Acute Airway Constriction Research Articles

Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone

Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the absence of epithelium-derived GABA contributes to greater airway smooth muscle force. Messenger RNA encoding glutamic acid decarboxylase (GAD) 65/67 was quantitatively measured in human airway epithelium and smooth muscle. HPLC quantified GABA levels in guinea pig tracheal ring segments under basal or stimulated conditions with or without epithelium. The role of endogenous GABA in the maintenance of an acetylcholine contraction in human airway and guinea pig airway smooth muscle was assessed in organ baths. A 37.5-fold greater amount of mRNA encoding GAD 67 was detected in human epithelium vs. airway smooth muscle cells. HPLC confirmed that guinea pig airways with intact epithelium have a higher constitutive elution of GABA under basal or KCl-depolarized conditions compared with epithelium-denuded airway rings. Inhibition of GABA transporters significantly suppressed KCl-mediated release of GABA from epithelium-intact airways, but tetrodotoxin was without effect. The presence of intact epithelium had a significant GABAergic-mediated prorelaxant effect on the maintenance of contractile tone. Airway epithelium is a predominant cellular source of endogenous GABA in the airway and contributes significant prorelaxant GABA effects on airway smooth muscle force.

The rise of passive airway smooth muscle mechanics

studies on airway hyperresponsiveness and asthma have traditionally focused on changes in the airway smooth muscle (ASM) contractility and associated signaling pathways, with little attention given to the passive smooth muscle properties. As acute airway constriction in asthma is presumably the

Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation

The prevalence of asthma has taken on pandemic proportions. Since this disease predisposes patients to severe acute airway constriction, novel mechanisms capable of promoting airway smooth muscle relaxation would be clinically valuable. We have recently demonstrated that activation of endogenous airway smooth muscle GABA(A) receptors potentiates β-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the α-subunit component of these GABA(A) receptors is limited to the α(4)- and α(5)-subunits. We questioned whether ligands with selective affinity for these GABA(A) receptors could promote relaxation of airway smooth muscle. RT-PCR analysis of GABA(A) receptor subunits was performed on RNA isolated by laser capture microdissection from human and guinea pig airway smooth muscle. Membrane potential and chloride-mediated current were measured in response to GABA(A) subunit-selective agonists in cultured human airway smooth muscle cells. Functional relaxation of precontracted guinea pig tracheal rings was assessed in the absence and presence of the α(4)-subunit-selective GABA(A) receptor agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the α(4)- and α(5)-GABA(A) receptor subunits was identified in RNA isolated by laser capture dissection from guinea pig and human airway smooth muscle tissues. Activation of airway smooth muscle GABA(A) receptors with agonists selective for these subunits resulted in appropriate membrane potential changes and chloride currents and promoted relaxation of airway smooth muscle. In conclusion, selective subunit targeting of endogenous airway smooth muscle-specific GABA(A) receptors may represent a novel therapeutic option for patients in severe bronchospasm.

Airway hyperresponsiveness in asthma: lessons fromin vitromodel systems and animal models: Fig. 1—

Airway hyperresponsiveness (AHR) is a hallmark clinical symptom of asthma. At least two components of AHR have been identified: 1) baseline AHR, which is persistent and presumably caused by airway remodelling due to chronic recurrent airway inflammation; and 2) acute and variable AHR, which is associated with an episodic increase in airway inflammation due to environmental factors such as allergen exposure. Despite intensive research, the mechanisms underlying acute and chronic AHR are poorly understood. Owing to the complex variety of interactive processes that may be involved, in vitro model systems and animal models are indispensable to the unravelling of these mechanisms at the cellular and molecular level. The present paper focuses on a number of translational studies addressing the emerging central role of the airway smooth muscle cell, as a multicompetent cell involved in acute airway constriction as well as structural changes in the airways, in the pathophysiology of airway hyperresponsiveness.

Eosinophil-dependent bromination in the pathogenesis of asthma

Eosinophil-dependent bromination in the pathogenesis of asthma

Diurnal variation in peak expiratory flow rate among polyvinylchloride compounding workers.

