期刊
TOXICOLOGICAL SCIENCES
卷 -, 期 -, 页码 -出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfad112
关键词
early-life exposure; dietary metal; environmental exposure; lung pathology; metabolic disruption; post-translational protein modification
类别
Early-life respiratory syncytial virus (RSV) infection is associated with serious pulmonary disease in children and a higher risk of developing asthma. Cadmium exposure following RSV infection reprograms lung metabolism and enhances its toxicity. Protein S-palmitoylation plays a crucial role in this process.
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 reprograms 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 reprograms 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 mu M). 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. The 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.
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