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

Details

• Personal Author:
  Caraher EJ ; Crowley G ; Haider SH ; Kwon S ; Lam R ; Liu M ; Mikhail M ; Nolan A ; Ostrofsky D ; Prezant DJ ; Schmidt AM ; Sunseri M ; Veerappan A ; Wang Y
• Description:
  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 a-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. [Description provided by NIOSH]
• Subjects:
  Animals Laboratories Lipids Lung Diseases Occupational Exposure Occupational Health Particulate Matter Respiratory Tract Diseases Safety September 11 Terrorist Attacks
• Keywords:
  Airway Hyperreactivity Animal Studies Author Keywords: Occupational Exposure Laboratory Animals Lung Disease Lung Injury Molecular Signaling Murine Models Occupational Exposure Particulate Matter Particulates Phospholipids Proteins World Trade Center WTC

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• ISSN:
  1044-1549
• Document Type:
  Text
• Funding:
  Cooperative Agreement ; Contract
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  219-233
• Volume:
  63
• Issue:
  2
• NIOSHTIC Number:
  nn:20061396
• Citation:
  Am J Respir Cell Mol Biol 2020 Aug; 63(2):219-233
• Contact Point Address:
  Anna Nolan, M.D., M.S., Division of Pulmonary, Critical Care and Sleep, Department of Medicine, New York University School of Medicine, New Bellevue, 16N Room 20 (Lab), Nolan Lab, First Avenue, New York, NY 10016
• Email:
  anna.nolan@med.nyu.edu
• Federal Fiscal Year:
  2020
• Performing Organization:
  New York University School of Medicine
• Peer Reviewed:
  True
• Start Date:
  20170701
• Source Full Name:
  American Journal of Respiratory Cell and Molecular Biology
• End Date:
  20260630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:e3913aa2b5e9465a89d27df6cb1453ae50480db07ed9df9f1d85121096a58ee704fddd691ee1fe2fce87cc08acbff5da865f81fa8b75451118fc0e6f0ccdb650
• Download URL:
  https://stacks.cdc.gov/view/cdc/224934/cdc_224934_DS1.pdf
• File Type:
  [PDF - 2.10 MB ]