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Published ahead of print on May 18, 2006, doi:10.1164/rccm.200509-1420OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 4, August 2006, 379-385

A more recent version of this article appeared on August 15, 2006
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Submitted on September 12, 2005
Accepted on May 16, 2006

Extracellular Matrix Regulates Enhanced Eotaxin Expression in Asthmatic Airway Smooth Muscle Cells

Vivien Chan1, Janette K Burgess2, Jonathan C Ratoff3, Brian J O'Connor3, Anne Greenough1, Tak H Lee1, and Stuart J Hirst1*

1 MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, King's College London School of Medicine, London, United Kingdom; Division of Asthma, Allergy and Lung Biology, King's College London School of Medicine, London, United Kingdom, 2 Woolcock Institute of Medical Research, Department of Pharmacology, University of Sydney, Sydney, Australia, 3 Division of Asthma, Allergy and Lung Biology, King's College London School of Medicine, London, United Kingdom

* To whom correspondence should be addressed. E-mail: stuart.hirst{at}kcl.ac.uk.

Rationale: Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with fibronectin and collagen are key features of asthma. Previously, we have reported these ECM proteins enhance ASM synthetic function. Objective: We compared ASM cultured from endobronchial biopsies from subjects with and without asthma to assess if asthmatic cells were hypersecretory and determined whether the underlying mechanism involved autocrine ECM production. Methods and measurements: Cells from subjects with and without asthma were cultured on plastic or in plates pre-coated with ECM proteins. Cytokine production was evaluated by enzyme-linked immunosorbent assay and by reverse transcriptase-polymerase chain reaction. Function blocking integrin antibodies were used to identify integrin involvement. Results: Baseline eotaxin and its production following stimulation with interleukin (IL)-13, IL-1{beta} or tumor necrosis factor-{alpha} was increased (2.5-to-6.0-fold) in ASM cells cultured from asthmatics compared with healthy subjects. When seeded on ECM from asthmatic ASM, IL-13-dependent eotaxin release from healthy or asthmatic ASM was enhanced compared with culture on healthy ECM. The ECM substrates fibronectin and type I collagen each enhanced IL-13-dependent eotaxin release and Western immunoblot indicated that fibronectin expression was higher in asthmatic ASM cells. Integrin blocking antibodies revealed that {alpha}5{beta}1 was required for more than 50% of the enhanced IL-13-dependent eotaxin release by ASM cells from asthmatics whilst {alpha}2{beta}1 or {alpha}v{beta}3 neutralization lacked effect. Conclusion: The data indicate that ASM cultured from asthmatics are hypersecretory compared with cells from healthy donors and that autocrine fibronectin secretion acting via {alpha}5{beta}1 in part underlies this effect.
Key words: airway remodeling, airway smooth muscle, eotaxin, extracellular matrix, integrin




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