Airway Narrowing In Asthma Research Articles

A combination with clinical recommended dosages of salmeterol and ipratropium is not more effective than salmeterol alone in patients with chronic obstructive pulmonary disease

The role of cholinergic bronchomotor tone may be magnified in circumstances which influence airway calibre adversely. Effective cholinergic blockade may, consequently, be of value in patients whose disease is manifested by decline in airway calibre (1). This is particularly true in chronic obstructive pulmonary disease (COPD) patients, because airway narrowing in asthma is due to more factors than vagal tone alone, whereas vagal tone may be the only reversible element in COPD (2). Although present anti-cholinergics often appear to be of greater efficacy than P-agonists in COPD, owing to their prolonged duration of bronchodilation, their onset of action may be slower (2). It is not a surprise, therefore, that a number of clinical studies have shown the benefit of adding a P-agonist to anti-cholinergics such as ipratropium in COPD (3). The introduction of long-acting P-agonist bronchodilators gives physicians additional therapeutic options for COPD, but their place in COPD treatment is currently not known. In any case, salmeterol appears to be more effective than salbutamol in patients with stable COPD (4). It also provides more sustained bronchodilation and slower onset of action than ipratropium (5). The present study was designed to answer the question whether combined administration of

Airway inflammation and asthma.

Asthma is currently identified by the presence of characteristic symptoms of wheezing, chest tightness, dyspnea and cough, and by the presence of reversible airway narrowing and/or airway hyperresponsiveness to a variety of inhaled bronchoconstrictor stimuli. Airway inflammation appears to be central to the pathogenesis of all of these clinical manifestations of asthma. There are increased numbers of activated eosinophils and of mast cells in the airways of patients with asthma, even those with mild disease. The presence and survival of these inflammatory cells may be promoted by the presence of increased levels of proinflammatory cytokines, such as GM-CSF, interleukin(IL)-3 or IL-5 in asthmatic airways. These cells have the capacity to release potent bronchoconstrictor mediators such as the cysteinyl leukotrienes, which are responsible, in part at least, for airway narrowing in asthma and for allergen-g exercise- and aspirin-induced asthma. Other cells, such as a subset of T-lymphocytes (TH2), may also be important in maintaining the inflammatory cascade through the formation and release of cytokines. Airway structural changes caused by the persisting inflammation, such as airway epithelial damage, or altered smooth muscle function or volume, are likely to be important in the pathogenesis of stable long-standing airway hyperresponsiveness. Mediators released from the inflammatory cells may be responsible for these changes. Despite the great increase in knowledge about the importance of airway inflammation in the pathogenesis of asthma, the precise sequence of events that leads to the presence of persisting airway inflammatory cells, airway structural changes and airway hyperresponsiveness in asthma remains to be clarified.

Drug delivery in asthma: A comparison of spacers with a jet nebuliser

Although spacer devices are frequently used for aerosol therapy in asthma, the commonly used spacers have undergone little controlled evaluation, and their relation to nebuliser therapy is unclear. The aims of this study were to compare three delivery methods (Breath-A-Tech spacer, Volumatic spacer and jet nebuliser) for the administration of salbutamol to reverse acute histamine induced airway narrowing in asthma (Study 1); and to assess asthma control during two weeks use of inhaled therapy via Volumatic or Breath-A-Tech spacer (Study 2). A randomised double-blind cross-over comparison was conducted. In Study 1, 27 adults with stable asthma who were currently using pressurised metered dose inhaler therapy attended for three study days. On each study day subjects inhaled doubling doses of histamine and were randomised to receive: (a) salbutamol 200 micrograms via Breath-A-Tech spacer and placebo 200 micrograms via Volumatic spacer; (b) placebo two puffs via Breath-A-Tech spacer and salbutamol 200 micrograms via Volumatic spacer; or (c) salbutamol 1 mg in 2 mL saline via jet nebuliser. FEV1 and FEF 25-75% were measured at two minute intervals for 20 minutes. In Study 2, subjects were randomised to use regular asthma medication by Volumatic or Breath-A-Tech spacers and recorded symptoms and peak expiratory flow (PEF) in a daily diary. Lung function improved from a baseline FEV1 of 51% predicted to 72% after salbutamol inhalation from each of the delivery systems. The spacers and nebulisers produced the same maximum improvement in FEV1, however, lung function improved more rapidly when salbutamol was delivered by spacer. There was no difference in asthma control comparing inhaler use via Breath-A-Tech with Volumatic spacer over two weeks use. Subject preference favoured the Breath-A-Tech spacer (72% vs 4%). The Volumatic and Breath-A-Tech spacer devices are effective delivery systems in asthma and may offer a more rapid response than jet nebulisation at a lower cost.

