TY - JOUR
T1 - Multiomics of world trade center particulate matter-induced persistent airway hyperreactivity role of receptor for advanced glycation end products
AU - Haider, Syed H.
AU - Veerappan, Arul
AU - Crowley, George
AU - Caraher, Erin J.
AU - Ostrofsky, Dean
AU - Mikhail, Mena
AU - Lam, Rachel
AU - Wang, Yuyan
AU - Sunseri, Maria
AU - Kwon, Sophia
AU - Prezant, David J.
AU - Liu, Mengling
AU - Schmidt, Ann Marie
AU - Nolan, Anna
N1 - Funding Information:
Supported by U.S. National Heart, Lung, and Blood Institute grant R01HL119326 (A.N.); CDC/National Institute for Occupational Safety and Health grant U01-OH11300 (A.N.); Clinical Center of Excellence grant 200-2017-93426; and Data Center grant 200-2017-93326.
Publisher Copyright:
© 2020 by the American Thoracic Society.
PY - 2020/8
Y1 - 2020/8
N2 - 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 (Ager2/2) mice were protected. PM-exposed WT mice also had histologic evidence of airspace disease, whereas Ager2/2 mice remained unchanged. Inflammatory mediators such as G-CSF (granulocyte colony-stimulating factor), IP-10 (IFN-g-induced protein 10), and KC (keratinocyte chemoattractant) were differentially expressed after WTC-PM exposure. WTC-PM induced a-SMA, DIAPH1 (protein diaphanous homolog 1), RAGE, and significant lung collagen deposition in WTcompared with Ager2/2 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 Ager2/2 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, N11N8- acetylspermidine, and succinylcarnitine [C4-DC]) between WT and Ager2/2 mice exposed to WTC-PM. RAGE can mediate WTC-PM-induced airway hyperreactivity and warrants further investigation.
AB - 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 (Ager2/2) mice were protected. PM-exposed WT mice also had histologic evidence of airspace disease, whereas Ager2/2 mice remained unchanged. Inflammatory mediators such as G-CSF (granulocyte colony-stimulating factor), IP-10 (IFN-g-induced protein 10), and KC (keratinocyte chemoattractant) were differentially expressed after WTC-PM exposure. WTC-PM induced a-SMA, DIAPH1 (protein diaphanous homolog 1), RAGE, and significant lung collagen deposition in WTcompared with Ager2/2 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 Ager2/2 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, N11N8- acetylspermidine, and succinylcarnitine [C4-DC]) between WT and Ager2/2 mice exposed to WTC-PM. RAGE can mediate WTC-PM-induced airway hyperreactivity and warrants further investigation.
KW - Airway hyperreactivity
KW - Lung injury
KW - Murine models
KW - Occupational exposure
KW - Particulate matter
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U2 - 10.1165/rcmb.2019-0064OC
DO - 10.1165/rcmb.2019-0064OC
M3 - Article
C2 - 32315541
AN - SCOPUS:85088209044
SN - 1044-1549
VL - 63
SP - 219
EP - 233
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
IS - 2
ER -