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Am J Physiol Lung Cell Mol Physiol 286: L437-L444, 2004; doi:10.1152/ajplung.00158.2003
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Retinoic acid reverses the airway hyperresponsiveness but not the parenchymal defect that is associated with vitamin A deficiency

Stephen E. McGowan, Amey Jo Holmes, and Jennifer Smith

Research Service, Veterans Affairs Medical Center and the Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242

Submitted 20 May 2003 ; accepted in final form 16 October 2003

Airway hyperresponsiveness (AHR) is influenced by structural components of the bronchial wall, including the smooth muscle and connective tissue elements and the neuromuscular function. AHR is also influenced by parenchymally derived tethering forces on the bronchial wall, which maintain airway caliber by producing outward radial traction. Our previous work has shown that vitamin A-deficient (VAD) rats exhibit cholinergic hyperresponsiveness and a decrease in the expression and function of the muscarinic-2 receptors (M2R). We hypothesized that if decreases in radial traction from airway or parenchymal structures contributed to the VAD-related increase in AHR, then the radial traction would normalize more slowly than VAD-related alterations in neurotransmitter signaling. Rats remained vitamin A sufficient (VAS) or were rendered VAD and then maintained on the VAD diet in the presence or absence of supplementation with all-trans retinoic acid (RA). VAD was associated with an approximately twofold increase in respiratory resistance and elastance compared with VAS rats. Exposure to RA for 12 days but not 4 days restored resistance and elastance to control (VAS) levels. In VAD rats, AHR was accompanied by decreases in bronchial M2R gene expression and function, which were restored after 12 days of RA supplementation. Subepithelial bronchial elastic fibers were decreased by ~50% in VAD rats and were significantly restored by RA. The increase in AHR that is associated with VAD is accompanied by decreases in M2R expression and function that can be restored by RA and a reduction in airway elastic fibers that can be partially restored by RA.

asthma; retinoids; retinol; cholinergic; muscarinic; elastin



Address for reprint requests and other correspondence: S. McGowan, C33B G. H., Dept. of Internal Medicine, Univ. of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242 (E-mail: stephen-mcgowan{at}uiowa.edu).




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