Glutathione reaction products with a chemical allergen, methylene-diphenyl diisocyanate, stimulate alternative macrophage activation and eosinophilic airway inflammation

Details

• Personal Author:
  Colangelo CM ; Liu J ; Wisnewski AV ; Colangelo CM ; Liu J ; Wisnewski AV
• Description:
  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. The present study provides in vivo evidence that a GSH mediated pathway underlies asthma-like eosinophilic inflammatory responses to respiratory tract isocyanate exposure. In naïve mice, a mixture of GSH reaction products with the chemical allergen, methylene-diphenyl diisocyanate (MDI), induced innate immune responses, characterized by significantly increased airway levels of Chitinase YM-1 and IL-12/IL-23beta (but not a) 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 mouse airway fluid was uniquely modified by GSH-MDI at position (414)K, a preferred site of MDI reactivity on human albumin. The (414)K-MDI conjugation appears to covalently cross-link GSH to albumin via GSH's NH2-terminus, a unique conformation possibly resulting from cyclized mono(GSH)-MDI or asymmetric (S,N'-linked) bis(GSH)-MDI conjugates. Together, the data support a possible thiol mediated transcarbamoylating mechanism linking MDI exposure to pathogenic eosinophilic inflammatory responses. [Description provided by NIOSH]
• Subjects:
  Asthma Asthma, Occupational Chemistry Chronic Disease Environmental Monitoring Hazardous Substances Hypersensitivity Immune System Isocyanates Laboratories Lung Lung Diseases Occupational Health Respiratory System Respiratory Tract Diseases Safety Sulfhydryl Compounds

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• Keywords:
  Airway-resistance Allergens Bronchial-asthma Chemical-reactions Chronic-inflammation Dose-response Exposure-assessment Immune-reaction Immunochemistry Immunological-tests In-vivo-study Laboratory-animals Laboratory-testing Lung-disorders Lung-irritants Pathogenesis Proteins Pulmonary-system-disorders Respiratory-system-disorders Thiols Thiones Toxic-effects

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• ISSN:
  0893-228X
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article ; Journal Article
• Place as Subject:
  Connecticut ; OSHA Region 1
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Volume:
  28
• Issue:
  4
• NIOSHTIC Number:
  nn:20047346
• Citation:
  Chem Res Toxicol 2015 Apr; 28(4):729-737
• Contact Point Address:
  Adam V. Wisnewski, Departments of Internal Medicine and Molecular Biophysics & Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8057, United States
• Email:
  adam.wisnewski@yale.edu
• CAS Registry Number:
  Diphenylmethane diisocyanate (CAS RN 101-68-8) ; Glutathione (CAS RN 70-18-8) ; 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:
  True
• Start Date:
  20130901
• Source Full Name:
  Chemical Research in Toxicology
• End Date:
  20160831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:a035bd4e2d052a947655209b08187ec784c874c4091b88c4fbdc7ce40ceae8015b8caba0b6808c391fc62d6885dfd2c4e889071a5af60d03242db825ab49f06a
• Download URL:
  https://stacks.cdc.gov/view/cdc/202451/cdc_202451_DS1.pdf
• File Type:
  [PDF - 4.64 MB ]