass ratio influenced the physical stability of powders against environmental humidity, and a high leucine concentration (30% w/w) protected amorphous trehalose from moisture induced crystallization. High weight ratio of leucine in the formulation, however, negatively impacted the aerosol performance. Thus, in terms of L-leucine inclusion in a formulation designed for pulmonary delivery, a balance needs to be found between physical stability and deposition characteristics.

Predicting worsening asthma control following the common cold.

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells.

A hallmark of asthma is mucin overproduction, a condition that contributes to airway obstruction. The events responsible for mucin overproduction are not known but are thought to be associated with mediators of chronic inflammation. Others have shown that T-helper 2 (Th2) lymphocytes are required for mucous cell metaplasia, which then leads to mucin overproduction in animal models of allergy. We hypothesized that Th2 cell mediators are present in asthmatic airway fluid and directly stimulate mucin synthesis in airway epithelial cells. Results in cultured airway epithelial cells showed that samples of asthmatic fluid stimulated mucin (MUC5AC) synthesis severalfold more potently than non-asthmatic fluid. Consistent with this, lavage fluid from the airways of allergen-challenged dogs stimulated mucin synthesis severalfold more potently than that from non-allergen-challenged dogs. Fractionation of dog samples revealed 2 active fractions at <10 kDa and 30-100 kDa. Th2 cytokines in these molecular weight ranges are IL-9 (36 kDa), IL-5 (56 kDa), and IL-13 (10 kDa). Antibody blockade of ligand-receptor interaction for IL-9 (but not IL-5 or IL-13) inhibited mucin stimulation by dog airway fluid. Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50-60% of the mucin-stimulating activity of lung fluids in allergic airway disease.

Basic mechanisms of asthma.

Results of studies of the epidemiology, physiology, histopathology, and cell biology of asthma have revised our conception of the disease. Epidemiologic studies have shown asthma to be an important cause of death, suffering, and economic hardship. Physiologic studies have shown that asthma is a chronic illness characterized by persistent bronchial hyperreactivity. Histopathologic studies have shown characteristic changes: epithelial damage, deposition of collagen beneath the basement membrane, eosinophilic and lymphocytic infiltration, and hypertrophy and hyperplasia of goblet cells, submucosal glands, and airway smooth muscle. Studies of the functions of cells in the airway mucosa suggest that asthma may be fundamentally mediated by a difference in the type of lymphocyte predominating in the airway mucosa but may also involve complex interactions among resident and migratory cells. Asthma may thus result from sensitization of a subpopulation of CD4+ lymphocytes, the Th2 subtype, in the airways. These lymphocytes produce a family of cytokines that favor IgE production and the growth and activation of mast cells and eosinophils, arming the airways with the mechanisms of response to subsequent reexposure to the allergen. This conceptual model has stimulated research along lines that will almost certainly lead to powerful new treatments, and it has already put current therapies in a new light, clarifying the role of antinflammatory agents, especially of inhaled corticosteroids. This conceptual model has some limitations: it ignores new evidence on the role of the mast cell in producing cytokines and depends on results of studies of the effects of inhalation of allergen, although most asthma exacerbations are provoked by viral respiratory infection. Preliminary studies suggest that viral infection and allergen inhalation may involve the activation of different pathways, with viral infection activating production of cytokines by airway epithelial cells. Similar study of the mechanisms activated by inhalation of air toxics may provide important clues as to how they might induce or exacerbate asthma.

The utility of peak flow, symptom scores, and beta-agonist use as outcome measures in asthma clinical research.

