INHIBITION OF LUNG SURFACTANT SECRETION FROM ALVEOLAR TYPE-II CELLS AND ANNEXIN-II TETRAMER-MEDIATED MEMBRANE-FUSION BY PHENOTHIAZINES

We investigated the effects of phenothiazines on lung surfactant secre tion from rat alveolar epithelial type II cells and on annexin II tetr amer (Anx IIt)-mediated membrane fusion. Trifluoperazine and promethaz ine inhibited ATP-stimulated phosphatidylcholine (PC) secretion from t ype II cells in a dose dependent manner. Concentrations that cause 50% inhibition (IC50) were approximately 3 and 25 mu M for trifluoperazin e and promethazine, respectively. Promethazine also inhibited PC secre tion of type II cells stimulated by other secretagogues, including cal cium ionophore A23187, phorbol 12-myristate 13-acetate, and terbutalin e that are known to stimulate PC secretion via different signal transd uction pathways. Since we have recently determined that Anx IIt is inv olved in PC secretion of type II cells, we examined whether phenothiaz ines influence Anx IIt's activity. Trifluoperazine and promethazine in hibited Anx IIt's ability to aggregate phosphatidylserine (PS) liposom es, to fuse PS/phosphatidylethanolamine (PE) liposomes, and to fuse PS /PE liposomes with lamellar bodies. These results suggest a relationsh ip between lung surfactant secretion and Anx IIt-mediated membrane fus ion. (C) 1997 Academic Press.