Exposure to the toxic mineral dust silica has been shown to produce an acute inflammatory response in the lungs of both humans and laboratory animals. Coating silica with phospholipids reduces its toxicity when studied with in vitro systems. The drug amiodarone increases phospholipid within the cells, airways, and alveoli of the lungs. This increase in phospholipid is due to amiodarone's ability to inhibit phospholipase activity within alveolar macrophages (AMs) and whole lung. The purpose of this study was to determine whether the amiodarone-induced increase in pulmonary phospholipid would protect the lungs from acute damage caused by the intratracheal instillation of silica. Treatment of male Fischer 344 rats with amiodarone for 14 days caused an increase in phospholipid content in bronchoalveolar lavage fluid and AMs compared to vehicle-treated controls. The rats were then instilled with silica or saline vehicle. At both 1 and 14 days after silica exposure, pulmonary phospholipidosis was associated with a marked reduction in acute silica-induced pulmonary damage as assessed by biochemical parameters in bronchoalveolar lavage fluid, however, the influx of neutrophils into the airspaces was not reduced. Four times more phospholipid was bound to the silica recovered from amiodarone-treated rats compared to controls. The results of these in vivo experiments indicate that pulmonary phospholipidosis attenuates the acute damage associated with the intratracheal instillation of silica in rats. By using an in vitro cell culture system, we demonstrated that, in contrast to control AMs, phospholipidotic AMs were significantly more resistant to the cytotoxicity of surfactant-coated silica.(ABSTRACT TRUNCATED AT 250 WORDS)