Regulation of lung surfactant secretion by intracellular pH.
We investigated secretion of lung surfactant phosphatidylcholine (PC) using isolated perfused rat lung preparation after labeling the lung lipids in vitro with [methyl-3H]choline. The perfusion medium was Krebs-Ringer bicarbonate buffer (pH 7.4) containing 10 mM glucose and 3% fatty acid-poor bovine serum albumin. After ventilation of lungs with air containing 5% CO2 (control) for 1 h, 0.91% +/- 0.04 (mean +/- SE, n = 6) of total lung lipid radioactivity (greater than 95% in PC) was recovered in the cell-free lavage fluid. The secretion of PC was increased with terbutaline (50 microM), 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP, 100 microM), phorbol L2-myristate 13-acetate (30 ng/ml), and ATP (1 mM), in each case by approximately 150%. Secretion of PC was also increased by 160% if the lungs were ventilated with air containing 0% CO2. The low CO2-mediated PC secretion was time and concentration dependent. The dose-response curve for 0-10% CO2 was S-shaped. The low CO2-induced increase in PC secretion could be largely reversed with diffusible weak acids (25 mM, acetate or butyrate) in the perfusion medium. An increase (70%) in secretion was also induced with 10 mM NH4Cl, suggesting a role for intracellular alkalosis. These observations suggest that intracellular alkalosis stimulates lung surfactant secretion. Alkalosis-stimulated secretion of PC was additive with that with terbutaline (5 X 10(-7) to 5 X 10(-4) M) or 10(-4) M 8-BrcAMP, suggesting that alkalosis effect was not mediated through the beta-adrenergic pathway of surfactant secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Chander
A
A
Institute for Environmental Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
D000085:Acetates / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002245:Carbon Dioxide / Q000494:pharmacology; D002794:Choline / Q000378:metabolism; D006706:Homeostasis; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010713:Phosphatidylcholines / Q000096:biosynthesis / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013726:Terbutaline / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D007507:Therapeutic Irrigation
D000085:Acetates; D002087:Butyrates; D010713:Phosphatidylcholines; D011663:Pulmonary Surfactants; D000643:Ammonium Chloride; D020148:Butyric Acid; D002245:Carbon Dioxide; D000255:Adenosine Triphosphate; D013726:Terbutaline; D002794:Choline; D013755:Tetradecanoylphorbol Acetate