Postexposure administration of a {beta}2-agonist decreases chlorine-induced airway hyperreactivity in mice.
Exposure to chlorine (Cl(2)) damages airway and alveolar epithelia, resulting in acute lung injury and reactive airway dysfunction syndrome. We evaluated the efficacy and mechanisms by which arformoterol, a long-term β(2)-agonist, administered after exposure, mitigated the extent of this injury. Exposure of C57BL/6 mice to 400 ppm Cl(2) for 30 minutes increased respiratory system resistance and airway responsiveness to aerosolized methacholine (assessed by FlexiVent) up to 6 days after exposure, and decreased Na(+)-dependent alveolar fluid clearance (AFC). Inducible Nitric Oxide Synthase (iNOS) knockout mice developed similar degrees of airway hyperreactivity as wild-type controls after Cl(2) exposure, indicating that reactive intermediates from iNOS do not contribute to Cl(2)-induced airway dysfunction in our model. Intranasal administration of arformoterol mitigated the Cl(2) effects on airway reactivity and AFC, presumably by increasing lung cyclic AMP level. Arformoterol did not modify the inflammatory responses, as evidenced by the number of inflammatory cells and concentrations of IL-6 and TNF-α in the bronchoalveolar lavage. NF-κB activity (assessed by p65 Western blots and electrophoretic mobility shift assay) remained at control levels up to 24 hours after Cl(2) exposure. Our results provide mechanistic insight into the effectiveness of long-term β(2)-agonists in reversing Cl(2)-induced reactive airway dysfunction syndrome and injury to distal lung epithelial cells.
Song
Weifeng
W
901 19th Street South, 224 BMR2, Birmingham, AL 35294, USA.
Wei
Shipeng
S
Liu
Gang
G
Yu
Zhihong
Z
Estell
Kim
K
Yadav
Amit K
AK
Schwiebert
Lisa M
LM
Matalon
Sadis
S
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002713:Chlorine / Q000633:toxicity*; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D058666:Adrenergic beta-2 Receptor Agonists; D002619:Chemical Warfare Agents; D004983:Ethanolamines; D015850:Interleukin-6; D018721:Muscarinic Agonists; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D002713:Chlorine; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D000068759:Formoterol Fumarate