Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke
Gene expression profiling in respiratory tissues from rats exposed to mainstream cigarette smoke
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DOI：
10.1093/carcin/bgg193
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发表时间：
2004-02-01
期刊：
影响因子：
4.7
通讯作者：
Müller, T
中科院分区：
文献类型：
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作者：
Gebel, S;Gerstmayer, B;Müller, T
众所周知，香烟烟雾（CS）会导致癌症和其他疾病，但对临床可检测症状出现之前发生的全球分子和细胞变化知之甚少。使用覆盖2031 cDNA探针的DNA微阵列，我们研究了大鼠呼吸道组织中的差异基因表达，即急性（3小时）或亚慢性（3小时/天，5天/周，3周）暴露于主流CS的大鼠呼吸道鼻上皮（RNE）和肺，暴露后立即或20小时死亡。差异基因表达在暴露一次的大鼠RNE中最为明显，其特征在于编码氧化应激反应和II期药物代谢酶的基因的强烈上调，如血红素加氧酶-1和NAD（P）H：醌氧化还原酶，这些酶都至少部分地受NF-E2相关因子2（Nrf 2）的转录调控。暴露3周后，这类基因的表达强度显著降低，表明适应性反应。暴露大鼠肺部的反应通常较低，表明活性烟雾成分从上呼吸道到下呼吸道的沉积梯度。与CS诱导的氧化应激和II相反应基因的表达形成鲜明对比的是，暴露3周后，编码I相药物代谢酶细胞色素P450（CYP 1A 1）1A 1和醛脱氢酶-3的基因的诱导没有减少，并且在肺和RNE中也同样高。恢复20小时后大鼠的基因表达模式显示，暴露后立即观察到的CS诱导的转录变化几乎完全恢复正常，即使在3周的重复CS暴露。一般来说，这些结果表明，CS在体内诱导特定的差异基因表达模式，这可能有助于确定导致炎症和/或形态学变化的发病的分子机制。
Cigarette smoke (CS) is known to cause cancer and other diseases, but little is known about the global molecular and cellular changes that occur prior to the appearance of clinically detectable symptoms. Using DNA microarrays covering 2031 cDNA probes, we investigated differential gene expression in tissues of the rat respiratory tract, i.e. respiratory nasal epithelium (RNE) and lungs of rats exposed either acutely (3 h) or subchronically (3 h/day, 5 days/week, 3 weeks) to mainstream CS with death either immediately or at 20 h after exposure. Differential gene expression was most evident in RNE of rats exposed once and was characterized by strong up-regulation of genes encoding oxidative stress-responsive and Phase II drug-metabolizing enzymes, such as haem oxygenase-1 and NAD(P)H:quinone oxidoreductase, which are all, at least in part, transcriptionally regulated by NF-E2-related factor 2 (Nrf2). After 3 weeks of exposure, the strength of expression of this class of genes was markedly reduced, pointing to an adaptive response. The generally lower response in the lungs of exposed rats is indicative of a deposition gradient of active smoke constituents from the upper to the lower respiratory tract. In sharp contrast to the CS-induced expression of oxidative stress and Phase II-responsive genes, induction of the genes encoding the Phase I drug-metabolizing enzymes cytochrome P450 (CYP)1A1 and aldehyde dehydrogenase-3 was not reduced after 3 weeks of exposure and was similarly high in lungs and RNE. Gene expression patterns in rats allowed to recover for 20 h showed that the CS-induced transcriptional changes observed immediately after exposure returned almost completely to normal, even after 3 weeks of repeated CS exposure. In general, these results demonstrate that CS induces a specific differential gene expression pattern in vivo, which may be instrumental in identifying the molecular mechanisms leading to the onset of inflammatory and/or morphological changes.