Changes In Airway Function Research Articles

Efficacy of inhaled corticosteroids in asthma

Inhaled corticosteroids have now become established as first-line therapy for patients with persistent asthma. Corticosteroids are the only currently available asthma therapy that suppress inflammation in asthmatic airways, and they inhibit almost every aspect of the inflammatory process in asthma. Inhaled corticosteroids are effective in most patients with asthma, irrespective of age or asthma severity. They not only control asthma symptoms and improve lung function but also prevent exacerbations and may reduce asthma mortality and the irreversible changes in airway function that occur in some patients. The dose-response curve to inhaled corticosteroids is relatively flat, and there is increasing evidence that addition of another class of therapy (long-acting inhaled β 2 -agonists, low-dose theophylline, or antileukotrienes) may be preferable to increasing the dose of inhaled corticosteroids in patients with moderate-to-severe asthma. Inhaled corticosteroids are convenient to use and are the most cost-effective treatment currently available for long-term asthma control. A small proportion of patients are resistant to the antiinflammatory effects of corticosteroids. Future developments may include inhaled corticosteroids with even fewer systemic effects or more specific antiinflammatory drugs. (J Allergy Clin Immunol 1998;102:531-8.)

Changes in airway function and bronchial responsiveness after acute occupational exposure to chlorine leading to treatment in a first aid unit.

OBJECTIVES: To describe the baseline characteristics and the time course of changes in lung function in workers accidentally inhaling high concentrations of chlorine in a prospective study. METHODS: Baseline spirometry...

Hyperinnervation of the Airways in Transgenic Mice Overexpressing Nerve Growth Factor

Neuropeptides released from sensory nerve endings are potential mediators of airway inflammation in asthma and lung injury induced by inhalation of respiratory irritants. To develop an in vivo model for assessing the contribution of neurogenic inflammation in these processes, we have generated transgenic mice with altered innervation of the lung. To generate mice with an increased innervation of the airways, we placed the gene that encodes nerve growth factor (NGF) under control of the lung-specific Clara-cell secretory protein (CCSP) promoter. Two lineages of CCSP-NGF transgenic mice overexpressed NGF in the lung and developed a hyperinnervation of the airways. Immunohistochemistry for substance P, a substance P enzyme immunoassay, and catecholamine histofluorescence indicated that both tachykinin-containing sensory fibers and sympathetic fibers were increased around the airways of CCSP-NGF mice. Treatment of CCSP-NGF mice with the sympathetic-specific neurotoxin 6-hydroxydopamine (6-OHDA) eliminated the sympathetic component of the airway innervation, leaving a specific hyperinnervation by tachykinin-containing sensory fibers. CCSP-NGF mice were more sensitive than normal mice to capsaicin-induced increases in respiratory system resistance, demonstrating that the increased sensory innervation led to a change in airway function. We conclude that NGF overexpression from a lung-specific promoter produces anatomic and functional changes in lung innervation, and that CCSP-NGF mice will be useful for studying the role of neurogenic inflammation in airway disease.

Early neutrophil but not eosinophil or platelet recruitment to the lungs of allergic horses following antigen exposure.

Previous studies have shown that bronchoalveolar lavage fluid from horses with allergic respiratory disease and showing clinical symptoms contains increased numbers of neutrophils. In some cases, the eosinophil count is also increased. In this study the time course of changes in lung function and the accumulation of radiolabelled leucocytes and platelets in the lungs of allergic and normal horses has been examined during a 7 hr allergen exposure. Antigen challenge had no effect on pleural pressure or the distribution of radiolabelled neutrophils, eosinophils or platelets in normal horses. In contrast, in 6/8 allergic horses, there was an increase in pleural pressure and neutrophil accumulation in the lungs, both of which were evident after 4-5 hr. However, during the 7 hr challenge period radiolabelled eosinophils were detected in the lungs of only 1/6 horses exhibiting an increase in pleural pressure and in 1/7 horses that failed to show a change in airway function despite a clinical history of allergic respiratory disease. Antigen challenge did not alter the distribution of radiolabelled platelets in the five allergic horses tested. These results demonstrate that increased pleural pressure is not accompanied by eosinophil or platelet accumulation in the lungs of horses with allergic respiratory disease following exposure to antigen. However, changes in airway function can be associated with neutrophil accumulation but can also take place in the absence of this cell recruitment. This raises the possibility that the presence of neutrophils in the lung is not a prerequisite for changes in lung function.

