title: Glutathione protects human airway proteins and epithelial cells from isocyanates.
abstract: BACKGROUND
  Glutathione (GSH), one of the major anti-oxidants of the lung, has been linked to the human response to isocyanate exposure. However, the ability of GSH to modulate key chemical reactions, thought to be central to the development of human isocyanate allergy, has not been directly analyzed under biologic exposure conditions.
  
  
  OBJECTIVE
  To better understand the potential role of GSH in the response to occupational isocyanate exposure, we evaluated its effects on two processes thought to be involved in the development of isocyanate allergy, isocyanate-protein conjugation and epithelial cell toxicity.
  
  
  METHODS
  The effects of GSH on (1) isocyanate conjugation with albumin, its major target in the airway fluid and (2) isocyanate-induced toxicity to human airway epithelial cell lines, A549 and NCI-H292, were tested using two different in vitro models. For protein conjugation studies, a newly described vapour exposure system was used to model the air/liquid interface at the surface of the epithelial fluid in the airways. Epithelial cell exposures were performed in fluid phase to mimic the in vivo exposure of airway cells covered by epithelial lining fluid.
  
  
  RESULTS
  Reduced GSH prevented hexamethylene diisocyanate (HDI) conjugation to albumin in a dose-dependent manner, while oxidized GSH (GSSG) conversely increased conjugation rates. GSH levels equivalent to those found in normal human airway fluid (100 microm) provided >90% protection against HDI-protein conjugation when albumin was exposed to HDI vapour levels 10-fold above permissible occupational limits. Physiologic levels of GSH, but not GSSG, also reduced HDI toxicity to human airway epithelial cells in a dose-dependent manner, when present extracellularly, however, drugs that modulate intra-cellular GSH levels did not significantly alter isocyanate toxicity.
  
  
  CONCLUSIONS
  Together with previously reported genetic and toxicity studies, the data suggest that airway GSH plays an important role in protection against HDI exposure and may help prevent the development of allergic sensitization and asthma.
authors.affiliation: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA. adam.wisnewsi@yale.edu
authors.forename: A V
authors.initials: AV
authors.lastname: Wisnewski
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.forename: C A
authors.initials: CA
authors.lastname: Redlich
mesh_terms: D000395:Air Pollutants, Occupational / Q000633:toxicity*; D001249:Asthma / Q000276:immunology; D002460:Cell Line; D003485:Cyanates / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology; D005978:Glutathione / Q000494:pharmacology*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D017953:Isocyanates; D009784:Occupational Diseases / Q000276:immunology*; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology
chemical_list: D000395:Air Pollutants, Occupational; D003485:Cyanates; D017953:Isocyanates; C015262:1,6-hexamethylene diisocyanate; D005978:Glutathione