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Published ahead of print on June 17, 2004, doi:10.1165/rcmb.2003-0241OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 4, October 2004, 440-445

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Submitted on June 24, 2003
Revised on June 16, 2004

Extracellular matrix modulates {beta}2-adrenergic receptor signalling in human airway smooth muscle cells

Anette M Freyer1*, Charlotte K Billington2, Raymond B Penn3, and Ian P Hall1

1 Division of Therapeutics and Molecular Biology, University of Nottingham, Nottingham, United Kingdom, 2 Division of Critical Care, Pulmonary, Allergic and Immunologic Diseases, Thomas Jefferson University, Philadelphia, PA, USA, 3 Center for Human Genomics, Wake Forest University Health Science Center, Wake Forest, NC, USA

* To whom correspondence should be addressed. E-mail: anette.freyer{at}nottingham.ac.uk.

The airways of patients with chronic asthma commonly develop an element of fixed airway obstruction, which fails to reverse with inhaled {beta}2-adrenoceptor agonists. Airway remodelling refers to the structural changes of the bronchi in longstanding asthma and is characterised by increased deposition and altered ratios of extracellular matrix (ECM) proteins. We therefore assessed whether ECM proteins alter {beta}2-adrenoceptor signalling in human airway smooth muscle (ASM) cells. We report that a fibronectin environment increases responses to {beta}2-adrenoceptor stimulation, whereas exposure to collagen V or laminin decreases accumulation of the second messenger cyclic AMP when compared to collagens I or IV. These differences are likely to be physiologically significant as they translate into altered phosphorylation of the downstream target VASP. The altered cAMP levels are due to differences in adenylyl cyclase activity, though expression of the relevant isoforms of enzyme appears unaltered. However, inhibition of G{alpha}i abrogates the differences in {beta}2-adrenoceptor-mediated cAMP accumulation in cells exposed to different matrix factors. The difference in G{alpha}i-signalling is not due to altered G{alpha}i expression. We conclude therefore that ECM modulates G{alpha}i activity in human ASM cells, and propose that these changes could contribute to the fixed airway obstruction seen in patients with chronic asthma.




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