REGULATION OF PULMONARY SURFACTANT SYSTEM AND ITS MODIFICATION BY TOXIC AGENTS

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Pulmonary surfactant is a complex mixture of lipids and proteins that prevents collapse of the alveoli and distal airways at low lung volumes. Silica dust causes massive increases in the surfactant content of the lungs but the mechanisms through which this occurs are not known. Examination of the rates at which surfactant phospholipids are synthesized, secreted, and cleared from the lungs of silica-treated rats revealed that expansion of the intra and extracellular pools of surfactant could be accounted for by imbalances between the rates at which surfactant phospholipids are synthesized by alveolar Type II cells, secreted, and then cleared from the alveoli. Under normal circumstances these rates of synthesis, secretion, and clearance are the same and the intra- and extra-cellular pools of surfactant do not change in size. Our studies indicate that central to the expansion of surfactant pools are alterations in the biosynthetic rates at which surfactant phospholipids are synthesized and that these increased biosynthetic rates are associated primarily with a subpopulation of Type II cells that are highly activated with regard to their ability to synthesize surfactant phospholipids. We have developed a method for the isolation of these activated Type II cells from the lungs of silica-treated rats and for the separation of those activated cells from the non-activated or normal Type II cells. Examination of the pathway by which phosphatidylcholine is synthesized reveals that increased synthesis is achieved by marked elevation in the activities of two enzymes; cytidylyltransferase and choline phosphotransferase. Activation of the surfactant pathway by silica may be mediated through these two critical enzymes in the biosynthetic pathway of phosphatidylcholine. In addition, it appears likely that these activated Type II cells play a role in the repair processes within the alveoli of the lungs. Preliminary evidence indicates that hyperactive Type II cells are also the proliferative cells within the alveoli. Future studies will involve further characterization of the hyperactive Type II cells and investigation of their role in repair processes- within the lungs.