| First Author | Haider SH | Year | 2020 |
| Journal | Am J Respir Cell Mol Biol | Volume | 63 |
| Issue | 2 | Pages | 219-233 |
| PubMed ID | 32315541 | Mgi Jnum | J:333229 |
| Mgi Id | MGI:6740926 | Doi | 10.1165/rcmb.2019-0064OC |
| Citation | Haider SH, et al. (2020) Multiomics of World Trade Center Particulate Matter-induced Persistent Airway Hyperreactivity. Role of Receptor for Advanced Glycation End Products. Am J Respir Cell Mol Biol 63(2):219-233 |
| abstractText | 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-gamma-induced protein 10), and KC (keratinocyte chemoattractant) were differentially expressed after WTC-PM exposure. WTC-PM induced alpha-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, N(1)+N(8)-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. |
