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 (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.