STUDY OBJECTIVES: Several methods of utilizing peak expiratory flow (PEF) and other markers of disease activity have been suggested as useful in the management of asthma. It remains unclear, however, as to which surrogate markers of disease status are discriminative indicators of treatment failure, suitable for use in clinical trials. DESIGN: We analyzed the operating characteristics of 66 surrogate markers of treatment failure using a receiver operating characteristic (ROC) curve analysis. PARTICIPANTS: Information regarding FEV(1), symptoms, beta(2)-agonist use, and PEF was available from 313 subjects previously enrolled in two Asthma Clinical Research Network trials, in which 71 treatment failures occurred (defined by a 20% fall in FEV(1) from baseline). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: None of the measures had an acceptable ability to discriminate subjects with a > or % fall in FEV(1) from those without, regardless of the duration of the period of analysis or the criteria for test positivity employed. Areas under the ROC curves generated ranged from 0.51 to 0.79, but none were statistically superior. Sensitivity and specificity combinations were generally poor at all cutoff values; true-positive rates could not be raised without unacceptably elevating false-positive rates concurrently. CONCLUSIONS: Studies that seek to detect treatment failure defined by a significant fall in FEV(1) should not use such individual surrogate measures to estimate disease severity.

Controversies involving inhaled beta-agonists and inhaled corticosteroids in the treatment of asthma.

Controversy over the use of inhaled beta-agonists has dated almost from their introduction as a treatment for asthma. Their effectiveness as bronchodilators is not disputed, but there is concern that they may worsen asthma control if used regularly and that excessive use may increase the risk of death from asthma. Five years after the report from Sears and colleagues suggested that regular use of fenoterol worsens asthma control, we do not have definitive corroborative evidence that this effect of fenoterol is real or is shared by other members of the beta-agonist class. It also remains disputed whether the documented association between excessive beta-agonist use and death from asthma is a causal or a spurious association. Undisputed is the fact that excessive beta-agonist use by asthmatics indicates an increased risk of death from asthma and so indicates a need for clinicians to advise anti-inflammatory medications for these patients. Happily, although there are legitimate concerns about the possible implications of the development of tolerance to the non-bronchodilating effects of beta-agonists, there is currently little evidence that treatment with conventional doses of the beta-agonists currently available in the United States, including salmeterol, is harmful to asthmatic patients. The controversies over the use of inhaled corticosteroids revolve around the issue of whether the clinical benefit easily demonstrated with their short-term use is justified in the face of their possible long-term systemic toxicity. Unsettled questions about their therapeutic use include whether dose dependence can be shown for the clinical benefits of inhaled corticosteroids, whether delay in initiating inhaled corticosteroid treatment reduces the benefit that can be achieved, and whether the benefits of even prolonged therapy are short-lasting. The great unsettled question about their toxicity is whether systemic absorption of inhaled corticosteroids increases the risk of long-term systemic complications, like osteoporosis, cataracts, and growth inhibition. Current evidence suggests that significant risk of such toxicity is not likely to be associated with the long-term use of the equivalent of 800 micrograms/d of beclomethasone in adults and 400 micrograms/d in children. If higher doses are used to obtain greater clinical benefit, the answers to these questions may determine the place of new inhaled corticosteroids with high local potency and little systemic activity.

Bacteraemia and fungaemia in adults with cystic fibrosis.

The incidence of bacteraemia and fungaemia was determined in 29 adults with cystic fibrosis (CF) during 50 consecutive admissions to hospital for management of infective exacerbations of pulmonary disease. Blood was drawn for aerobic, anaerobic and fungal cultures from all patients who were febrile on admission or who became febrile during treatment. The population included eight patients who had indwelling venous access systems in situ. The overall incidence of positive blood cultures in febrile patients was 3.5% [95% confidence interval (C.I.), 1-6%]. We recorded one case of Pseudomonas aeruginosa bacteraemia and two cases of Candida albicans fungaemia. The patient with P. aeruginosa bacteraemia died 5 days after isolation of the organism from her blood. The two patients with C. albicans bacteraemia had totally implantable venous access systems (TIVAS) in situ and both recovered following appropriate therapy. These observations suggest that bacteraemia is rare in patients with CF but that there is a significant risk of fungaemia in a susceptible minority. The implications of these findings, as they relate to management of infections and care of indwelling catheters in such patients, are discussed.

High-resolution computed tomography of airway changes after induced bronchoconstriction and bronchodilation in asthmatic volunteers.

