Glutathione reaction products with the chemical allergen, methylene-diphenyl diisocyanate (MDI), stimulate eosinophilic airway inflammation and alternative macrophage activation

Details

• Personal Author:
  Liu J ; Redlich CA ; Wisnewski A
• Description:
  RATIONALE: Isocyanates have been a leading chemical cause of occupational asthma since their utility for generating polyurethane was first recognized over 60 years ago, yet the mechanisms of isocyanate asthma pathogenesis remain unclear. We tested the hypothesis that glutathione (GSH) reaction products with the chemical allergen, methylene-diphenyl diisocyanate (MDI), mediate asthma-like inflammatory responses upon respiratory tract isocyanate exposure. METHODS: Reaction products between GSH and MDI (GSH-MDI) were generated in vitro and characterized by liquid chromatography-mass spectrometry (LC-MS). Balb/C mice were exposed to GSH-MDI via the respiratory tract, and airway inflammatory responses were characterized based on analysis of airway lavage fluid, and lung tissue samples. Additional analysis of airway fluid was performed using isobaric tags for relative and absolute quantitation (iTRAQ) of protein levels. RESULTS: In naive mice, GSH-MDI induced innate immune responses, characterized by significantly increased airway levels of chitinase YM-1, and IL-12/IL-23beta (but not alpha) subunit. However, in mice immunologically sensitized to MDI via prior skin exposure, identical GSH-MDI doses induced substantially greater inflammatory responses, including significantly increased airway eosinophil numbers and mucus production, along with IL-12/IL-23beta, chitinases and other indicators of alternative macrophage activation. The "self"-protein, albumin, in airway fluid was uniquely modified by GSH-MDI reaction products, at the same site (Lys414) previously identified as a favored site for MDI conjugation to human albumin in vitro. CONCLUSION: The data suggest a thiol-mediated transcarbamoylating mechanism links MDI exposure and pathogenic inflammatory responses. [Description provided by NIOSH]
• Subjects:
  Albumins Asthma Asthma, Occupational Blood Chemistry Hypersensitivity Immune System Isocyanates Laboratories Lung Macrophages Occupational Health Respiratory System Respiratory Tract Diseases Safety Sulfhydryl Compounds

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• Keywords:
  4,4'methylenebisphenyl Isocyanate Albumin Allergens Bronchial Asthma Chemical Agents Chemical Reactions Diisocyanates Exposure Assessment Fluids Immune Reaction Immunological Tests In Vitro Study Laboratory Animals Laboratory Testing Liquid Chromatography Lung Cells Lung Tissue Mass Spectrometry MDI Occupational Asthma Pathogenesis Proteins Respiratory System Disorders Sensitizers Thiols

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• ISSN:
  1073-449X
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  Connecticut ; OSHA Region 1
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  191
• NIOSHTIC Number:
  nn:20048520
• Citation:
  Am J Respir Crit Care Med 2015 May; 191(Abstract Issue):A2583
• Contact Point Address:
  A. Wisnewski, Yale University, New Haven, CT
• Email:
  adam.wisnewski@yale.edu
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8) ; Glutathione (CAS RN 70-18-8)
• Federal Fiscal Year:
  2015
• Performing Organization:
  Yale University, New Haven, Connecticut
• Peer Reviewed:
  False
• Source Full Name:
  American Journal of Respiratory and Critical Care Medicine
• Supplement:
  Abstract Issue
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:9ffcce4f1aa4d5aed5d648d35da949274b30817242bf456eb9582a864af4f8abef422fb486eb3989d0099648a29a1360b4909c894f27a6eb1bfd344231f0ca9f
• Download URL:
  https://stacks.cdc.gov/view/cdc/203260/cdc_203260_DS1.pdf
• File Type:
  [PDF - 41.68 KB ]