Structural and Functional Abnormalities of the Airways of Hyperoxia-Exposed Immature Rats

Asthma and bronchopulmonary dysplasia are prevalent diseases characterized by airway constrictor hyperresponsiveness and excessive airway smooth muscle accumulation. It is now well accepted that some alterations in airway wall architecture can increase lumenal narrowing for a given degree of smooth muscle activation. For example, increasing the thickness of the submucosal layer between airway smooth muscle and airway lumen can magnify the airflow obstruction induced by a fixed proportion of airway smooth muscle shortening, an effect especially pronounced in smaller airways. 1 James AL Paré PD Hogg JC The mechanics of airway narrowing in asthma. Am Rev Respir Dis. 1989; 139: 242-246 Crossref PubMed Scopus (670) Google Scholar Also, structural changes that result in thickening of the adventitial portion of an airway might lead to excessive lumenal narrowing on smooth muscle activation, by reducing (or uncoupling) the external load ordinarily applied by the lung parenchyma to the airway through alveolar septal attachments that surround the circumference of intrapulmonary airways.

Is Asthma a Vascular Disorder?

Is Asthma a Vascular Disorder?

Effects of inhaled substance P on airway responsiveness to methacholine in asthmatic subjects in vivo

We tested the hypothesis that the inhaled tachykinin substance P (SP) can induce hyperresponsiveness to methacholine in asthmatic subjects in vivo. Nine atopic nonsmoking asthmatic males with normal forced expiratory volume in 1 s (FEV1; > 80% predicted) and increased methacholine sensitivity [provocative concn causing 20% fall in FEV1 (PC20) < 8 mg/ml] participated in a two-period placebo-controlled crossover study. Dose-response curves to SP (0.25-8 mg/ml) and placebo were recorded on 2 randomized days at least 1 wk apart, and methacholine tests were done 24 h before and 2 and 24 h after these challenges. The responses were measured by FEV1 (%fall from baseline). The position of the methacholine dose-response curves was expressed by the PC20 FEV1 and by the maximal response by the plateau level (MFEV1). SP caused a dose-dependent fall in FEV1 (P < 0.001). There was a slight increase in the PC20 FEV1 at 2 and 24 h, which was not significantly different between placebo and SP. Similarly, there was a reduction in MFEV1 at 2 h after both pretreatments. However, at 24 h after SP inhalation, MFEV1 increased compared with placebo. These changes in MFEV1 were significantly different between SP and placebo by 5.2 +/- 2.2% fall (SE) (P < 0.05). We conclude that 1) a bronchoconstrictive dose of SP, compared with placebo, enhances maximal airway narrowing to methacholine in asthma 24 h after inhalation and 2) tolerance develops to high doses of inhaled methacholine. These findings are suggestive of a role of SP in causing excessive airway narrowing in asthma by inflammatory mechanisms.

Airway blood flow and bronchovascular congestion in sheep.

