Division of Cardiovascular Medicine, and the EPR Center, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
Division of Cardiovascular Medicine, and the EPR Center, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA.
J Biol Chem. 2024 Sep;300(9):107626. doi: 10.1016/j.jbc.2024.107626. Epub 2024 Aug 2.
With the increasing use of vaping devices that deliver high levels of nicotine (NIC) to the lungs, sporadic lung injury has been observed. Commercial vaping solutions can contain high NIC concentrations of 150 mM or more. With high NIC levels, its metabolic products may induce toxicity. NIC is primarily metabolized to form NIC iminium (NICI) which is further metabolized by aldehyde oxidase (AOX) to cotinine. We determine that NICI in the presence of AOX is a potent trigger of superoxide generation. NICI stimulated superoxide generation from AOX with K = 2.7 μM and V = 794 nmol/min/mg measured by cytochrome-c reduction. EPR spin-trapping confirmed that NICI in the presence of AOX is a potent source of superoxide. AOX is expressed in the lungs and chronic e-cigarette exposure in mice greatly increased AOX expression. NICI or NIC stimulated superoxide production in the lungs of control mice with an even greater increase after chronic e-cigarette exposure. This superoxide production was quenched by AOX inhibition. Furthermore, e-cigarette-mediated NIC delivery triggered oxidative lung damage that was blocked by AOX inhibition. Thus, NIC metabolism triggers AOX-mediated superoxide generation that can cause lung injury. Therefore, high uncontrolled levels of NIC inhalation, as occur with e-cigarette use, can induce oxidative lung damage.
随着向肺部输送高浓度尼古丁 (NIC) 的蒸气设备的使用越来越多，已经观察到零星的肺损伤。商业蒸气产品可能含有高达 150mM 或更高浓度的 NIC。由于 NIC 浓度高，其代谢产物可能会引起毒性。NIC 主要代谢为形成尼古丁亚硝鎓（NICI），然后进一步被醛氧化酶（AOX）代谢为可替宁。我们确定 AOX 存在时，NICI 是超氧化物生成的有力触发因素。NICI 通过细胞色素 c 还原法以 K=2.7μM 和 V=794nmol/min/mg 测量，刺激 AOX 产生超氧化物。电子顺磁共振自旋捕获证实，AOX 存在时，NICI 是超氧化物的一个有力来源。AOX 在肺部表达，并且在小鼠中慢性电子烟暴露大大增加了 AOX 的表达。NICI 或 NIC 刺激对照小鼠的肺部产生超氧化物，在慢性电子烟暴露后甚至有更大的增加。这种超氧化物的产生被 AOX 抑制所抑制。此外，电子烟介导的 NIC 输送引发了氧化肺损伤，而 AOX 抑制可阻断这种损伤。因此，NIC 代谢引发 AOX 介导的超氧化物生成，从而可能导致肺损伤。因此，高浓度的 NIC 吸入，如电子烟使用中所发生的，会导致氧化肺损伤。