RATIONALE AND OBJECTIVES: We examined whether high-resolution computed tomography (HRCT) would detect and quantify induced airway changes in asthmatic volunteers. METHODS: We performed pulmonary function tests and HRCT on eight asthmatic adults and two nonasthmatic control adults under three conditions: baseline, after methacholine inhalation, and after albuterol inhalation. Changes in pulmonary function, airway internal luminal diameter (AILD), and airway wall thickness (AWT) in the three conditions were compared. RESULTS: After methacholine inhalation, pulmonary function showed significant airflow obstruction in the asthmatic volunteers compared with two nonasthmatic control volunteers. The median value for AILD decreased by 17% (p = .04). After subsequent inhalation of albuterol, pulmonary function improved to above the baseline levels in the eight asthmatic volunteers. The median value for AILD increased by 18% above the baseline value (p = .001). No changes in pulmonary function or AILD were seen in the two nonasthmatic volunteers. AWT did not change significantly in either the asthmatic or nonasthmatic volunteers after inhalation of methacholine or albuterol. CONCLUSION: HRCT can quantify changes in the internal luminal diameter of asthmatic airways provoked by methacholine and albuterol inhalation.

Reducing IgE levels as a strategy for the treatment of asthma.

IgE secretion by B lymphocytes defines the allergic state and nearly all asthmatics have higher than normal IgE levels in serum following adjustment for age and sex. It is thought that allergic mechanisms may be responsible for the increasing prevalence of asthma. In particular, in utero changes may encourage T cells to differentiate into Th2 subtypes. Th2 cells produce cytokines such as IL-4 and IL-5, which can act indirectly via B cells, mast cells and eosinophils to mediate the asthma phenotype. Alternatively, IL-4 and IL-13 may act directly on the airway. Th2 lymphocyte inflammation in asthma predisposes subjects to B cell and IgE-mediated airway inflammation. IgE binds to receptors on the surface of a variety of effector cells causing them to release a variety of mediators that promote airway hyperresponsiveness, mucus secretion and increased vascular permeability. Several strategies for decreasing IgE have been developed as a possible treatment for asthma. For example, anti-IgE monoclonal antibodies such as rhuMAb-E25 and CGP 56901 block binding of IgE to its high-affinity receptor and have been shown to reduce IgE levels in humans without causing anaphylaxis. IgE levels must be nearly completely suppressed. Recent clinical studies in subjects with asthma have shown that rhuMAb-E25 attenuates both the early and late phase responses to inhaled allergen, and reduces the associated increase in eosinophils in induced sputum. rhuMAb-E25 is well tolerated and has shown promising results in improving symptoms and lung function in patients with moderate to severe asthma. Other strategies for decreasing IgE levels include interferon gamma, IL-4 antibodies, IL-4 receptor antibodies and soluble IL-4 receptors.

Remodeling of the airway epithelium in asthma.

Several pathologic changes occur in the airway epithelium in asthma, but the relationship between these changes and the initiation and progression of asthma remains poorly understood. One possibility is that changes in the structure and function of the epithelium induced by environmental exposure in genetically susceptible subjects represent primary pivotal events that occur early in the pathogenesis of asthma. Alternatively, these epithelial changes may occur simply as a consequence of pivotal early events in other systems, such as immune deviation in childhood to a helper T cell type 2 (Th2) subtype of CD4(+) cells. Epithelial desquamation in asthma represents a pathologic change that is frequently cited as important for the mechanisms of airway remodeling and airway hyperresponsiveness. Desquamation of the epithelium may not represent true pathology, however, but may instead be an artifact of tissue sampling and handling. Evidence is more firm for other pathologic changes in the epithelium. For example, goblet cell numbers are increased in asthma, leading to increases in stored mucins in the epithelium and in secreted mucins in sputum. The functional consequences of these changes include sputum production and airway narrowing, which lead to asthma exacerbations. Currently available data suggest that an important mechanism for goblet cell hyperplasia in asthma is the action of Th2 cytokines. Improved understanding of epithelial goblet cell abnormalities in asthma will hopefully lead to novel therapies for mucin hypersecretion, which is an important cause of morbidity and mortality.

Safety of one method of sputum induction in asthmatic subjects.

