LYSOPHOSPHATIDIC ACID AND EGF STIMULATE MITOGENESIS IN HUMAN AIRWAY SMOOTH-MUSCLE CELLS

Enhanced proliferation of airway smooth muscle is thought to contribut e to the pathogenesis of asthma and other obstructive airway diseases. Lysophosphatidic acid (LPA) is a simple bioactive lipid mediator that stimulates mitogenesis in fibroblasts and some other cell types. The effects of LPA on mitogenesis of cultured human airway smooth muscle c ells were determined by measuring [H-3]thymidine incorporation into ce llular DNA. LPA induced a concentration-dependent stimulation of [H-3] thymidine incorporation of a similar magnitude to that induced by seru m, with the effects of 50 mu M LPA being similar to those of 5% serum. Stimulation by LPA and by serum was almost completely eliminated in c ells exposed to pertussis toxin, indicating involvement of a pertussis toxin-sensitive G protein in mitogenic signaling by these agents. Epi dermal growth factor (EGF) induced stimulation of a similar magnitude as that with LPA, but the stimulation by EGF was insensitive to pertus sis toxin. LPA and EGF, when added together, exhibited a markedly syne rgistic stimulation of [H-3]thymidine incorporation that was typically 10-fold greater than the stimulation with either agent alone. LPA and EGF also stimulated mitogenesis assessed by cell growth, and again LP A and EGF together exhibited synergism. These results suggest the poss ibility that stimulation of airway smooth muscle cell proliferation by LPA, either alone or by enhancing effects of other growth factors, co uld play a role in normal airway remodeling or in the pathological pro liferation of smooth muscle in various airway diseases.