PDF(Pubmed)
Abstract：
Early-life respiratory syncytial virus (RSV) infection (eRSV) is one of the leading causes of serious pulmonary disease in children. eRSV is associated with higher risk of developing asthma and compromised lung function later in life. Cadmium (Cd) is a toxic metal, widely present in the environment and in food. We recently showed that eRSV re-programs metabolism and potentiates Cd toxicity in the lung, and our transcriptome-metabolome-wide study showed strong associations between S-palmitoyl transferase expression and Cd-stimulated lung inflammation and fibrosis signaling. Limited information is available on the mechanism by which eRSV re-programs metabolism and potentiates Cd toxicity in the lung. In the current study, we used a mouse model to examine the role of protein S-palmitoylation (Pr-S-Pal) in low dose Cd-elevated lung metabolic disruption and inflammation following eRSV. Mice exposed to eRSV were later treated with Cd (3.3 mg CdCl2/L) in drinking water for 6 weeks (RSV+Cd). The role of Pr-S-Pal was studied using a palmitoyl transferase inhibitor, 2-bromopalmitate (BP, 10 µM). Inflammatory marker analysis showed that cytokines, chemokines and inflammatory cells were highest in the RSV+Cd group, and BP decreased inflammatory markers. Lung metabolomics analysis showed that pathways including phenylalanine, tyrosine and tryptophan, phosphatidylinositol and sphingolipid were altered across treatments. BP antagonized metabolic disruption of sphingolipid and glycosaminoglycan metabolism by RSV+Cd, consistent with BP effect on inflammatory markers. This study shows that Cd exposure following eRSV has a significant impact on subsequent inflammatory response and lung metabolism, which is mediated by Pr-S-Pal, and warrants future research for a therapeutic target.
摘要：
早期呼吸道合胞病毒（RSV）感染（eRSV）是儿童严重肺部疾病的主要原因之一。eRSV与以后发生哮喘和肺功能受损的风险较高相关。镉（Cd）是一种有毒金属，广泛存在于环境和食品中。我们最近表明，eRSV重新编程代谢并增强肺中的Cd毒性，我们的转录-代谢组研究显示,S-棕榈酰转移酶的表达与Cd刺激的肺部炎症和纤维化信号之间有很强的关联.关于eRSV重新编程代谢并增强肺部Cd毒性的机制的信息有限。在目前的研究中,我们使用小鼠模型来检查蛋白质S-棕榈酰化（Pr-S-帕尔）在低剂量Cd升高的肺代谢破坏和eRSV后炎症中的作用。随后用饮用水中的Cd(3.3mgCdCl2/L)处理暴露于eRSV的小鼠6周(RSV+Cd)。使用棕榈酰转移酶抑制剂研究了Pr-S-帕尔的作用，2-溴棕榈酸酯（BP，10µM)。炎症标志物分析表明,细胞因子,RSV+Cd组趋化因子和炎症细胞最高,和BP降低炎症标志物。肺代谢组学分析显示,包括苯丙氨酸、酪氨酸和色氨酸,磷脂酰肌醇和鞘脂在治疗过程中发生了变化。BP拮抗RSVCd对鞘脂和糖胺聚糖代谢的代谢破坏，与BP对炎症标志物的影响一致。这项研究表明，Cd暴露后的eRSV对随后的炎症反应和肺代谢有显著影响，这是由Pr-S-帕尔介导的，并保证未来对治疗目标的研究。
