The airway smooth muscle cell: a major contributor to asthma?
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Asthma↗
Biomedical subjects
K F Chung
Publications and source records attributed to K F Chung.
Delivering effective asthma care--how do we implement asthma guidelines?
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Adult↗
Airway smooth muscle cells: contributing to and regulating airway mucosal inflammation?
In addition to its contractile properties, airway smooth muscle may contribute to the pathogenesis of asthma by increased proliferation, and by the expression and secretion of pro-inflammatory cytokines and mediators. Studies of airway smooth muscle cells in culture have shown that many mitogenic mediators can induce proliferation, and that these may therefore, contribute to the increase in airway smooth muscle mass observed in asthma. Other mechanisms for airway smooth muscle proliferation include the interaction with inflammatory cells such as T-cells and eosinophils. Airway smooth muscle cells may also be a source of inflammatory mediators and cytokines, in particular chemokines, thus implicating airway smooth muscle cells as contributors to the inflammatory mechanisms of asthma. The pro-activating signals for converting airway smooth muscle cells into a proliferative and secretory cell in asthma are unknown, but may include viruses and immunoglobulin E. Airway smooth muscle contractility may also be altered in response to inflammation. Airway smooth muscle cells may play an important interactive role with inflammatory and other structural cells, contributing to inflammation, injury and repair of the airways. Such a recognition makes it imperative to consider the airway smooth muscle as a target of therapeutic drugs for suppressing not only the contractile but also the proliferative and secretory effects of asthma.
Asthma↗
New immunological approaches and cytokine targets in asthma and allergy.
The aims of current asthma treatment are to suppress airway inflammation and control symptoms, and corticosteroids maintain a commanding position in this role. Steroids effectively suppress inflammation in the majority of patients but have little impact on the natural history of this disease. In severe asthmatics, corticosteroids may have relatively less beneficial effects. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which may provide valuable flexibility in the therapeutic approach to asthma. The novel immunological approaches include the prevention of T-cell activation, attempts to influence the balance of T-helper cell (Th) populations to inhibit or prevent Th2-derived cytokine expression, and the inhibition or blockade of the downstream actions of these cytokines such as effects on immunoglobulin-E and eosinophils. These approaches provide broad as well as highly specific targeting, and also prospects for prevention and reversal of immunological and inflammatory abnormalities associated with asthma. Hopefully, the development of effective antiasthma agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of asthma.
Anti-Asthmatic Agents↗
Unmet needs in adult asthma.
Guidelines have been developed to provide an objective framework for the effective management of asthma. They are based on a mix of sound clinical practice and evidence-based medicine. The aims of asthma management are to ensure that the patient is symptom free and living an unrestricted life with normal physical activity, lung function normalized as much as possible, using minimum therapy, that exacerbations are kept to a minimum and mortality is reduced or abolished. In practice, however, these aims are not being met. Thus, unmet needs exist in asthma and need to be addressed. One particular unmet need is poor delivery of asthma care. Undertreatment of asthma is common, especially in severe asthma. However, studies suggest that some patients with severe asthma do not respond to any available treatments. Many outcome measures have been used in asthma and different outcomes will ensue according to which outcome measure is chosen, which in turn depends on the population studied. Asthma is a heterogeneous disease and there is heterogeneity in the response to treatment. However, at present there are no means to determine which patients will be a responder or non-responder to a particular treatment. In clinical trials of potential new asthma treatment we need to target the patient population more carefully according to the selected outcome measure, which should reflect the patient's perspective.
Adult↗
Computed tomographic cephalometric analysis of Chinese patients with obstructive sleep apnoea.
Variations of craniofacial and upper airway structures are recognized to contribute to the phenomenon of obstructive sleep apnoea (OSA). Most previous cephalometric studies were performed using erect lateral radiographs in Caucasian patients. The present project aims to determine cephalometric measurements, utilizing CT, in normal Chinese subjects and in Chinese patients with OSA. Computed tomography of 25 patients with OSA (proven using overnight polysomnography), and of 25 age-, sex-, height-, bodyweight- and body mass index (BMI)-matched control subjects were prospectively performed. Thirteen standard bony and soft-tissue measurements were obtained from the CT lateral scout view of the head and neck, taken with each subject in the neutral supine position. The cross-sectional area was calculated at two axial levels (velopharynx and hypopharynx). The measurements in the two groups, OSA and control subjects, were compared. The measurements for hyoid position (P = 0.00), nasal cavity length (P = 0.01), mandibular prognathism (P = 0.05), tongue size (P = 0.02), oropharyngeal airway space (P = 0.02), posterior tongue airway space (P = 0.04) and cross-sectional areas at the level of the velopharynx (P = 0.00) and hypopharynx (P = 0.01) differed significantly between the two groups. In conclusion, CT cephalometric measurements show that certain anatomical variations in the head and neck are likely to contribute to the pathogenesis of OSA in Chinese patients.
