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Modulation of Human Airway Smooth Muscle Migration by Lipid Mediators and Th-2 Cytokines

Firestone Institute for Respiratory Health, St. Joseph's Healthcare and Department of Medicine, McMaster University, Hamilton, Ontario, Canada; and Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Dr. K. Parameswaran, Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6 Canada. E-mail: parames{at}mcmaster.ca

Cysteinyl leukotrienes and the T helper (Th)-2 cytokines IL-5 and IL-13 directly modulate human airway smooth muscle functions such as contraction and proliferation. We studied the effects of other lipid mediators involved in asthma pathophysiology such as prostaglandin D₂ (PGD₂), lipoxin, and isoprostanes, and the cytokines, IL-5, IL-4, and IL-13 on human airway smooth muscle cell migration. Chemotaxis and chemokinesis of cultured airway smooth muscle cells from humans without asthma (second to fifth passages, n = 6) were studied using collagen-I–coated polycarbonate membranes in Transwell culture plates. Receptor expression and kinase activation were studied by flow cytometry, polymerase chain reaction, and Western blotting techniques. In contrast to LTE₄- stimulated (10^–6 M) chemokinesis and LTE₄-primed migration toward platelet-derived growth factor (PDGF), isoprostane 15-F_2t-IsoP, and IL-5 were neither chemotactic nor chemokinetic. PGD₂ (10^–10–10^–6 M) was a chemoattractant and primed migration toward PDGF through the DP₂/CRTh₂ receptor. Although airway smooth muscle cells did not express the lipoxin A₄ cognate receptor, LTE₄-primed migration toward PDGF was blocked by lipoxin A₄ (10^–6 M), suggesting that this is mediated through CysLT₁R antagonism. IL-13 (10 ng/ml), but not IL-4 (0.1–100 ng/ml), augmented migration toward PDGF. This was associated with increased Src-kinase phosphorylation and up-regulation of PDGF- and - receptors, and was attenuated by IL-13R– and IL-4R–neutralizing antibodies, an Src-kinase antagonist (PP1, 3 µM), a CysLT₁R antagonist, montelukast (10^–6 M), and by lipoxin A₄ (10^–6 M). PGD₂ and IL-13 promote human airway smooth muscle migration. IL-13 can promote airway smooth muscle migration through Src-kinase and leukotriene-dependent pathways. This may contribute to the accumulation of smooth muscle cells in remodeled airway submucosa.

Key Words: airway smooth muscle migration • IL-13 • PGD₂ • cysteinyl leukotriene • CRTh2 receptor

CLINICAL RELEVANCE We demonstrate novel biological effects of prostaglandin D2 and IL-13 on human airway smooth muscle cells. Both of these can promote human airway smooth muscle migration, and this may contribute to the accumulation of smooth muscle cells in remodeled airway submucosa.

 

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