To assess the safety of sputum induction in asthmatic subjects, we conducted a retrospective review of data from 351 sputum inductions in 78 subjects from our institution. The sputum induction protcol consisted of baseline FEV1, pretreatment with albuterol 180 micrograms, postbronchodilator spirometry 15 min later, the induction procedure itself (inhalation of 3% saline for 20 min), and postsputum induction spirometry. We found that sputum induction was usually well tolerated, although some subjects developed wheeze and dyspnea. Overall, 11 of the 78 subjects (14%) had a fall in FEV1 of > or = 20% from the postbronchodilator baseline ("excessive bronchoconstriction") during their first sputum induction (range: -20 to -69%); no subject developed refractory bronchoconstriction requiring hospitalization or emergency room treatment. Only one of the 54 subjects (1.9%) with a baseline prebronchodilator FEV1 > 80% had excessive bronchoconstriction, whereas 10 of the 24 subjects (42%) whose baseline FEV1 was < or = 80% predicted did so. The change in FEV1 during sputum induction was significantly correlated with the baseline prebronchodilator FEV1% predicted, the baseline postbronchodilator FEV1% predicted, the PC20 for methacholine, and the percentage of eosinophils in induced sputum. We conclude that 180 micrograms albuterol does not prevent excessive bronchoconstriction in all asthmatic subjects undergoing sputum induction, especially in asthmatic subjects with a low baseline FEV1. Pulmonary function should be monitored regularly during sputum induction in asthmatic subjects to monitor for excessive bronchoconstriction.

Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation.

The effects of usual or low doses of inhaled corticosteroids on airway mucosal inflammation have not yet been examined. We therefore, compared the effects of inhaled beclomethasone dipropionate (BDP) 336 microg x day(-1) on asthma control outcomes and markers of airway inflammation. Twenty-four adult subjects with mild and moderate asthma were randomized to receive either BDP or placebo for four weeks; then subjects entered a single blind four week placebo run-in period. We found that the BDP group had significantly greater improvements in forced expiratory volume in one second (FEV1), morning peak flow, and rescue salbutamol use than the placebo-treated group. The improvement in FEV1 largely reversed one week after treatment was stopped. The decrease in the median percentage of eosinophils in induced sputum in the BDP group from 3.8% to 3.4% was not significant, but because eosinophils increased from 8.4% to 12.7% in the placebo group, there was a significant difference between treatment groups (p=0.03). There was no significant difference between groups during treatment in the levels of eosinophil cationic protein (ECP), tryptase mucin-like glycoprotein, or fibrinogen in induced sputum. The change in FEV1 in the BDP group did not correlate significantly with the change in eosinophil percentage or ECP levels. We concluded that four weeks of treatment with inhaled beclomethasone dipropionate 336 microg x day(-1) was associated with significant improvements in peak flow, forced expiratory volume in one second, and rescue salbutamol use in asthmatic subjects but was not associated with large reductions in markers of eosinophilic inflammation, bronchovascular permeability, or mucus hypersecretion.

Relationship of epidermal growth factor receptors to goblet cell production in human bronchi.

To determine the relationship of epidermal growth factor receptor (EGFR) expression to mucin synthesis in human airways, we examined EGFR and MUC5AC expression at both gene and protein levels using in situ hybridization and immunohistochemical analysis in human bronchi. Bronchial mucosal biopsy specimens were obtained from 12 asthmatic subjects and 11 healthy subjects. In asthmatic airways, EGFR mRNA was expressed in the airway epithelium. EGFR immunoreactivity staining patterns varied among the asthmatic airways: staining was positive mainly in goblet cells, in basal cells, or in both. In contrast, healthy airways showed little expression of EGFR mRNA; EGFR immunoreactivity was observed mainly in goblet cells. In parallel to EGFR expression, MUC5AC mRNA expression was greater in asthmatic airways; mucous glycoconjugates that stained positively with Alcian blue/PAS were also increased in asthmatic airways. Ciliated cells were negative for EGFR and MUC5AC both in asthmatic and in healthy subjects at both mRNA and protein levels. There was a significant positive correlation between EGFR immunoreactivity and the area of MUC5AC-positive staining in both asthmatics and healthy subjects. These findings suggest a sequence of events by which EGFR activation is involved in mucin expression in asthmatic airway epithelium.

Airway inflammation and remodeling in asthma.

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