Fleming R E, Whitman I P, Gitlin J D
Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Am J Physiol. 1991 Feb;260(2 Pt 1):L68-74. doi: 10.1152/ajplung.1991.260.2.L68.
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.
为了确定炎症对肝外铜蓝蛋白基因表达的影响，我们检测了内毒素注射后成年大鼠组织中铜蓝蛋白mRNA的含量。注射一剂内毒素后8小时内，肝脏中铜蓝蛋白mRNA含量如预期增加，且在肺中也可检测到。内毒素的作用具有组织特异性，因为在其他肝外组织中未能持续检测到铜蓝蛋白mRNA。肺和肝组织中铜蓝蛋白mRNA积累的动力学相似，在24小时内每个组织中铜蓝蛋白mRNA含量最多增加7至9倍。内毒素注射后3小时内，两个组织中铜蓝蛋白基因转录的相对速率均增加，表明炎症期间铜蓝蛋白基因表达的调控机制相似。发现在炎症肺中铜蓝蛋白产生的一个细胞位点是肺泡巨噬细胞，其在体外对内毒素反应时表达铜蓝蛋白基因并合成铜蓝蛋白蛋白。基于这些发现，我们还研究了高氧对铜蓝蛋白基因表达的影响。成年大鼠暴露于95%氧气中46小时内，肺组织中铜蓝蛋白mRNA诱导增加5至6倍，且这种反应具有时间依赖性，在86小时达到最大值。铜蓝蛋白mRNA的高氧诱导特异性地发生在肺中，而非全身炎症的结果，因为肝脏中铜蓝蛋白mRNA含量保持恒定。这些数据表明，在炎症和高氧期间，肺是铜蓝蛋白基因表达的一个重要位点，并提示这种蛋白可能在肺损伤或修复中发挥了以前未被认识到的作用。
