Genomic analysis of murine pulmonary tissue following carbonyl chloride inhalation
Genomic analysis of murine pulmonary tissue following carbonyl chloride inhalation
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DOI：
10.1021/tx050126f
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发表时间：
2005-11-01
影响因子：
4.1
通讯作者：
Dillman, JF
中科院分区：
文献类型：
--
作者：
Sciuto, AM;Phillips, CS;Dillman, JF
碳酰氯（光气）是一种有毒的工业化合物，广泛用于工业合成产品的生产，如泡沫橡胶，塑料和染料。暴露于光气会导致潜伏性（1-24小时）、可能危及生命的肺水肿和不可逆的急性肺损伤。本研究采用基因组学方法探讨了β-内酰胺酶基因诱导肺损伤的分子机制。将CD-1雄性小鼠全身暴露于空气或浓度×时间量为32 mg/m3（8 ppm）的光气20 min（640 mg × min/m3）。在暴露后0.5、1、4、8、12、24、48和72 h，从暴露于空气或苯并三唑的小鼠中收集肺组织。从肺中提取RNA，并用作探测寡核苷酸微阵列的起始材料，以确定光气暴露后基因表达的变化。使用主成分分析法对数据进行分析，以确定数据变异性的最大来源。进行基于暴露、时间和样品的三因素方差分析，以鉴定作为光气暴露结果的最显著改变的基因。这些基因按p值排序，并根据分子功能和生物学过程进行分类。基因表达的一些最显著变化反映了谷胱甘肽合成和细胞氧化还原调节的变化，包括谷胱甘肽S-转移酶α-2、谷胱甘肽过氧化物酶2和谷氨酸-半胱氨酸连接酶催化亚基（也称为γ-谷氨酰半胱氨酸合成酶）的上调。这与先前描述光气暴露后氧化还原酶活性变化的观察结果一致。我们还在研究对光气暴露有反应的其他途径，以确定毒性机制和潜在的治疗靶点。
Carbonyl chloride (phosgene) is a toxic industrial compound widely used in industry for the production of synthetic products, such as polyfoam rubber, plastics, and dyes. Exposure to phosgene results in a latent (1-24 h), potentially life-threatening pulmonary edema and irreversible acute lung injury. A genomic approach was utilized to investigate the molecular mechanism of phosgene-induced lung injury. CD-1 male mice were exposed whole body to either air or a concentration x time amount of 32 mg/m(3) (8 ppm) phosgene for 20 min (640 mg x min/m(3)). Lung tissue was collected from air- or phosgene-exposed mice at 0.5, 1, 4, 8, 12, 24, 48, and 72 h postexposure. RNA was extracted from the lung and used as starting material for the probing of oligonucleotide microarrays to determine changes in gene expression following phosgene exposure. The data were analyzed using principal component analysis to determine the greatest sources of data variability. A three-way analysis of variance based on exposure, time, and sample was performed to identify the genes most significantly changed as a result of phosgene exposure. These genes were rank ordered by p values and categorized based on molecular function and biological process. Some of the most significant changes in gene expression reflect changes in glutathione synthesis and redox regulation of the cell, including upregulation of glutathione S-transferase alpha-2, glutathione peroxidase 2, and glutamate-cysteine ligase, catalytic subunit (also known as gamma-glutamyl cysteine synthetase). This is in agreement with previous observations describing changes in redox enzyme activity after phosgene exposure. We are also investigating other pathways that are responsive to phosgene exposure to identify mechanisms of toxicity and potential therapeutic targets.