Multiomics of World Trade Center Particulate Matter-induced Persistent Airway Hyperreactivity. Role of Receptor for Advanced Glycation End Products.

Pulmonary disease after World Trade Center particulate matter (WTC-PM) exposure is associated with dyslipidemia and the receptor for advanced glycation end products however, the mechanisms are not well understood. We used a murine model and a multiomics assessment to understand the role of 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 (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), 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 duanyu1648 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. duanyu1648 can mediate WTC-PM-induced airway hyperreactivity and warrants further investigation.

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