REGULATION OF PULMONARY SURFACTANT SYSTEM AND ITS MODIFICATION BY TOXIC AGENTS

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Pulmonary surfactant is synthesized and secreted by alveolar Type II cells. It is a complex mixture of lipids and proteins that prevents collapse of the alveoli and distal airways at low lung volumes. The pulmonary surfactant system is affected by numerous chemical and particulate toxicants through unknown mechanisms. Silica dust, when administered by either intratracheal injection or by inhalation, causes massive increases in the surfactant content of the lungs. The objectives of this work are to elucidate the mechanisms through which the pulmonary surfactant system is stimulated by silica and the processes responsible for the accumulation of phospholipids in the lungs. Twenty-eight days after a single intratracheal injection of silica into the lungs of rats (200mg/Kg) the phospholipid content of the lungs increased from 29.6 plus/minus 4.4 to 476.1 plus/minus 129.2 mg. Intracellular and extracellular surfactant pools accounted for 59.1 and 24.6% of this increase in phospholipids, respectively. These silica-induced increases in phospholipids of the intra- and extracellular surfactant pools were both dose- and time-dependent. Although the phospholipid content increased, the phospholipid composition of pulmonary surfactant did not change, in response to silica. Silica (10mg/Kg) increased surfactant phospholipid biosynthesis in the lungs of rats approximately 4-fold. Phospholipid fluxes between the intra- and extracellular pools increased from 115 Mug/hr to 437 Mug/hr. The turnover time for phospholipid in the intracellular pool was increased 3.5-fold from 13 hr to 45.4 hr but the turnover time for the extracellular pool increased only marginally from 10.4 hr to 13.9 hr. No evidence for recycling of surfactant was found. These data indicate that the expansion of the intra- and extracellular pools of surfactant phospholipids was due to increases in the biosynthesis of phospholipids and alterations in the kinetic relationship between the two pools.