Lung injury induced by butylated hydroxytoluene: cytodynamic and biochemical studies in mice

Butylated hydroxytoluene, a common food additive, is known to produce proliferative pulmonary changes characterized by increased DNA, RNA, and lung weight. In the present study, reactive hyperplasia and fibrosis were produced within 9 days after a single intraperitoneal injection of 400 mg. per kg. of butylated hydroxytoluene was given to mice. Initial perivascular edema with cell infiltrates was followed by necrosis of type 1 alveolar epithelial cells and by division of type 2 cells which repopulated the alveolar wall with unusually large epithelial cells containing abundant cytoplasm. DNA synthesis, as indexed by thymidine and uridine kinase levels and by 3H-thymidine uptake, increased at 2 days, peaked at 4 days, and dropped gradually to near normal by day 9. Differential counts of labeled cells revealed that the early rise was due to epithelial cell proliferation; in turn, interstitial and endothelial cells entered the proliferative phase. Endothelial labeling peaked at day 6 immediately following ultrastructural evidence of endothelial injury. It is concluded that the proliferative pulmonary changes that occur after the administration of butylated hydroxytoluene are a consequence of cell injury and necrosis. The reparative processes occur predominantly at the alveolar epithelium and interstitium with the production of fibrosis. The cellular hypertrophy and hyperplasia observed in this study account for the biochemical changes in pulmonary RNA and DNA that have been described previously.