氰化物中毒影响调节体内心脏损伤的基因途径,Chemical Research in Toxicology

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氰化物中毒影响调节体内心脏损伤的基因途径
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2021-04-29 , DOI: 10.1021/acs.chemrestox.0c00467
Ki H Ma ₁ , Dennean S Lippner ₁ , Kelly A Basi ₂ , Susan M DeLeon ₁ , William R Cappuccio ₁ , Melissa O Rhoomes ₁ , Diane M Hildenberger ₁ , Heidi M Hoard-Fruchey ₁ , Gary A Rockwood ₁

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在美国，从建筑物火灾中吸入烟雾是氰化物中毒的常见途径。氰化物会抑制细胞呼吸，通常会导致死亡。其在全身的快速分布可导致多个器官受伤，据报道，氰化物受害者会出现心肌梗塞和其他心脏并发症。然而，此类并发症的分子机制尚待阐明。虽然 FDA 批准的 CN 解毒剂如硫代硫酸钠和羟钴胺素已在临床上使用，但它们在大规模伤亡情况下具有可预见的局限性，因为它们需要静脉给药。为了促进更好的解毒剂和治疗方法的开发，有必要全面了解氰化物暴露引起的分子变化。作为一种探索性的追求，我们进行了寡核苷酸微阵列，以建立仅用鼻子吸入氰化氢 (HCN) 的动物模型的心脏转录组，这与吸入烟雾有关。我们还分析了皮下注射氰化钾 (KCN) 后的心脏转录组。尽管 KCN 注射模型经常被用于评估医疗对策，但这项研究表明，在暴露后 24 小时内的多个时间点，心脏转录组与 HCN 吸入模型的转录组有很大不同。通路分析发现，HCN 诱导的转录组富含编码对心脏并发症调节至关重要的通路介质的基因，并且大量此类基因的表达显着降低。

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Cyanide Poisoning Compromises Gene Pathways Modulating Cardiac Injury in Vivo

Smoke inhalation from a structure fire is a common route of cyanide poisoning in the U.S. Cyanide inhibits cellular respiration, often leading to death. Its rapid distribution throughout the body can result in injuries to multiple organs, and cyanide victims were reported to experience myocardial infarction and other cardiac complications. However, molecular mechanisms of such complications are yet to be elucidated. While FDA-approved CN antidotes such as sodium thiosulfate and hydroxocobalamin are clinically used, they have foreseeable limitations during mass casualty situations because they require intravenous administration. To facilitate the development of better antidotes and therapeutic treatments, a global view of molecular changes induced by cyanide exposure is necessary. As an exploratory pursuit, we performed oligonucleotide microarrays to establish cardiac transcriptomes of an animal model of nose-only inhalation exposure to hydrogen cyanide (HCN), which is relevant to smoke inhalation. We also profiled cardiac transcriptomes after subcutaneous injection of potassium cyanide (KCN). Although the KCN injection model has often been used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 h after exposure. Pathway analysis identified that HCN-induced transcriptomes were enriched with genes encoding mediators of pathways critical in modulation of cardiac complications and that a large number of such genes were significantly decreased in expression. We utilized the upstream regulatory analysis to propose drugs that can be potentially employed to treat cyanide-induced cardiac complications.

更新日期：2021-06-21

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