Adult↗
Compliance with an oral asthma medication: a pilot study using an electronic monitoring device.
Compliance with prescribed asthma medication is commonly estimated from tablet counts for oral medications and canister weights for inhaled medications. Recently, electronic medication monitoring devices, developed to evaluate numerical compliance as well as drug use patterns, were used to assess compliance with inhaled steroids and beta2-agonists. This was the first study to electronically assess compliance with an oral asthma medication. Fifty-seven asthmatic patients, stable on inhaled beta2-agonists only with a mean FEV1 of 77% predicted (+/- 13%, SD) began 12 weeks of treatment with zafirlukast 20 mg twice daily. The monitoring device, an electronic TrackCap, recorded the date and time on each occasion that patients removed and replaced their medication bottle caps. Patients were told that compliance would be assessed as part of the study, but patients were not told about the specifics of the TrackCap. Compliance was defined: 1. as the number of TrackCap events per number of prescribed tablets; and 2. as the difference between number of tablets dispensed and number returned per number prescribed. Adherence was defined as the number of days with two TrackCap events at least 8 h apart per the total number of days' dosing. Forty-seven patients completed the study with a median compliance of 89% (mean. 80%) and a median adherence of 71% (mean, 64%) as measured by TrackCap events. Compliance as estimated from return-tablet count was slightly higher (median, 92%). High rates of compliance were maintained throughout the trial. These results show that compliance with and adherence to a treatment of an oral, twice-daily, maintenance asthma medication, such as zafirlukast, is high.
Administration, Oral↗
Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice.
BACKGROUND: Theophylline is widely used in the treatment of asthma, and there is evidence that theophylline has anti-inflammatory or immunomodulatory effects. A study was undertaken to determine whether theophylline added to low dose inhaled steroids would be as efficacious as high dose inhaled steroids in asthma. METHODS: In a study in general practice of 155 recruited asthmatic patients with continuing symptomatic asthma while on 400 microgram beclomethasone dipropionate (BDP) daily and inhaled beta(2) agonist as required, the effect of (1) continuing low dose inhaled steroids alone (LDS, 200 microgram BDP twice daily), (2) low dose inhaled steroids plus low dose theophylline (LDT, 400 mg daily), or (3) high dose inhaled steroids (HDS, 500 microgram BDP) over a six month period was examined. RESULTS: One hundred and thirty patients completed the study. Between group comparison using analysis of variance showed no overall differences in peak flow measurements, diurnal variation, and symptom scores. Changes in evening peak flows approached significance at the 5% level (p=0.077). The mean improvement in evening peak flow in the LDT compared with the LDS group was 20.6 l/min (95% confidence interval (CI) -2.5 to 38.8). In the LDT group there was an increase in evening peak flows at the end of the study compared with entry values (22.5 l/min), while in the LDS and HDS groups evening peak flows increased by 1.9 and 8.3 l/min, respectively. There was no significant difference in exacerbations or in side effects. CONCLUSION: There were no overall significant differences between the low dose steroid, low dose steroid with theophylline, and the high dose steroid groups. The greatest within-group improvement in evening peak flows was found after theophylline. A larger study may be necessary to show significant effects.
Adolescent↗
Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in mild to moderately severe asthma.
BACKGROUND: Exhaled levels of nitric oxide (NO) are raised in asthma but the relationship between exhaled NO levels and a direct measure of airway inflammation has not been investigated in asthmatic patients treated with inhaled steroids. METHODS: The relationship between exhaled NO levels, clinical measures of asthma control, and direct markers of airway inflammation were studied in patients with asthma treated with and without inhaled corticosteroids. Thirty two asthmatic patients (16 not using inhaled steroids and 16 using inhaled beclomethasone dipropionate, 400-1000 microg/day) were monitored with respect to measures of asthma control including lung function, symptom scores, medication usage, and variability of peak expiratory flow (PEF) for one month. Measurements of exhaled NO and fibreoptic bronchoscopy were performed at the end of the monitoring period. Bronchial mucosal biopsy specimens were stained with an anti-MBP antibody for quantification of eosinophils. RESULTS: There was no significant difference in lung function, symptom scores, or medication usage between the two groups, but there was a significant difference in PEF variability (8.7 (1.2)% in steroid naive patients versus 13.6 (1.9)% in steroid treated patients, p<0.05) and exhaled NO levels (9.9 (3.5) ppb in steroid naive patients versus 13.6 (2.0) ppb in steroid treated patients, p<0.05). There was no correlation between exhaled NO and mucosal eosinophils, or between NO and conventional measures of asthma control. There was a significant correlation between mucosal eosinophils and lung function (r = -0.43, p<0.05). CONCLUSIONS: Exhaled NO levels do not reflect airway mucosal eosinophilia and these markers reflect different aspects of airway inflammation. The clinical usefulness of exhaled NO needs to be determined in prospective longitudinal studies.
