The hypothesis that pulmonary fibrosis, a chronic and incurable respiratory disease in man, could develop if reepithelialization following acute lung damage was compromised by a second toxic agent was investigated. Previous work suggested that in the lung dividing alveolar type II cells are more susceptible to the cytotoxic effect of oxygen than dividing interstitial cells. Male BALB c mice were injected ip with 400 mg/kg butylated hydroxytoluene (BHT) and placed immediately in 70% oxygen or air for 6 days. In vivo incorporation of thymidine into pulmonary DNA was significantly inhibited by exposure to oxygen 2 and 4 days after BHT administration, whereas after 6 days it was markedly elevated as compared to treatment with BHT alone. Animals exposed to oxygen following BHT developed extensive interstitial fibrosis by Day 14, as determined by both hydroxyproline analysis and histopathological examination. No fibrosis developed in mice treated with oxygen alone or when oxygen treatment was delayed until 7 days following BHT injection. Mice treated with BHT alone showed only slight lung fibrosis. The minimum length of exposure to oxygen resulting in increased lung hydroxyproline was 24 hr. Pretreatment for 7 days with oxygen, followed by BHT, did not enhance the development of fibrosis. The combined effects of BHT and oxygen, when given in the correct temporal sequence, were synergistic and not simply additive. We concluded that pulmonary fibrosis can result from interaction between an agent causing acute lung damage and a second toxic agent which compromises reepithelialization.
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