The Asthma Symptom Profile: A psychophysically based scale for assessment of asthma symptoms

The Asthma Symptom Profile (ASP) assesses phasic changes in three dimensions of asthma symptoms: intensity, unpleasantness, and quality of sensations. Quantification data on verbal descriptors were gathered from 46 adult asthmatics for each of these scales, using bimodality scaling: i.e., with numerical estimates and drawing lines varying length. Close agreement was obtained between these two modalities. The ASP was analyzed before and after a bronchodilator in 44 asthmatics using ipratropium bromide (IB). Forty of these subjects were also tested in a placebo condition. Although ASP changes produced by IB were no greater than those produced by the placebo, correlations with changes in spirometry variables were significant. There were no significant differences in correlations with line drawings vs. numerical ratings. The ASP appears to be useful measure of phasic changes in asthma symptoms. Asthmatics with mild airway obstruction do not appear to be able to discriminate small changes in airway function.

Adhesion molecules in a primate model of allergic asthma: clinical implications for respiratory care.

Prompted by the realization of the importance of chronic airway inflammation in allergic asthma, recent interest has focused on defining the role of adhesion glycoproteins in the development of airway inflammation and subsequent changes in airway function. Many studies in vitro and in vivo have demonstrated an increased expression of certain adhesion molecules on vascular endothelium, airway epithelium and circulating leukocytes associated with the inflammatory response to allergen. Studies with animal models of allergic asthma have shown the effectiveness of antagonists of adhesion molecules in blocking the development of airway inflammation and changes in airways function. These studies suggest that inhibitors of cellular adhesion molecules may represent a novel form of treatment directed specifically at the chronic airway inflammation characteristic of bronchial asthma.

Bronchial Reactivity in Patients Undergoing Long-Term Haemodialysis for Chronic Renal Failure

Trapping of neutrophils within the lung occurs in patients undergoing haemodialysis and is also a possible mechanism in the pathogenesis of bronchial hyper-responsiveness. Falls in peak expiratory flow rate occur in most dialysis patients, and some develop overt asthmatic symptoms. To see whether these changes in airway function are secondary to increases in bronchial reactivity during haemodialysis, we therefore performed histamine challenge testing in 6 non-asthmatic patients before and after haemodialysis. No change in reactivity was observed, suggesting that haemodialysis does not commonly result in bronchial hyper-reactivity in non-asthmatic individuals.

The inflammatory response in asthma exacerbation: changes in circulating eosinophils, basophils and their progenitors

Circulating eosinophils, basophils and eosinophil/basophil (Eo/B) progenitors were examined in 12 patients at the time of an exacerbation of asthma accompanied by sputum eosinophilia and after resolution of the exacerbation with inhaled corticosteroid treatment. Differential counts were performed and peripheral blood non-adherent mononuclear cells were cultured for 14 days in methyl-cellulose to determine the number of Eo/B and granulocyte-macrophage (GM) colonies without knowledge of the clinical conditions or findings. With resolution of the asthma exacerbation on beclomethasone therapy, there were significant falls in circulating eosinophils, basophils and Eo/B colonies whereas GM colonies were unchanged. To elucidate whether the observed changes could be due to systemic absorption or local action of inhaled corticosteroid, seven subjects with allergic rhinitis and no current evidence of lower airway inflammation (no symptoms of asthma and normal methacholine airway responsiveness) received 14 days' treatment with the same dose of inhaled beclomethasone or of placebo in a double-blind randomized cross-over study. No significant changes in airway function or in circulating cell counts were observed. The results suggest reduced production of eosinophils and basophils after the resolution of an exacerbation of asthma. This effect may be due to reduced levels of airway-derived eosinophil-basophil growth and differentiation factors.

Pulmonary antigen challenge in rats passively sensitized with a monoclonal IgE antibody induces immediate but not late changes in airway mechanics.

