The goal of this program is to evaluate control of lung and surfactant phosphatidylcholine synthesis with special emphasis on the role of choline as a rate-limiting substrate. Using nutritional choline deficiency as a probe, we have shown that, in contrast to a large decrease in liver phosphatidyl choline, there is only a slight decrease in the pool of lung phosphatidylcholine. The capacity of the CDP-choline pathway of phosphatidylcholine synthesis in lung was not altered. The pathway for synthesis by N-methylation of phosphatidylethanolamine was stimulated 3-fold in the lung but nevertheless could not contribute significantly to the maintenance of lung phosphatidylcholine pools. Increased palmitate and glucose incorporation indicated increased rates of PC synthesis in the lung suggesting increased rates of PC turnover. These observations indicate compensatory changes in lung phosphatidyl choline metabolism as a consequence of choline deficiency in order to maintain the lung PC pool. We, therfore, propose to investigate possible compensatory mechanisms by the study of changes in choline transport, phosphatidylcholine turnover, and kinetics for the enzymes of CDP-choline pathway in lung in response to dietary choline deficiency using in vivo models, isolated perfused lung, and granular pneumocytes in primary culture. Choline transport mechanisms will be evaluated from measurement of tissue accumulation, metabolic fate, effect of metabolic substrates and inhibitors, and effect of specific inhibitors of choline uptake. Turnover of different moieties of lung phosphatidylcholine will be compared and the contribution of reuptake of surfactant phosphatidylcholine will be evaluated. Kinetics of the enzymes involved in the synthesis of phosphatidyl choline by the CDP-choline pathway will be evaluated from changes in specific activities and pool sizes of intermediates of this pathway. These studies will provide new information about the mechanisms through which choline can control the turnover of lung phosphatidyl choline.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory and Applied Physiology Study Section (RAP)
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University of Pennsylvania
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Fisher, A B; Dodia, C; Chander, A et al. (1992) Transport of choline by plasma membrane vesicles from lung-derived epithelial cells. Am J Physiol 263:C1250-7
Dodia, C; Fisher, A B; Chander, A et al. (1992) Inhibitors of choline transport in alveolar type II epithelial cells. Am J Respir Cell Mol Biol 6:426-9
Fisher, A B; Chander, A; Dodia, C et al. (1989) Choline transport by lung epithelium. Am J Respir Cell Mol Biol 1:455-62
Fisher, A B; Dodia, C; Chander, A (1987) Degradation and reutilization of alveolar phosphatidylcholine by rat lungs. J Appl Physiol 62:2295-9
Chander, A; Reicherter, J; Fisher, A B (1987) Degradation of dipalmitoyl phosphatidylcholine by isolated rat granular pneumocytes and reutilization for surfactant synthesis. J Clin Invest 79:1133-8
Fisher, A B; Chander, A; Reicherter, J (1987) Uptake and degradation of natural surfactant by isolated rat granular pneumocytes. Am J Physiol 253:C792-6
Yost, R W; Chander, A; Dodia, C et al. (1986) Stimulation of the methylation pathway for phosphatidylcholine synthesis in rat lungs by choline deficiency. Biochim Biophys Acta 875:122-5
Yost, R W; Chander, A; Dodia, C et al. (1986) Synthesis of phosphatidylcholine by rat lung during choline deficiency. J Appl Physiol 61:2040-4
Yost, R W; Chander, A; Fisher, A B (1985) Differential response of lung and liver of juvenile rats to choline deficiency. J Appl Physiol 59:738-42
Glass, M; Sutherland, M W; Forman, H J et al. (1985) Selenium deficiency potentiates paraquat-induced lipid peroxidation in isolated perfused rat lung. J Appl Physiol 59:619-22