Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine.
Division of Biostatistics, Department of Population Health.
Am J Respir Cell Mol Biol. 2020 Aug;63(2):219-233. doi: 10.1165/rcmb.2019-0064OC.
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 () mice were protected. PM-exposed WT mice also had histologic evidence of airspace disease, whereas 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 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 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 B metabolites, sphingolipids, fatty acids, and phosphatidylcholines. Treatment with a partial RAGE antagonist, pioglitazone, yielded similar fold-change expression of metabolites (N-carboxymethyllysine, 1-methylnicotinamide, N+N-acetylspermidine, and succinylcarnitine [C4-DC]) between WT and mice exposed to WTC-PM. RAGE can mediate WTC-PM-induced airway hyperreactivity and warrants further investigation.
暴露于世界贸易中心颗粒物（WTC-PM）后引发的肺部疾病与血脂异常和晚期糖基化终产物受体（RAGE）有关，但其中的机制尚不清楚。我们使用了一种小鼠模型和一种多组学评估方法来了解 RAGE 在单次高强度暴露于 WTC-PM 后对肺部的长期影响中的作用。在 1 个月后，暴露于 WTC-PM 的野生型（WT）小鼠出现了气道高反应性，而 RAGE 缺失（）小鼠则受到了保护。暴露于 PM 的 WT 小鼠也出现了气腔疾病的组织学证据，而 小鼠则没有变化。在暴露于 WTC-PM 后，像 G-CSF（粒细胞集落刺激因子）、IP-10（IFN-γ 诱导蛋白 10）和 KC（角质细胞化学引诱物）等炎症介质的表达也出现了差异。与暴露于 PM 的 WT 小鼠相比，WTC-PM 诱导了 WT 小鼠中α-SMA、DIAPH1（蛋白 diaphanous 同源物 1）、RAGE 和显著的肺胶原沉积。与暴露于 PM 的 WT 小鼠相比，暴露于 PM 的 小鼠中磷酸化 CREB（cAMP 反应元件结合蛋白）与总 CREB 的比值（CREB）和 JNK（c-Jun N-末端激酶）的相对表达显著增加，而 Akt（蛋白激酶 B）则减少。经过精炼的肺部代谢组学特征的随机森林对 92%的研究对象进行了分类；主成分分析捕获了三个成分中的 86.7%的方差，并证明了主要的亚途径参与，包括肺部疾病的已知介质，如维生素 B 代谢物、鞘脂、脂肪酸和磷脂酰胆碱。使用部分 RAGE 拮抗剂吡格列酮治疗暴露于 WTC-PM 的 WT 和 小鼠，可产生代谢物（N-羧甲基赖氨酸、1-甲基烟酰胺、N+N-乙酰腐胺和琥珀酰肉碱[C4-DC]）的类似倍数变化表达。RAGE 可介导 WTC-PM 诱导的气道高反应性，值得进一步研究。
