Ahmad Shaheer, Single Sierra, Liu Yuelong, Hough Kenneth P, Wang Yong, Thannickal Victor J, Athar Mohammad, Goliwas Kayla F, Deshane Jessy S
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL 35294-0006, USA.
John W. Deming Department of Medicine, Tulane University School of Medicine and Southeast Veterans Healthcare System, New Orleans, LA 70119-6535, USA.
Antioxidants (Basel). 2024 Aug 12;13(8):978. doi: 10.3390/antiox13080978.
Exposure to heavy metals (HMs) is often associated with inflammation and cell death, exacerbating respiratory diseases including asthma. Most inhaled particulate HM exposures result in the deposition of HM-bound fine particulate matter, PM, in pulmonary cell populations. While localized high concentrations of HMs may be a causative factor, existing studies have mostly evaluated the effects of systemic or low-dose chronic HM exposures. This report investigates the impact of local high concentrations of specific HMs (NaAsO, MnCl, and CdCl) on sphingolipid homeostasis and oxidative stress, as both play a role in mediating responses to HM exposure and have been implicated in asthma. Utilizing an in vitro model system and three-dimensional ex vivo human tissue models, we evaluated the expression of enzymatic regulators of the salvage, recycling, and de novo synthesis pathways of sphingolipid metabolism, and observed differential modulation in these enzymes between HM exposures. Sphingolipidomic analyses of specific HM-exposed cells showed increased levels of anti-apoptotic sphingolipids and reduced pro-apoptotic sphingolipids, suggesting activation of the salvage and de novo synthesis pathways. Differential sphingolipid regulation was observed within HM-exposed lung tissues, with CdCl exposure and NaAsO exposure activating the salvage and de novo synthesis pathway, respectively. Additionally, using spatial transcriptomics and quantitative real-time PCR, we identified HM exposure-induced transcriptomic signatures of oxidative stress in epithelial cells and human lung tissues.
接触重金属（HMs）通常与炎症和细胞死亡相关，会加重包括哮喘在内的呼吸系统疾病。大多数吸入的颗粒状重金属暴露会导致结合重金属的细颗粒物（PM）在肺细胞群体中沉积。虽然局部高浓度的重金属可能是一个致病因素，但现有研究大多评估了全身性或低剂量慢性重金属暴露的影响。本报告研究了局部高浓度的特定重金属（NaAsO₂、MnCl₂和CdCl₂）对鞘脂稳态和氧化应激的影响，因为这两者在介导对重金属暴露的反应中都起作用，并且与哮喘有关。利用体外模型系统和三维离体人体组织模型，我们评估了鞘脂代谢的补救、再循环和从头合成途径的酶调节剂的表达，并观察到不同重金属暴露之间这些酶的差异调节。对特定重金属暴露细胞的鞘脂组学分析显示，抗凋亡鞘脂水平升高，促凋亡鞘脂水平降低，这表明补救和从头合成途径被激活。在暴露于重金属的肺组织中观察到鞘脂的差异调节，CdCl₂暴露和NaAsO₂暴露分别激活了补救和从头合成途径。此外，使用空间转录组学和定量实时PCR，我们确定了重金属暴露诱导的上皮细胞和人肺组织中氧化应激的转录组特征。