Pulmonary antigen challenge in sensitized individuals results in isolated immediate, isolated late, or dual reactions consisting of both an immediate and late change in airway function. The immediate response appears to be dependent on the presence of IgE antibody and mast cell mediator release. Although the late phase of dual responses is considered to be related to or a continuum of the immediate hypersensitivity response, its precise pathogenesis remains to be determined. To increase both the sensitivity and specificity of analyzing the pathogenesis of IgE-dependent pulmonary responses, we have used a Sprague-Dawley rat model system in which rats are passively sensitized with a murine monoclonal IgE anti-dinitrophenol (DNP) antibody prior to challenge with DNP-bovine serum albumin (DNP-BSA). Pathogen-free rats were injected with IgE or saline in a randomized blinded protocol, and in 24 to 48 h were anesthetized with urethane (1.2 g/kg intraperitoneally) and instrumented to measure lung resistance (RL) and dynamic compliance (Cdyn). Rats were then challenged with aerosolized DNP-BSA (10 mg/ml), and RL and Cdyn monitored through 7 h after challenge. Both RL (0.30 +/- 0.10 versus 0.13 +/- 0.02 cm H2O/ml.sec-1) and Cdyn (0.41 +/- 0.10 versus 0.25 +/- 0.08 ml/cm H2O) were significantly different (p less than 0.05) in sensitized rats compared to control rats immediately after challenge. No late changes were observed in either the treated or control animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary Function Analysis in the Rabbit Following Bronchochallenge to Causative Agents and Mediators of the Acute Byssinotic Response

New Zealand White rabbits were acutely bronchochallenged for 5 min to ascertain airway responsiveness with six potential byssinogenic agents and mediators: 0.1 g/mL cotton dust extract (CDE), 0.1 g/mL cotton bract extract (CBE), 1 mg/mL endotoxin, 1 mg/mL n-formyl methionyl peptide (n-fMet), 10 mg/mL 5-hydroxytryptamine (5-HT), and 1 mg/mL prostaglandin F2 alpha (PGF2 alpha). Methacholine (MC), 10 mg/mL, was used as a control bronchoconstrictor. Clinically objective criteria were established using increases in resistance values compared to those obtained with saline controls. Animals were classified as: mild responders (Mi) = 125-149%; moderate responders (Mo) = 150-199%; or severe responders (S) = greater than 200%. Three of five (2Mo, 1S) rabbits showed increased pulmonary resistance to CDE bronchochallenge, 3/5 (1Mi, 1Mo, 1S) to CBE, 1/5 (Mo) to purified endotoxin, 4/5 (1Mo, 3S) to n-fMet, 3/5 (1Mi, 1Mo, 1S) to 5-HT, and 2/5 (1Mo, 1S) to PGF2 alpha. All five rabbits (1Mo, 4S) responded to MC bronchochallenge. Rabbits responded minimally to saline, the common solvent of all test agents; however, when challenged with methacholine, a known bronchoconstrictor, rabbits showed significant overt symptoms of acute respiratory distress with immediate and substantial increases in resistance over saline controls. CDE, CBE, and n-fMet inhalation challenge resulted in a majority or all animals showing increased resistance. 5-HT contained in CDE and CBE, exhibited similar resistance increases; however, endotoxin, also found in cotton dust, showed little airway reactivity. The rabbit is useful for characterizing changes in pulmonary function parameters seen in the acute byssinotic reaction. This study has demonstrated that bronchochallenge in the rabbit with potential byssinogenic agents (CDE, CBE, endotoxin, and n-fMet) and mediators (5-HT and PGF2 alpha) result in measurable changes in airway function, particularly increased resistance. Since bronchoconstriction is the major clinical manifestation of the acute byssinotic reaction in man and animals, it is likely that bronchoconstriction observed in cotton mill workers may be in part or totally the result of inherent dust constrictor substances or secondarily released mediators.

Pulmonary function analysis in the rabbit following bronchochallenge to causative agents and mediators of the acute byssinotic response.

