Pulmonary surfactant is composed of a mixture of lipids and proteins which is synthesized and secreted by Type II cells in the alveoli of the lungs. The major lipid component of surfactant, dipalmitoylphosphatidylcholine, and the major surfactant-specific proteins, SP-A, SP-B, and SP-C act together to lower surface tension at the air-cell interface. Biosynthesis and secretion of these surfactant components fy alveolar Type II cells is critical for the stabilization and function of the lungs. Silica dust causes massive increases in both the surfactant phospholipid and SPA content of the lung. We have shown that these increases are due to the activation of some, but not all, Type II cells. Activated Type II cells make and secrete surfactant phospholipids and protein at a rate many times faster than normal Type II cells. To understand how silica dust brings about the activation of Type II cells, we are studying regulation of surfactant protein genes in Type II cells. Intratracheal administration of rats with silica results in increased levels of the mRNAs for SPA and SPC. Isolated Type II cells also respond to silica in vitro with increased production of the surfactant protein mRNAs. These results indicate that at least part of the effect of silica is a direct effect on the Type II cell. Stimulation of surfactant production in Type II cells is dependent upon the inflammatory condition generated in the lungs by silica. Intratracheal injection of silica results in acute pulmonary inflammation, evidenced by the accumulation of various inflammatory cells. If the inflammatory condition is blocked by the use of dexamethasone then stimulation of the surfactant system is inhibited. Furthermore, depletion of neutrophils and macrophages in the airspace inhibits silica-induced changes in the surfactant phospholipid component, although not in surfactant protein A (SPA). Inhibition of the phospholipid response indicates that these inflammatory cells play a role in mediating at least some of the silica- induced changes in surfactant. Evidence suggests that the inflammatory cytokine interleukin-1beta (IL-1beta), but not tumor necrosis factor-alpha (TNFalpha) may play a role in mediating the lung's response to silica. The levels of protein and mRNA for IL-1beta and TNFalpha increase in the lungs of silica-exposed rats. Intratracheal administration of IL-1beta increases the number of inflammatory cells in the airspace and the levels of surfactant components both in vivo an in vitro. Conversely, TNFalpha does not elicit an influx of inflammatory cells into the lungs, nor does it have any stimulatory effect on surfactant phospholipids of SPA either in vivo or in vitro.
