Abstract
Tumor promoter 12–0–tetradecanoylphorbol 13-acetate (TPA) is a potent secretagogue for surfactant release from lung: its mechanism of action remains unknown. Since TPA activates a Ca2+, phospholipid (PL) C-kinase in other cells we tested whether TPA alters surfactant release from isolated Type II cells in a Ca2+ dependent fashion and whether polymixin B, a known inhibitor of C-kinase, blocks effects of TPA. TPA caused a dose dependent release of 3H-choline labelled phosphatidylcholine (3H-PC) from purified rat Type II cells in primary culture:TPA was not toxic as monitored by lactate dehydrogenase release. Since C-kinase is a Ca2+ PL dependent enzyme, effects of calcium ionophore A23187 and TPA together on surfactant release were studied. TPA-induced (100nM) 3H-PC release was significantly potentiated by A23187 (10nM): Control 1.40±0.23%; A23187 1.61±.24%; TPA 3.30±0.40%; A23187+TPA 5.63±0.39% (p<0.001 for A23187+TPA vs. controU p<0.05 for TPA vs. control). Polymixin B, a known inhibitor of Ca2+ -PL kinase, partially blocked TPA-induced 3H-PC release: Control 1.17±0.17%; polymixin B 0.40±0.08%; TPA 4.07±0.34%; TPA+polymixin B 2.43±0.29% (p<0.05 for TPA vs. control and TPA+polymixin B vs. polymixin B alone). These data provide support for C-kinase involvement in regulation of TPA-induced surfactant secretion. Supported by the American Lung Association, NIH-HL-28623 and HD-11725.
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