title: Alteration of Airway Reactivity and Reduction of Ryanodine Receptor Expression by Cigarette Smoke in Mice.
abstract: Small airways are a major site of airflow limitation in chronic obstructive pulmonary disease (COPD). Despite the detrimental effects of long-term smoking in COPD, the effects of acute cigarette smoke (CS) exposure on small airway reactivity have not been fully elucidated. Balb/C mice were exposed to room air (sham) or CS for 4 days to cause airway inflammation. Changes in small airway lumen area in response to contractile agents were measured in lung slices in situ using phase-contrast microscopy. Separate slices were pharmacologically maintained at constant intracellular Ca(2+) using caffeine/ryanodine before contractile measurements. Gene and protein analysis of contractile signaling pathways were performed on separate lungs. Monophasic contraction to serotonin became biphasic after CS exposure, whereas contraction to methacholine was unaltered. This altered pattern of contraction was normalized by caffeine/ryanodine. Expression of contractile agonist-specific receptors was unaltered; however, all isoforms of the ryanodine receptor were down-regulated. This is the first study to show that acute CS exposure selectively alters small airway contraction to serotonin and down-regulates ryanodine receptors involved in maintaining Ca(2+) oscillations in airway smooth muscle. Understanding the contribution of ryanodine receptors to altered airway reactivity may inform the development of novel treatment strategies for COPD.
authors.affiliation: 1 Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Chantal
authors.initials: C
authors.lastname: Donovan
authors.affiliation: 1 Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Huei Jiunn
authors.initials: HJ
authors.lastname: Seow
authors.affiliation: 2 Department of Pharmacology, Monash University, Clayton, Victoria, Australia; and.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Royce
authors.affiliation: 1 Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.|2 Department of Pharmacology, Monash University, Clayton, Victoria, Australia; and.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Bourke
authors.affiliation: 1 Lung Health Research Centre, Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia.|3 School of Health Sciences, Health Innovations Research Institute, RMIT University, Bundoora, Victoria, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Vlahos
mesh_terms: D000403:Airway Resistance; D000818:Animals; D020013:Calcium Signaling; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D012907:Smoking / Q000009:adverse effects*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D016210:Methacholine Chloride; D012701:Serotonin
keywords: Ca2+ signaling; airway reactivity; cigarette smoke; lung slices; small airways