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Multiomics of World Trade Center Particulate Matter-induced Persistent Airway Hyperreactivity. Role of Receptor for Advanced Glycation End Products.
American Journal of Respiratory Cell and Molecular Biology ( IF 5.9 ) Pub Date : 2020-07-31 , DOI: 10.1165/rcmb.2019-0064oc
Syed H Haider 1 , Arul Veerappan 1 , George Crowley 1 , Erin J Caraher 1 , Dean Ostrofsky 1 , Mena Mikhail 1 , Rachel Lam 1 , Yuyan Wang 2 , Maria Sunseri 1 , Sophia Kwon 1 , David J Prezant 3, 4 , Mengling Liu 2, 5 , Ann Marie Schmidt 6 , Anna Nolan 1, 3, 5
Affiliation  

Pulmonary disease after World Trade Center particulate matter (WTC-PM) exposure is associated with dyslipidemia and the receptor for advanced glycation end products (RAGE); however, the mechanisms are not well understood. We used a murine model and a multiomics assessment to understand the role of RAGE in the pulmonary long-term effects of a single high-intensity exposure to WTC-PM. After 1 month, WTC-PM–exposed wild-type (WT) mice had airway hyperreactivity, whereas RAGE-deficient (Ager−/−) mice were protected. PM-exposed WT mice also had histologic evidence of airspace disease, whereas Ager/ mice remained unchanged. Inflammatory mediators such as G-CSF (granulocyte colony–stimulating factor), IP-10 (IFN-γ–induced protein 10), and KC (keratinocyte chemoattractant) were differentially expressed after WTC-PM exposure. WTC-PM induced α-SMA, DIAPH1 (protein diaphanous homolog 1), RAGE, and significant lung collagen deposition in WT compared with Ager−/− mice. Compared with WT mice with PM exposure, relative expression of phosphorylated to total CREB (cAMP response element–binding protein) and JNK (c-Jun N-terminal kinase) was significantly increased in the lung of PM-exposed Ager−/− mice, whereas Akt (protein kinase B) was decreased. Random forests of the refined lung metabolomic profile classified subjects with 92% accuracy; principal component analysis captured 86.7% of the variance in three components and demonstrated prominent subpathway involvement, including known mediators of lung disease such as vitamin B6 metabolites, sphingolipids, fatty acids, and phosphatidylcholines. Treatment with a partial RAGE antagonist, pioglitazone, yielded similar fold-change expression of metabolites (N6-carboxymethyllysine, 1-methylnicotinamide, N1+N8-acetylspermidine, and succinylcarnitine [C4-DC]) between WT and Ager−/− mice exposed to WTC-PM. RAGE can mediate WTC-PM–induced airway hyperreactivity and warrants further investigation.



中文翻译:

世界贸易中心颗粒物引起的持续性气道高反应性的多组学。受体在高级糖化终产物中的作用。

世贸中心颗粒物 (WTC-PM) 暴露后的肺部疾病与血脂异常和晚期糖基化终产物 (RAGE) 受体有关;然而,这些机制还不是很清楚。我们使用小鼠模型和多组学评估来了解 RAGE 在单次高强度暴露于 WTC-PM 对肺部长期影响中的作用。1 个月后,暴露于 WTC-PM 的野生型 (WT) 小鼠出现气道高反应性,而 RAGE 缺陷型 ( Ager -/- ) 小鼠受到保护。PM 暴露的 WT 小鼠也有空域疾病的组织学证据,而Ager - / -老鼠保持不变。炎症介质如 G-CSF(粒细胞集落刺激因子)、IP-10(IFN-γ 诱导蛋白 10)和 KC(角质形成细胞化学引诱物)在 WTC-PM 暴露后差异表达。与Ager -/-小鼠相比,WTC-PM 在 WT 中诱导了 α-SMA、DIAPH1(蛋白质透明同源物 1)、RAGE 和显着的肺胶原沉积。与暴露于 PM 的 WT 小鼠相比,在暴露于 PM 的Ager -/-肺中,磷酸化至总 CREB(cAMP 反应元件结合蛋白)和 JNK(c-Jun N-末端激酶)的相对表达显着增加小鼠,而 Akt(蛋白激酶 B)减少。精细肺代谢组学特征的随机森林以 92% 的准确率对受试者进行分类;主成分分析在三个成分中捕获了 86.7% 的方差,并证明了显着的亚途径参与,包括已知的肺部疾病介质,如维生素 B 6代谢物、鞘脂、脂肪酸和磷脂酰胆碱。用部分 RAGE 拮抗剂吡格列酮治疗在 WT 和Ager之间产生类似的代谢物倍数变化表达(N 6 -羧甲基赖氨酸、1-甲基烟酰胺、N 1 +N 8 -乙酰亚精胺和琥珀酰肉碱 [C4-DC])-/-暴露于 WTC-PM 的小鼠。RAGE 可以调节 WTC-PM 引起的气道高反应性,值得进一步研究。

更新日期:2020-08-20
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