New Zealand White rabbits were acutely bronchochallenged for 5 min to ascertain airway responsiveness with six potential byssinogenic agents and mediators: 0.1 g/mL cotton dust extract (CDE), 0.1 g/mL cotton bract extract (CBE), 1 mg/mL endotoxin, 1 mg/mL n-formyl methionyl peptide (n-fMet), 10 mg/mL 5-hydroxytryptamine (5-HT), and 1 mg/mL prostaglandin F2 alpha (PGF2 alpha). Methacholine (MC), 10 mg/mL, was used as a control bronchoconstrictor. Clinically objective criteria were established using increases in resistance values compared to those obtained with saline controls. Animals were classified as: mild responders (Mi) = 125-149%; moderate responders (Mo) = 150-199%; or severe responders (S) = greater than 200%. Three of five (2Mo, 1S) rabbits showed increased pulmonary resistance to CDE bronchochallenge, 3/5 (1Mi, 1Mo, 1S) to CBE, 1/5 (Mo) to purified endotoxin, 4/5 (1Mo, 3S) to n-fMet, 3/5 (1Mi, 1Mo, 1S) to 5-HT, and 2/5 (1Mo, 1S) to PGF2 alpha. All five rabbits (1Mo, 4S) responded to MC bronchochallenge. Rabbits responded minimally to saline, the common solvent of all test agents; however, when challenged with methacholine, a known bronchoconstrictor, rabbits showed significant overt symptoms of acute respiratory distress with immediate and substantial increases in resistance over saline controls. CDE, CBE, and n-fMet inhalation challenge resulted in a majority or all animals showing increased resistance. 5-HT contained in CDE and CBE, exhibited similar resistance increases; however, endotoxin, also found in cotton dust, showed little airway reactivity. The rabbit is useful for characterizing changes in pulmonary function parameters seen in the acute byssinotic reaction. This study has demonstrated that bronchochallenge in the rabbit with potential byssinogenic agents (CDE, CBE, endotoxin, and n-fMet) and mediators (5-HT and PGF2 alpha) result in measurable changes in airway function, particularly increased resistance. Since bronchoconstriction is the major clinical manifestation of the acute byssinotic reaction in man and animals, it is likely that bronchoconstriction observed in cotton mill workers may be in part or totally the result of inherent dust constrictor substances or secondarily released mediators.

The effect of acute small airway inflammation on pulmonary function in dog.

To test the hypothesis that acute inflammation in peripheral airways can cause changes in airway function, we measured lung mechanics and assessed postmortem histology in 20 dogs. After baseline measurements of subdivisions of lung volume, pressure volume curves, pulmonary resistance (RL), dynamic compliance (Cdyn), closing capacity (CC), and the slope of phase 3 of the single breath N2 washout curve (delta N2/L), 10 dogs breathed nebulized 0.25% HCl (Group 2) and 10 breathed nebulized normal saline (Group 1). Measurements were repeated at 90-min intervals for 4 h. Animals were killed and 1 lung fixed in inflation and sampled for quantitative histology. The severity of the inflammatory reaction was assessed by evaluating the number of polymorphonuclear leukocytes per airway. Wet-to-dry-weight ratios were measured in the other lung. In Group 2, RL, delta N2/L, residual volume, and CC increased, whereas Cdyn decreased after acid inhalation; Cdyn and delta N2/L remained significantly different at the end of the experiment. Bilateral vagotomy, carried out in 5 dogs from each group, did not alter the acid-induced effects in Group 2. There was no difference between groups in wet-to-dry weight ratios. Group 2 had a more severe inflammatory reaction in the peripheral airways than Group 1 (p less than 0.025). We conclude that minimal, acute peripheral airway inflammation is associated with detectable abnormalities in small airway function.

Acute effects of smoking a single cigarette on the airway resistance and the maximal and partial forced expiratory flow volume curves

The acute airway response to smoking a single cigarette was assessed in eight symptom-free male smokers. The changes in airway function were determined using a computer analysis of maximal and partial expiratory flow volume curves together with measurement of airway resistance. The amount of smoke inhaled was assessed by measuring levels of nicotine in venous blood. When the results of all studies were analysed for the group as a whole only small and inconsistent changes in airway function were observed after smoking a cigarette, although all the subjects appeared to inhale the smoke. Although the group showed inconsistent changes, one subject exhibited a change on all four occasions in the studies using the maximal and partial expiratory flow volume curves. This was seen particularly for Vmax50 and Vmax40 obtained from the maximal and partial expiratory flow volume curves respectively. There appeared to be no difference between the two manoeuvres in their sensitivity to smoke-induced change. One subject showed a response to smoking when airways resistance was measured but this was on only one of two occasions. It is therefore possible that certain smokers are more susceptible to inhaled cigarette smoke and such individuals may be those who develop chronic airflow obstruction. The absence of a group effect was attributed to any smoking response being smaller than the other factors which affect measurements of airway function.

