Dual effects of lysophosphatidic acid on human airway smooth muscle cell proliferation and survival

Lysophosphatidic acid (LPA) is a phospholipid growth mediator found in serum at 2-20 muM. In many cell types, including human airway smooth muscle (HASM) cells, LPA-induced proliferation occurs at 10-100 muM LPA. At these concentrations LPA forms Ca2+ precipitates. The potential involvement of Ca2+ and Ca2+-LPA precipitates in LPA-induced HASM cell mitogenesis was investigated. In the absence of extracellular Ca2+, 10 and 30 muM LPA stimulated HASM cell mitogenesis. However, with 100 muM LPA in the absence of extracellular Ca2+, HASM cells exhibited a profound shape change and loss of viability, determined to be apoptosis by both DNA staining and assessment of cytosolic nucleosomal reactivity. A bioassay based on the adenosine 3':5'-cyclic monophosphate response of C62B rat glioma cells was used to measure the bioactivity of LPA solutions prepared in Ca2+-free and Ca2+-containing medium. After 24 h, a 100 muM LPA solution in Ca2+-free medium contained markedly greater bioactivity than a 100 muM LPA solution made in Ca2+-containing medium. In summary, formation of Ca2+-LPA precipitates decreases the amount of biologically active LPA in solution, and high concentrations of bioactive LPA achieved in Ca2+-free but not in Ca2+-containing medium induce apoptosis of HASM cells. (C) 2001 Elsevier Science B.V. All rights reserved.