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Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

ABSTRACT: In vitro and animal experiments have shown that the transport and signaling of ?2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic ?2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway.Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (?Q?aw) were assessed.Mean?±?SE EBC pH (units) and ?Q?aw (?l.min(-1).mL(-1)) were 6.4?±?0.1 and 16.8?±?1.9 during quiet breathing, 6.3?±?0.1 and 14.5?±?2.4 during eucapnic hyperventilation, 6.6?±?0.2 and -0.2?±?1.8 during hypocapnic hyperventilation (p?=?0.02 and <0.01 vs. quiet breathing), and 5.9?±?0.1 and 2.0?±?1.5 during hypercapnic hyperventilation (p?=?0.02 and <0.02 vs quiet breathing).Albuterol responsiveness in the airway as assessed by ?Q?aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic ?2-adrenergic agonists during airway disease exacerbations associated with changes in pH.Registered at clinicaltrials.gov: NCT01216748 .

SUBMITTER: Cancado JE

PROVIDER: S-EPMC4384333 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

Cancado Jose E JE Mendes Eliana S ES Arana Johana J Horvath Gabor G Monzon Maria E ME Salathe Matthias M Wanner Adam A

BMC pharmacology & toxicology 20150402

<h4>Background</h4>In vitro and animal experiments have shown that the transport and signaling of β2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic β2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to ...[more]

PMID: 25889594

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Project description:Selective stimulation of IL-4 receptor on smooth muscle induces airway hyper-responsiveness in mice. Abstract: Production of the cytokines IL-4 and IL-13 is increased in both human asthma and mouse asthma models and Stat6 activation by the common IL-4/IL-13R drives most mouse model pathophysiology, including airway hyperresponsiveness (AHR). However, the precise cellular mechanisms through which IL-4Rα induces AHR remain unclear. Overzealous bronchial smooth muscle constriction is thought to underlie AHR in human asthma, but the smooth muscle contribution to AHR has never been directly assessed. Furthermore, differences in mouse vs. human airway anatomy and observations that selective IL-13 stimulation of Stat6 in airway epithelium induces murine AHR raise questions about the importance of direct IL-4R effects on smooth muscle in murine asthma models and relevance of these models to human asthma. Using transgenic mice in which smooth muscle is the only cell type that expresses or fails to express IL-4Rα, we demonstrate that direct smooth muscle activation by IL-4, IL-13, or allergen is sufficient, but not necessary, to induce AHR and show that 5 genes known to promote smooth muscle migration, proliferation and contractility are activated by IL-13 in smooth muscle in vivo. These observations demonstrate that IL-4Rα promotes AHR through multiple mechanisms and provide a model for testing smooth muscle-directed asthma therapeutics. For the microarray aspect of of the study, there were three groups of mice: 1. IL4R gene knockout (KO) mice 2. WT mice 3. IL4R KO mice that were also transgenic for a gene construct that expressed IL4R under the control of the smooth muscle-specific promoter from the SMP8 gene All mice were subjected to intratracheal IL13 exposure for 7 days, and whole lung RNA was prepared for microarray analysis 24 hours after the last instillation. Per treatment and genotype: Two RNA pools were made from four mice each. These were labeled and hybridized to make a total of 6 microarrays. RNA was labeled with the standard Affymetrix 3' labeling protocol to make cDNA that was hybridized to Mouse MOE 430 plus 2.0 GeneChips. Gene transcripts were identified that differed in their relative expression as a function of IL4R expression on the smooth muscle cells.

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Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

Publications

Effect of airway acidosis and alkalosis on airway vascular smooth muscle responsiveness to albuterol.

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