Cysteinyl Leukotrienes Promote Human Airway Smooth Muscle Migration

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Abstract
Cysteinyl leukotrienes promote airway smooth muscle (ASM) contraction and proliferation. Little is known about their role in ASM migration. We investigated this using cultured human ASMs (between the second and fifth passages) obtained from the large airways of resected nonasthmatic lung. Platelet-derived growth factor-BB (1 ng/ml) promoted significant (3.5-fold) ASM migration of myocytes across collagen-coated 8-μm polycarbonate membranes in Transwell culture plates. Leukotriene E4 (10−7, 10−8, 10−9 M) did not demonstrate a chemotactic effect; it did promote chemokinesis. Priming by leukotriene E4 (10−7 M) significantly augmented the directional migratory response to platelet-derived growth factor (1.5-fold, p < 0.05). This was blocked by montelukast (10−6 M), demonstrating the effect to be mediated by the cysteinyl leukotriene receptor. The “priming effect” was also partially attenuated by prostaglandin E2 (10−7 M). Whereas both the chemokinetic and the chemotactic “primed” responses were equally attenuated by a p38 mitogen-activated protein kinase inhibitor (SB203580, 25 μM) and by a Rho-kinase inhibitor (Y27632, 10 μM), the chemotactic response showed greater inhibition than chemokinesis by a phosphatidylinositol-3 kinase inhibitor (LY294002, 50 μM). These experiments suggest that cysteinyl leukotrienes play an augmentary role in human ASM migration. The phosphatidylinositol-3 kinase pathway is a key signaling mechanism in the chemotactic migration of ASM cells in response to cysteinyl leukotrienes.