To determine the effect of inflammation on extrahepatic ceruloplasmin gene expression we examined the ceruloplasmin mRNA content of adult rat tissues after endotoxin injection. Within 8 h of a dose of endotoxin ceruloplasmin mRNA content increased in the liver as expected and was also detectable in the lung. The effect of endotoxin was tissue specific because ceruloplasmin mRNA was not consistently detected in other extrahepatic tissues. The kinetics of ceruloplasmin mRNA accumulation in lung and liver tissue were similar with a maximum seven- to ninefold increase in ceruloplasmin mRNA content in each tissue within 24 h. The relative rate of ceruloplasmin gene transcription was increased in both tissues within 3 h of endotoxin, suggesting similar mechanisms of regulation of ceruloplasmin gene expression during inflammation. One cellular site of ceruloplasmin production in the inflamed lung was found to be the alveolar macrophage, which expressed the ceruloplasmin gene and synthesized ceruloplasmin protein in response to endotoxin in vitro. Because of these findings we also examined the effects of hyperoxia on ceruloplasmin gene expression. Exposure of adult rats to 95% O2 resulted in a five- to sixfold induction of ceruloplasmin mRNA in lung tissue within 46 h, and this response was time dependent, reaching maximum values at 86 h. Hyperoxic induction of ceruloplasmin mRNA was specific to the lung and not the result of systemic inflammation because hepatic ceruloplasmin mRNA content remained constant. These data indicate that the lung is a prominent site of ceruloplasmin gene expression during inflammation and hyperoxia and suggest that this protein may play a previously unappreciated role in pulmonary injury or repair.