Receptor for Advanced Glycation End-Products and World Trade Center Particulate Induced Lung Function Loss: A Case-Cohort Study and Murine Model of Acute Particulate Exposure

Details

• Personal Author:
  Caraher EJ ; Chen L-C ; Crowley G ; Ebrahim M ; Gordon T ; Haider SH ; Kwon S ; Lee A ; Liu M ; Nolan A ; Prezant DJ ; Schmidt AM ; Zhang L
• Description:
  World Trade Center-particulate matter(WTC-PM) exposure and metabolic-risk are associated with WTC-Lung Injury(WTC-LI). The receptor for advanced glycation end-products (RAGE) is most highly expressed in the lung, mediates metabolic risk, and single-nucleotide polymorphisms at the AGER-locus predict forced expiratory volume(FEV). Our objectives were to test the hypotheses that RAGE is a biomarker of WTC-LI in the FDNY-cohort and that loss of RAGE in a murine model would protect against acute PM-induced lung disease. We know from previous work that early intense exposure at the time of the WTC collapse was most predictive of WTC-LI therefore we utilized a murine model of intense acute PM-exposure to determine if loss of RAGE is protective and to identify signaling/cytokine intermediates. This study builds on a continuing effort to identify serum biomarkers that predict the development of WTC-LI. A case-cohort design was used to analyze a focused cohort of male never-smokers with normal pre-9/11 lung function. Odds of developing WTC-LI increased by 1.2, 1.8 and 1.0 in firefighters with soluble RAGE (sRAGE) >/= 97pg/mL, CRP >/= 2.4mg/L, and MMP-9 ≤ 397ng/mL, respectively, assessed in a multivariate logistic regression model (ROCAUC of 0.72). Wild type(WT) and RAGE-deficient(Ager-/-) mice were exposed to PM or PBS-control by oropharyngeal aspiration. Lung function, airway hyperreactivity, bronchoalveolar lavage, histology, transcription factors and plasma/BAL cytokines were quantified. WT-PM mice had decreased FEV and compliance, and increased airway resistance and methacholine reactivity after 24-hours. Decreased IFN-gamma and increased LPA were observed in WT-PM mice; similar findings have been reported for firefighters who eventually develop WTC-LI. In the murine model, lack of RAGE was protective from loss of lung function and airway hyperreactivity and was associated with modulation of MAP kinases. We conclude that in a multivariate adjusted model increased sRAGE is associated with WTC-LI. In our murine model, absence of RAGE mitigated acute deleterious effects of PM and may be a biologically plausible mediator of PM-related lung disease. [Description provided by NIOSH]
• Subjects:
  Biomarkers Case Reports Cohort Studies Dust Energy Metabolism Environmental Exposure Firefighters Laboratories Lung Lung Diseases Men Methacholine Compounds Nucleotides Occupational Exposure Occupational Health Particulate Matter Respiratory System Respiratory Tract Diseases Safety September 11 Terrorist Attacks

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• Keywords:
  Acute Exposure Analytical Models Case Studies Cell Signaling Cohort Studies Cytokines Exposure Assessment Exposure Levels Fire Fighters Laboratory Animals Lung Disease Lung Function Metabolic Effects Methacholines Morphology Particulate Dust Particulates Pulmonary System Disorders Regression Analysis Respiratory System Disorders World Trade Center WTC

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• ISSN:
  1932-6203
• 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
• Volume:
  12
• Issue:
  9
• NIOSHTIC Number:
  nn:20050446
• Citation:
  PLoS One 2017 Sep; 12(9):e0184331
• Contact Point Address:
  Anna Nolan, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, New York University School of Medicine, New York, New York, United States of America
• Email:
  anna.nolan@med.nyu.edu
• Federal Fiscal Year:
  2017
• Performing Organization:
  New York City Fire Department
• Peer Reviewed:
  True
• Start Date:
  20040701
• Source Full Name:
  PLoS One
• End Date:
  20110630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:b89b1f7bf9e62ba42f9442a08e8a67e7a4a3c2808055879bec4775f04b254496fd836a518cdc387fa981c9ea33e0591c5d2faa5d89d54164fa96aff649322376
• Download URL:
  https://stacks.cdc.gov/view/cdc/210780/cdc_210780_DS1.pdf
• File Type:
  [PDF - 10.53 MB ]