Airway smooth muscle and mast cell-derived CC chemokine ligand 19 mediate airway smooth muscle migration in asthma.
BACKGROUND
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.


OBJECTIVE
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.


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.
Kaur
Davinder
D
Institute for Lung Health, and Department of Infection, Inflammation and Immunity, University of Leicester, Leicester, United Kingdom.
Saunders
Ruth
R
Berger
Patrick
P
Siddiqui
Salman
S
Woodman
Lucy
L
Wardlaw
Andrew
A
Bradding
Peter
P
Brightling
Christopher E
CE
D001249:Asthma / Q000473:pathology / Q000503:physiopathology*; D001980:Bronchi / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D008407:Mast Cells / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology* / Q000502:physiology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology
C515370:CCR7 protein, human; D054400:Receptors, CCR7; D019707:Receptors, Chemokine