Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS
Cigarette Smoke and Nicotine-Containing E-cigarette Vapor Downregulate Lung WWOX Expression Which is Associated with Increased Severity of Murine ARDS
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香烟烟雾和含尼古丁的电子烟蒸气会下调肺部 WWOX 表达，这与小鼠 ARDS 严重程度增加有关
DOI：
10.1165/rcmb.2020-0145oc
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Singla S
中科院分区：
文献类型：
--
作者：
Zeng Z;Chen W;Moshensky A;Shakir Z;Khan R;Crotty Alex;er LE;Ware LB;Aldaz CM;Jacobson JR;Dudek SM;Natarajan V;Machado RF;Singla S
已知长期吸烟史会增加急性呼吸窘迫综合征 (ARDS) 的风险，但与长期使用电子烟相关的相应风险在很大程度上尚不清楚。染色体脆弱位点基因 WWOX 对环境暴露引起的基因毒性应激高度敏感，因此是研究暴露相关肺部疾病的一个有趣的候选基因。与以前/从不吸烟者相比，从当前吸烟者采集的肺中 WWOX mRNA 水平降低了 47%。与媒介物处理的对照组相比，接触含尼古丁的电子烟蒸汽导致 WWOX mRNA 水平平均下降 57%。在单独的研究中，在产生 ARDS 的条件下对内皮 (EC) 特异性 WWOX 敲除 (KO) 小鼠与 WWOX flox 对照小鼠进行了检查。 EC WWOX KO 小鼠表现出显着更高水平的血管渗漏和组织学肺损伤。使用流式细胞术对 CD31+CD45−细胞进行分选，从未处理的 EC WWOX KO 小鼠的消化肺中分离出 EC。这些细胞在培养物中生长，通过 RT-PCR 和蛋白质印迹法证实 WWOX 缺陷，并通过细胞阻抗传感以及 FITC 葡聚糖 Transwell 测定分析其在耐甲氧西林金黄色葡萄球菌或 LPS 暴露期间的屏障特性。与来自 WWOX flox 对照的细胞相比，WWOX KO EC 在任一甲氧西林耐药期间均表现出屏障功能显着更大的下降。通过细胞阻抗传感和 Transwell 测定测量金黄色葡萄球菌 LPS 治疗。在长期吸烟者中观察到的 ARDS 风险增加可能在机制上至少部分与肺部 WWOX 下调有关，并且这种现象也可能在不久的将来在长期电子烟使用者中显现出来。
A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31+CD45−cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistantStaphylococcus aureusor LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistantS. aureusor LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.