Vascular congestion could play an important role in causing airway narrowing in asthma. However, the effects of altered bronchial vascular volume and blood flow on airway morphology and pulmonary resistance have not been studied. The aim of this study was to measure airway calibre and vascular volume during inhalation of reputed dilators and constrictors of the airway vasculature in sheep. After baseline measurements of pulmonary resistance (RL) and airway blood flow (Qaw), anaesthetized sheep inhaled an aerosol of either: 0.9% saline (n = 6); histamine 16 mg.ml-1 (n = 5); phenylephrine 0.1-10 mg.ml-1 (n = 6), or methoxamine 1 mg.ml-1 (n = 5). RL and Qaw were measured at the time of peak bronchoconstriction, and the sheep were rapidly killed and lung blood loss prevented. Right lung Qaw was calculated and left lung processed for histology; measurements of cartilaginous airway size, wall thickness and fraction of the wall occupied by blood were made using morphometric techniques. Results showed that 20-30% of the airway wall was occupied by blood vessels. Inhalation of histamine caused an increase in Qaw and RL, and a 50% increase in the vascular volume fraction of the airway wall, whereas inhaled alpha-agonists did not reduce Qaw or vascular volume fraction. We conclude that the major cause of airway narrowing after inhalation of histamine is contraction of the smooth muscle, and the bronchovascular congestion contributes little to airway narrowing in cartilaginous airways of sheep. In addition inhaled alpha-agonists do not constrict the bronchial microvasculature under baseline conditions. Therefore, our results do not support the hypothesis that protection against bronchoconstriction provided by alpha-agonists is due to vasoconstriction.

Airway narrowing in excised canine lungs measured by high-resolution computed tomography.

The exact site of airway narrowing in asthma and chronic obstructive pulmonary disease is unknown. High-resolution computed tomography (HRCT) is a sensitive noninvasive imaging technique that can be used to measure airway dimensions. After determining the optimal computed tomographic parameters using a phantom, we measured lobe volume and airway dimensions of isolated canine lung lobes at a transpulmonary pressure of 25 cmH2O. These measurements were repeated after deflation and administration of aerosolized saline and carbachol (256 mg/ml). Lobe volume decreased with all treatments. The maximal lobar volume change was 26% at 6 cmH2O after carbachol. Average airway lumen area decreased with all treatments. After carbachol, at transpulmonary pressures of 25, 15, 10, 8, and 6 cmH2O, lumen area decreased by 7.3 +/- 4.1, 62.0 +/- 4.9, 77.5 +/- 3.0, 31.9 +/- 9.0, and 95.2 +/- 1.0% (SE), respectively. When the airways were divided into four categories on the basis of initial lumen diameter (less than 2, 2-4, 4-6, and greater than 6 mm), the greatest decreases in luminal area after carbachol were seen in intermediate-sized airways (2-4 mm, 56 +/- 4%; 4-6 mm, 59 +/- 3%). HRCT can be used to make accurate measurements of airway dimensions and airway narrowing in excised lungs. HRCT may allow measurement of airway wall thickness and determination of the site of airway narrowing in asthma.

A model of airway narrowing in asthma and in chronic obstructive pulmonary disease.

We have examined the effect of airway wall thickening, loss of lung recoil, and airway smooth muscle shortening on the increase in airway resistance using a model of the human tracheobronchial tree. The values for airway wall thickening were determined morphometrically on the postmortem or surgically resected lungs of normal subjects, patients with moderate chronic obstructive pulmonary disease, and patients with severe asthma. Loss of recoil was simulated by deflating airways along their pressure-area curves by 1 to 3 cm H2O. Values of smooth muscle shortening between 20 and 40% were used in the model to generate sigmoidal-shaped "dose-response" curves. The analysis shows that moderate amounts of airway wall thickening, which have little effect on baseline resistance, can profoundly affect the airway narrowing caused by smooth muscle shortening--especially if the wall thickening is localized in peripheral airways. The combination of a loss of recoil and airway wall thickening are more than additive in their effect on simulated airway responsiveness. We conclude that airway wall thickening and a loss of lung recoil can partially explain the airway hyperresponsiveness observed in patients with chronic obstructive lung disease and asthma.

