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.

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。