The diurnal variation in peak expiratory flow rate (PEFR) was studied in 24 mixers and 24 non-mixers in three polyvinylchloride (PVC) compounding plants and 24 non-PVC controls from a marine police workshop. The three groups (all men) were matched for age, race, and smoking. The mean respirable dust concentration (essentially PVC dust) was 1.6 mg/m3 for mixers and 0.4 mg/m3 for nonmixers. The mean diurnal variation in PEFR of the mixers was 6.5%. This was significantly higher than the 4.8% for non-mixers and 4.3% for the non-PVC controls. Six mixers had a diurnal variation of more than 15% on at least one day compared with none among the other two groups. Twenty nine per cent of mixers complained of wheezing compared with 4% of non-mixers and none among non-PVC workers. These differences were significant. Forced expiratory volume in one second (FEV1) for the mixers was 10% below the predicted values whereas that of non-PVC workers was 2% below predicted values. The study indicates a significant acute airway constriction from occupational exposure to PVC dust.

Airway constrictor response to cotton bract extracts in the absence of endotoxin.

Crude and purified aqueous extracts of cotton bracts shown to cause airway constriction in naive subjects were assayed for endotoxin content. Pulmonary function measured by flow changes on partial expiratory flow volume curves was used to assess airway responses to the bract extracts after their inhalation by a panel of volunteers. These responses are similar to the acute responses experienced by cotton textile workers. Crude aqueous extracts from various bracts harvested before and after senescence of the cotton plant displayed endotoxin concentrations ranging widely from 0.086 to 50 micrograms/ml. No correlation was found between these differences in endotoxin content and the severity of the airway constrictor response. Purifying the bract extract by a series of procedures that included precipitation of polymeric material by addition of methanol and chromatography on an anion exchange column of DEAE-Sephacel resulted in the elimination of almost all the endotoxin. The partially purified extract contained less than 1 ng/ml of endotoxin. The panel of volunteers responded to this purified bract extract, however, with a decrease in pulmonary function which was more than 60% of that seen with the crude extract of bracts. It is concluded that aqueous extracts of cotton bract contain an agent(s) other than endotoxin that causes acute airway constriction in people.

Biologic Activity of Purified Cotton Bract Extracts in Man and Guinea Pig

Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.

Biologic activity of purified cotton bract extracts in man and guinea pig.

Purified aqueous extracts of cotton bract induce acute airway constriction in healthy volunteers never before exposed to cotton bract. The response is similar to that of textile workers who inhale cotton dust. Approximately 60% of volunteers respond to bract extract with significant decreases in lung function, and these volunteers show an increased number of lymphocytes present in their lungs. Following inhalation of bract, the percent of polymorphonuclear leukocytes increases. Macrophages obtained by bronchoalveolar lavage from volunteers pre-challenged with bract extract release increased amounts of chemotactic factor and superoxide anion. Efforts to detect release of histamine and leukotrienes in volunteers following challenge with bract show no increase in urinary histamine and no significant release of leukotrienes in lung lavage fluid. Purified extracts exhibit chemotactic activity in vitro. They also contract guinea pig ileal longitudinal muscle in vitro. This preparation contains mast cells but no basophils, and the H-1 blocker, mepyramine blocks the contraction. Purified bract extracts contain no histamine or endotoxin but other contractors of smooth muscle may be present. The purified extract exhibits spectral, fluorescent, and radioimmune assay properties similar to a leukotriene B-like component. Cotton bract appears to have direct as well as cell-mediated activities.

POSSIBLE MECHANISM OF AIRWAY RESPONSES IN OCCUPATIONAL EXPOSURE TO RESPIRATORY IRRITANTS

Bronchial reactivity was studied in four groups of subjects exposed to dusts and gaseous irritants (hemp dust, hairsprays, polyester resins, fluorine). Subjects with different respiratory symptoms were chosen for the study. Ventilatory capacity was measured by recording maximum expiratory flow-volume (MEFV) curves before and after exposure following pretreatment with propranolol (80 mg), atropine sulphate (1 mg subcutaneously) or a placebo. The exposure to selected irritants caused acute airway constriction. In a number of workers this effect was inhibited by atropine and potentiated by propranolol. The results of the study are consistent with the view that the autonomic nervous system is important in determining the lung's response to irritants. Some other relevant factors such as the alterations in airway smooth muscle or damage of the airway epithelium which may result in sensitization of sensory receptors are discussed.