Control of Airway Caliber by Autonomic Nerves in Asthma and in Chronic Obstructive Pulmonary Disease

Autonomic nerves can influence airway caliber via their effects on airway smooth muscle, bronchial vessels, and mucous glands and may therefore contribute to airway narrowing in asthma or in chronic obstructive pulmonary disease (COPD). Human lungs receive cholinergic, noradrenergic, and peptidergic efferents and several types of afferents. Cholinergic nerve activity contributes to airway narrowing both in asthma and in COPD. Reflex vagal activity may be enhanced because of epithelial damage and exposition of sensory nerve endings to nonspecific irritants. Other possible mechanisms include defects in prejunctional receptors that inhibit acetylcholine release, several postjunctional factors that nonspecifically enhance the effect of a given degree of cholinergic muscle contraction on airway caliber, and interactions between inflammatory mediators and the cholinergic system. The main direct bronchodilating nerve activity in human lungs is nonadrenergic, and scanty data suggest that nonadrenergic inhibitory nerve activity may be variably reduced in asthmatics. Human airway muscle virtually lacks adrenergic innervation, but adrenergic nerves may influence airway caliber by acting on bronchial vessels, mucous glands, and parasympathetic nerves and ganglia. The response of asthmatic airways to beta-agonists seems intrinsically normal, but it may be reduced during severe asthma attacks. There are no convincing data that abnormal adrenergic control is present in the airways of patients with COPD. The physiologic relevance of excitatory neuropeptides in sensory nerves in human airways is uncertain. Tachykinins have proinflammatory and spasmogenic properties and are therefore of potential interest as a factor in the pathogenesis of obstructive airway disease. In conclusion, the data presently available support an abnormal autonomic control of the airways in asthma but not in COPD.

The role of neurotransmitters in bronchial asthma

Neural control of airway caliber is far from simple and it is likely to contribute to the airway narrowing in asthma and chronic obstructive airway disease (COAD). Complex interactions may occur between the different components of autonomic control and inflammatory mediators released from cells in the inflamed airway may profoundly alter the balance of neural control. Further elucidation of these interactions should shed light on the mechanisms of airway disease and may lead to therapeutic advances.

Bronchial blood flow and microvascular permeability in the pathophysiology of asthma

Bronchial smooth muscle contraction is not the only causative factor of airway narrowing in asthma. Other components, such as mucosal and submucosal oedema and mucosal inflammation, also intervene in the processes leading to bronchial obstruction. Re-analysing the role of the tracheo-bronchial circulation is therefore necessary, since participation of the latter, through modification of bronchial blood flow and/or alteration of microvascular permeability, very likely modifies mucosal thickness of the bronchial wall and/or clearance of bronchoactive substances from the airways. This also implies that more attention should be paid on the vascular actions of compounds which are either currently prescribed or under development for future treatment of asthma.

The mechanics of airway narrowing in asthma.

This study was designed to determine the potential importance of airway wall thickening in the pathogenesis of the excess airways narrowing of asthma. The airways in postmortem specimens of lung obtained from 18 patients who suffered from asthma were compared to similar airways from 23 patients without asthma. Each airway was projected onto a digitizing board of a microcomputer to trace the internal and external perimeter of the airway and to calculate the submucosal and mucosal thicknesses. The relaxed length of the airway smooth muscle and the shortening required to occlude the airway lumen were calculated. These data show that the wall area was greater (p less than 0.001) in the membranous and cartilaginous airways of asthmatic patients and the airway smooth muscle shortening required to occlude the lumen was less in asthmatic than nonasthmatic airways (p less than 0.001). The increased wall area was due to increased areas of epithelium, muscle, and submucosa. We conclude that the walls of the airways of patients with asthma are thickened by chronic inflammation and that this thickening could be as important as smooth muscle shortening in determining the airway responsiveness of these patients.

Pulmonary conductance and elastic recoil relationships in asthma and emphysema.

Pulmonary conductance and elastic recoil relationships in asthma and emphysema.