Adult↗
Effects of inhaled corticosteroid therapy on expression and DNA-binding activity of nuclear factor kappaB in asthma.
We determined whether inhaled corticosteroid therapy modulates the expression of the transcription factor, nuclear factor kappa B (NF-kappaB), in patients with asthma. Fifteen stable patients with mild asthma underwent bronchoalveolar lavage (BAL) with bronchial biopsies in a double-blind, placebo-controlled and crossover study after placebo or after inhaled fluticasone propionate (500 microg twice daily). Fluticasone reduced the number of eosinophils in BAL fluid (BALF) and in airway biopsies, together with an improvement of bronchial responsiveness to methacholine. However, NF-kappaB DNA-binding in alveolar macrophages and in bronchial biopsies was not affected by fluticasone treatment. NF-kappaB expression was also measured by immunohistochemical staining with an antibody to the p65 component of NF-kappaB. Fluticasone caused an increase in the number of positive nuclear staining cells in the airway epithelium from 34. 1 +/- 5.0 to 64.1 +/- 8.0 per mm(2) (p = 0.002). In vitro studies of A549 epithelial cells stimulated by interleukin-1beta (IL-1beta) showed that dexamethasone increased p65 protein expression analyzed by Western blot. Despite an anti-inflammatory effect of fluticasone, there was no decrease in NF-kappaB-DNA binding and activation, indicating that this may not be a mechanism by which corticosteroids act in asthma. The significance of corticosteroid-induced increase in p65 protein expression is not known.
Administration, Inhalation↗
No effect of inhaled budesonide on the response to inhaled ozone in normal subjects.
Inhalation of ozone in normal subjects causes a neutrophilic inflammatory response in the airways. Pretreatment with inhaled corticosteroids reduces the inflammatory response to inhaled ozone in dogs. We undertook a double-blind, randomized, placebo-controlled, crossover study to investigate the effects of 2 wk of treatment with inhaled budesonide 800 microg twice daily or placebo prior to ozone exposure in humans. Fifteen (six male; mean age, 31.1 +/- 2.1 yr) healthy nonsmokers were exposed to 400 parts per billion (ppb) ozone for 2 h with intermittent exercise. Spirometry, exhaled carbon monoxide (CO) and nitric oxide (NO) levels, measurement of methacholine reactivity, and collection of exhaled air condensate and induced sputum samples were performed at baseline, preexposure, and at intervals up to 24 h postexposure. Ozone exposure led to significant decreases in spirometry and increased methacholine reactivity and sputum neutrophils and myeloperoxidase (MPO). There were no changes in exhaled NO and CO levels, or exhaled breath nitrite after ozone exposure. There were no differences in any of the parameters after treatment with budesonide compared with placebo, and no differences in the response to ozone between treatment groups. We conclude that a high dose of inhaled corticosteroid does not protect against the effects of ozone exposure in normal subjects.
Administration, Inhalation↗
Airway inflammation after controlled exposure to diesel exhaust particulates.
Epidemiologic evidence suggests a link between morbidity and mortality and levels of particulate matter in the atmosphere. We studied the inflammatory response to inhalation of diesel exhaust particulates (DEP) in normal volunteers. DEP were collected from the exhaust of a stationary diesel engine and were resuspended in an exposure chamber. Ten nonsmoking healthy volunteers were exposed for 2 h at rest to a controlled concentration of DEP (monitored at 200 microg/m(3) particulate matter of less than 10 microm aerodynamic diameter [PM(10)]) or air in a double-blind, randomized, crossover study. Exposures were followed by serial spirometry and measurement of pulse, blood pressure, exhaled carbon monoxide (CO), and methacholine reactivity, as well as sputum induction and venesection for up to 4 h after exposure, and a repeat of all these procedures at 24 h after exposure. There were no changes in cardiovascular parameters or lung function following exposure to DEP. Levels of exhaled CO were increased ater exposure to DEP, and were maximal at 1 h (air: 2.9 +/- 0.2 ppm [mean +/- SEM]; DEP: 4.4 +/- 0.3 ppm; p < 0.001). There was an increase in sputum neutrophils and myeloperoxidase (MPO) at 4 h after DEP exposure as compared with 4 h after air exposure (neutrophils: 41 +/- 4% versus 32 +/- 4%; MPO: 151 ng/ml versus 115 ng/ml, p < 0.01), but no change in concentrations of inflammatory markers in peripheral blood. Exposure to DEPs at high ambient concentrations leads to an airway inflammatory response in normal volunteers.
