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Airway Smooth Muscle and Mast Cell–derived CC Chemokine Ligand 19 Mediate Airway Smooth Muscle Migration in Asthma

Institute for Lung Health, and Department of Infection, Inflammation and Immunity, University of Leicester, Leicester, United Kingdom; Laboratoire de Physiologie Cellulaire Respiratoire, INSERM E356; and Université Victor Segalen, Bordeaux, France

Correspondence and requests for reprints should be addressed to Dr. C.E. Brightling, M.R.C.P., Ph.D., Department of Respiratory Medicine, University Hospitals of Leicester, Groby Road, Leicester LE3 9QP, UK. E-mail: ceb17{at}le.ac.uk

Rationale: Airway smooth muscle (ASM) hyperplasia is a feature of asthma, and increases with disease severity. We hypothesized that this results from migration of ASM or progenitors in response to chemokines derived from ASM or mast cells within the ASM bundle.

Objectives: To examine expression of the chemokine receptor, CC chemokine receptor (CCR) 7, in vivo by ASM in patients with asthma and healthy control subjects, and by primary cultures of ASM and fibroblasts; to define expression of its ligands, CC chemokine ligand (CCL) 19 and CCL21, in bronchial biopsies, and primary cultures of ASM and mast cells; and to investigate CCR7's role in ASM migration and repair.

Methods: ASM was isolated from bronchoscopy and resection tissue. Receptor and chemokine expression was examined by immunohistochemistry, immunofluorescence, flow cytometry, ELISA, and reverse transcriptase–polymerase chain reaction. CCR7 function was examined by intracellular calcium measurements, chemotaxis, wound healing assays, and measurement of cell proliferation.

Measurements and Main Results: ASM, 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, ASM in severe disease, and ex vivo ASM and mast cells. ASM CCR7 activation by CCL19-mediated intracellular calcium elevation and concentration-dependent migration, but not proliferation. Importantly, mast cell and ASM-derived CCL19 mediated ASM migration and repair.

Conclusions: The CCL19/CCR7 axis may play an important role in the development of ASM hyperplasia in asthma.

Key Words: airway smooth muscle • asthma • CC chemokine ligand 19 • CC chemokine receptor 7 • mast cells

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Both an increase in mast cell numbers in the airway smooth muscle (ASM) bundles and smooth muscle hyperplasia are features of asthma. The cause of this smooth muscle hyperplasia is unknown; emerging evidence suggests that ASM progenitors may migrate to the smooth muscle bundle in asthma to contribute to this hyperplasia. What This Study Adds to the Field We report for the first time that ASM and fibroblasts express functional CCR7, and that both ASM and mast cell-derived CCL19 mediate ASM migration in asthma via activation of CCR7, providing a novel chemotactic pathway for the recruitment of ASM or ASM progenitors to the asthmatic ASM compartment.

 

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