Acute effects of smoking a single cigarette on the airway resistance and the maximal and partial forced expiratory flow volume curves

The acute airway response to smoking a single cigarette was assessed in eight symptom-free male smokers. The changes in airway function were determined using a computer analysis of maximal and partial expiratory flow volume curves together with measurement of airway resistance. The amount of smoke inhaled was assessed by measuring levels of nicotine in venous blood. When the results of all studies were analysed for the group as a whole only small and inconsistent changes in airway function were observed after smoking a cigarette, although all the subjects appeared to inhale the smoke. Although the group showed inconsistent changes, one subject exhibited a change on all four occasions in the studies using the maximal and partial expiratory flow volume curves. This was seen particularly for Vmax50 and Vmax40 obtained from the maximal and partial expiratory flow volume curves respectively. There appeared to be no difference between the two manoeuvres in their sensitivity to smoke-induced change. One subject showed a response to smoking when airways resistance was measured but this was on only one of two occasions. It is therefore possible that certain smokers are more susceptible to inhaled cigarette smoke and such individuals may be those who develop chronic airflow obstruction. The absence of a group effect was attributed to any smoking response being smaller than the other factors which affect measurements of airway function.

Response of the lung airway to exercise testing in asthma and rhinitis

The reactivity of the large and small airways of the lung in a group of ten atopic subjects with rhinitis was compared with that in ten non-atopic control subjects and in 17 with atopic asthma. Atopic state was assessed by skin prick testing with 22 common allergens and by measurement of total serum immunoglobulin E (IgE) antibody. The atopic state of the rhinitis and asthma patients was similar. Exercise provocation tests were performed on each subject and changes in airway function were measured by peak expiratory flow rate, forced expiratory volume in one second, vital capacity, maximal expiratory flow volume curves and closing volume. There were no statistically significant differences between the changes in lung function after exercise in the rhinitis patients compared with the controls. There were, however, statistically significant changes in all the measurements of respiratory function in those with asthma compared with the other two groups. The falls in forced expiratory flow rates in the asthmatic subjects were greater at lower lung volumes than near the total lung capacity, perhaps indicating that narrowing of small, as well as large, airways was occurring. No correlation was found between the magnitude of the airway response to exercise and either the total serum IgE antibody or the mean weal diameter of positive skin tests in each subject. Atopic subjects with rhinitis but not asthma showed no evidence of bronchial hyper-reactivity on exercise testing. It is therefore suggested that single exercise provocation test can discriminate subjects with atopic asthma from those with other atopic disorders.

A Comparison of Metoprolol and Propranolol on Blood Pressure and Respiratory Function in Patients with Hypertension

Summary: The effects on blood pressure and airway function of the chronic oral administration of two beta blocking agents, propranolol and metoprolol, were studied. Mean arterial pressure (MAP) fall was maximum with 160 mg of propranolol daily (‐12 mmHg, P < 0 05) and 100 mg of metoprolol (‐9 mmHg, P < 0 05) and MAP did not fall further with an increase in dose of either drug. Nine of ten patients whose lung function was assessed showed a change in airway function, with a mean fall in maximal mid‐expiratory flow rate (MMFR) of 05 litres per second (I.sec‐1) on propranolol and 0–36 I.sec‐1on metoprolol. The fall was not related to smoking or to atopic status. These data support the hypothesis that there is resting beta adrenergic bronchodilator activity in non‐asthmatic subjects. This activity can be blocked by chronic oral administration of beta blocking drugs. The fall in MMFR in subjects with prior but unrecognized obstruction in the small airways may be sufficient to cause severe malfunction and these drugs should be used with caution in patients with chronic airways obstruction. The fall in MMFR was reversed by salbutamol while the patients were taking metoprolol, but not while they were taking propranolol, suggesting that propranolol has greater affinity than metoprolol for the bronchial beta adrenergic receptors.