Adult↗
Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Regulation by interleukin-10.
An imbalance between proteases and antiproteases may play a role in emphysema, which is characterized by increased degradation of extracellular matrix, and in airway remodeling in chronic bronchitis and asthma, in which there is increased collagen deposition. We assessed the effect of smoking on release of matrix metalloprotease-9 (MMP-9) and of its inhibitor, tissue inhibitor of metalloprotease-1 (TIMP-1), from alveolar macrophages, and determined the effects of proinflammatory (interleukin [IL]-1beta and lipopolysaccharide [LPS]) and antiinflammatory (IL-10) stimuli on the release of MMP-9 and TIMP-1. We performed bronchoalveolar lavage in 11 smokers and 11 nonsmokers, and cultured airway macrophages in the presence of control medium, IL-1beta, and LPS. Airway macrophages from smokers released greater amounts of MMP-9 and TIMP-1 at baseline and in response to IL-1beta and LPS than did those of nonsmokers. Airway macrophages from smokers produced more TNF-alpha and IL-10. IL-10 increased TIMP-1 release without modifying that of MMP-9, leading to a decrease in the MMP-9 to TIMP-1 ratio. Anti-IL-10 antibody had no effect on MMP-9 production induced by LPS. We conclude that the release of proteases and antiproteases by airway macrophages is increased in cigarette smokers, and can be regulated by exogenous IL-10.
Adult↗
Expression of heme oxygenase isoenzymes 1 and 2 in normal and asthmatic airways: effect of inhaled corticosteroids.
Heme oxygenase (HO) is considered to be an antioxidant enzyme that catabolizes heme to produce carbon monoxide (CO) and biliverdin. We determined the expression and distribution of HO-1 and HO-2, two isoenzymes of HO, in the airways of patients with asthma, and determined the effect of inhaled corticosteroid therapy. Immunostaining for both enzymes was widely distributed in the airways' submucosa, particularly in airway epithelium and submucosal macrophages (CD68(+)) as determined by double immunostaining. There was no difference in intensity and extent of staining in biopsies from normal subjects (n = 10) and subjects with asthma (n = 10). Following 1 mo of treatment with inhaled corticosteroids (budesonide 1,600 microg/d), there was no significant change in the expression and distribution of either HO-1 or HO-2 in the airways' submucosa in eight subjects with mild asthma, despite a significant reduction in airway eosinophils and a reduction in bronchial responsiveness to methacholine. Levels of exhaled nitric oxide were significantly reduced, but exhaled CO levels remained unchanged by the treatment. Treatment with a placebo inhaler (n = 8) had no effects on these parameters. Thus, both HO-1 and HO-2 are extensively distributed equally in normal subjects and subjects with asthma, and are not modulated by inhaled corticosteroid therapy in subjects with asthma. HO may be an important endogenous antioxidant enzyme.
Administration, Inhalation↗
Contribution of upregulated airway endothelin-1 expression to airway smooth muscle and epithelial cell DNA synthesis after repeated allergen exposure of sensitized Brown-Norway rats.
Endothelin-1 is a potent bronchoconstrictor peptide with pro-inflammatory and growth-promoting properties. After exposure of sensitized Brown-Norway rats to six repeated ovalbumin exposures, there was an increase in pro-endothelin (ET)-1 messenger RNA compared with saline-exposed control rats 24 h after the final exposure (P < 0.01). ET-1 immunoreactivity was increased sixfold in the bronchial epithelium of the larger conducting airways in the repeated allergen-exposed rats (P < 0.001). After repeated allergen exposure, there were increased rates of DNA synthesis in the airway smooth muscle (ASM) cells (P < 0.001) and epithelial cells (P < 0. 001) compared with saline-exposed controls, as measured by bromodeoxyuridine incorporation. Treatment with a dual endothelin A and B (ET(A+B)) receptor antagonist caused a significant attenuation in both ASM (P < 0.001) and epithelial cell (P < 0.001) bromodeoxyuridine incorporation compared with the allergen-challenged and vehicle-treated group. The dual ET(A+B) antagonist attenuated eosinophil recruitment into the airways (P < 0. 05) but had no significant effect on increased bronchial reactivity to acetylcholine in allergen-exposed rats. Increased levels of ET-1 in the airways may contribute to inflammation and ASM and epithelial cell DNA synthesis after repeated allergen exposure. Such processes may underlie increased proliferation of resident cells leading to airway wall remodeling in asthmatics.
