Published ahead of print on September 7, 2006, doi:10.1164/rccm.200603-394OC
Am. J. Respir. Crit. Care Med., Volume 174, Number 11, December 2006, 1179-1188
A more recent version of this article appeared on December 1, 2006
Submitted on March 17, 2006
Accepted on September 6, 2006
Airway Smooth Muscle and Mast Cell-derived CCL19 Mediate Airway Smooth Muscle Migration in Asthma
Davinder Kaur1, Ruth Saunders1, Patrick Berger2, Salman Siddiqui1, Lucy Woodman1, Andrew Wardlaw1, Peter Bradding1, and Christopher E Brightling1*
1 Department of Infection, Inflammation and Immunity, University of Leicester, Institute for Lung Health, Leicester, United Kingdom,
2 Laboratoire de Physiologie Cellulaire Respiratoire, Universite Victor Segalen Bordeaux 2, INSERM E356, Bordeaux 2, France
* To whom correspondence should be addressed. E-mail: ceb17{at}le.ac.uk.
Rationale: Airway smooth muscle hyperplasia is a feature of asthma, and increases with disease severity. We hypothesised that this results from migration of airway
smooth muscle or progenitors in response to chemokines derived from airway smooth muscle or mast cells within the airway smooth muscle bundle. Objectives: to examine expression of the chemokine receptor, CCR7, in vivo by airway smooth muscle in asthmatics and healthy controls and by primary cultures of airway smooth muscle and fibroblasts, to define expression of its ligands, CCL19 and
CCL21, in bronchial biopsies, and primary cultures of airway smooth muscle and mast cells, and to investigate CCR7's role in airway smooth muscle migration and repair. Methods: Airway smooth muscle was isolated from bronchoscopy and resection tissue. Receptor and chemokine expression was examined by immunohistochemistry,
immunofluorescence, flow cytometry, ELISA and RT-PCR. CCR7 function was examined by intracellular calcium measurements, chemotaxis, wound healing assays and measurement of cell proliferation. Measurements and main results: Airway smooth muscle, myofibroblasts and fibroblasts expressed CCR7. CCL19, but not CCL21 was highly expressed in bronchial biopsies by mast cells and vessels in asthma of all severities, airway smooth muscle in severe disease and ex vivo airway smooth muscle and mast cells. Airway smooth muscle CCR7 activation by CCL19 mediated intracellular calcium elevation and concentration-dependent migration, but not proliferation. Importantly, mast cell and airway smooth muscle-derived CCL19 mediated airway smooth muscle migration and repair. Conclusions: The CCL19/CCR7 axis may play an important role in the development of airway smooth muscle hyperplasia in asthma.
Key words: Asthma, airway smooth muscle, mast cells, CCR7, CCL19
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