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Published ahead of print on June 17, 2004, doi:10.1165/rcmb.2003-0241OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 31, pp. 440-445, 2004
© 2004 American Thoracic Society
DOI: 10.1165/rcmb.2003-0241OC

Extracellular Matrix Modulates ß2-Adrenergic Receptor Signaling in Human Airway Smooth Muscle Cells

Anette M. Freyer, Charlotte K. Billington, Raymond B. Penn and Ian P. Hall

Division of Therapeutics and Molecular Biology, University of Nottingham, Queens Medical Centre, Nottingham, United Kingdom; Division of Critical Care, Pulmonary, Allergic and Immunologic Diseases, Thomas Jefferson University, Philadelphia, Pennsylvania; and Wake Forest University Health Science Center, Center for Human Genomics, Winston-Salem, North Carolina

Address correspondence to: Anette M. Freyer, Division of Therapeutics and Molecular Biology, University of Nottingham, D Floor, South Block, Queens Medical Centre, Nottingham NG7 2UH, UK. 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 ß2-adrenoceptor agonists. Airway remodeling refers to the structural changes of the bronchi in longstanding asthma and is characterized by increased deposition and altered ratios of extracellular matrix (ECM) proteins. We therefore assessed whether ECM proteins alter ß2-adrenoceptor signaling in human airway smooth muscle cells. We report that a fibronectin environment increases responses to ß2-adrenoceptor stimulation, whereas exposure to collagen V or laminin decreases accumulation of the second messenger cyclic AMP when compared with 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, although expression of the relevant isoforms of enzyme appears unaltered. However, inhibition of G{alpha}i abrogates the differences in ß2-adrenoceptor–mediated cAMP accumulation in cells exposed to different matrix factors. The difference in G{alpha}i signaling is not due to altered G{alpha}i expression. We conclude therefore that ECM modulates G{alpha}i activity in human airway smooth muscle cells, and propose that these changes could contribute to the fixed airway obstruction seen in patients with chronic asthma.

Abbreviations: actinomycin D, ACD • airway smooth muscle, ASM • specific binding sites, Bmax • cyclic AMP, cAMP • cycloheximide, CHX • Dulbecco's modified Eagle's medium, DMEM • extracellular matrix, ECM • fibronectin, FN • forskolin, FSK • isoproterenol, ISO • laminin, LN • mitogen-activated protein kinase, MAPK • phosphate-buffered saline, PBS • phosphodiesterase, PDE • cAMP-dependent protein kinase, PKA • pertussis toxin, PTX • tris-buffered saline, TBS •




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