Allergens↗
Future treatments of allergic diseases and asthma.
Recent advances in the understanding of the inflammatory and immunological mechanisms of allergic diseases have illuminated many potential therapeutic strategies that may prevent or even reverse the abnormalities of allergic inflammation. As the roles of effector cells, and of signalling and adhesion molecules are better understood, the opportunities to inhibit or prevent the inflammatory cascade have increased. In addition, there have been advances in the synthesis of proteins, monoclonal antibodies and new small molecule chemical entities, which provide further valuable flexibility in the therapeutic approach to asthma. Such new approaches are aimed at prevention of T-cell activation; redressing the imbalance of T helper cell populations thus inhibiting or preventing Th-2-derived cytokine expression; and the inhibition or blockade of the downstream actions of these cytokines such as effects on IgE and eosinophils. Approaches such as these allow both broad and highly specific targeting, and may pave the way towards the prevention and reversal of the immunological and inflammatory processes driving asthma, allergic rhinitis and atopic dermatitis. The development of effective agents with effects beyond those provided by current therapies coupled with lesser side-effects will further address the unmet needs of allergic disease.
Adjuvants, Immunologic↗
Post-transcriptional regulation of bradykinin B1 and B2 receptor gene expression in human lung fibroblasts by tumor necrosis factor-alpha: modulation by dexamethasone.
The cellular and molecular mechanisms governing bradykinin B1 and B2 receptor expression and function are poorly understood. We investigated the regulation of both B1 and B2 receptors in human embryonic lung fibroblasts (HEL 299) by the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). TNF-alpha and IL-1beta both induced a rapid and transient increase in B1 and B2 receptor mRNA expression that was maximal by 2 h, accompanied by an increase in B1 and B2 receptor protein, as measured by radioligand binding assay with [(3)H]des-Arg(10)-kallidin, and [(3)H]bradykinin, respectively. The induced B1 receptors were functionally coupled, because the B1 agonist, des-Arg(10)-kallidin, induced an increase in arachidonic acid release in TNF-alpha-stimulated cells but not in control cells. The induction of B1 and the up-regulation of B2 receptors by TNF-alpha was partly mediated through activation of p38 mitogen-activated protein kinase and that of B2 receptor by protein kinase A. TNF-alpha and IL-1beta regulation of both B1 and B2 receptors was inhibited by dexamethasone. When compared with vehicle-treated cells, dexamethasone increased the rate of decline of both B1 and B2 receptor mRNAs. Nuclear run-on experiments demonstrate that the induction of B1 and the up-regulation of B2 receptors as well as the inhibitory effect of dexamethasone are entirely mediated through post-transcriptional mechanisms.
Anti-Inflammatory Agents↗
Increased interleukin-10 and macrophage inflammatory protein-1 alpha release from blood monocytes ex vivo during late-phase response to allergen in asthma.
BACKGROUND: We determined the effect of late-phase responses to allergen challenge of mildly allergic asthmatic patients on the expression and release of the cytokines IL-10 and MIP-1alpha from peripheral blood monocytes. METHODS: Sixteen mildly allergic asthmatics were exposed to increasing concentrations of allergen aerosol. Nine demonstrated an early response alone (single responders), while seven had an early followed by a late response (dual responders). Monocytes were isolated from venous blood before and 24 h after allergen challenge, and placed in short-term culture for determination of IL-10 mRNA expression by reverse-transcription polymerase chain reaction and protein release. MIP-1alpha protein release was measured by radioimmunoassay. RESULTS: IL-10 mRNA expression was significantly higher in dual responders than early responders alone, for unstimulated monocytes or for monocytes exposed to lipopolysaccharide or IL-1beta. In addition, the release of IL-10 and MIP-1alpha from monocytes of dual responders was also enhanced. CONCLUSIONS: Circulating monocytes are primed to release more of the cytokines, IL-10 and MIP-1alpha, in dual but not in single responders, at 24 h after allergen. They may contribute to allergen-induced inflammatory responses in the airways.
Adult↗