Reaction products of hexamethylene diisocyanate vapors with "self" molecules in the airways of rabbits exposed via tracheostomy

Xenobiotica. 2018 May;48(5):488-497. doi: 10.1080/00498254.2017.1329569. Epub 2017 Jun 1.

Abstract

1. Hexamethylenediisocyanate (HDI) is a widely used aliphatic diisocyanate and a well-recognized cause of occupational asthma. 2. "Self" molecules (peptides/proteins) in the lower airways, susceptible to chemical reactivity with HDI, have been hypothesized to play a role in asthma pathogenesis and/or chemical metabolism, but remain poorly characterized. 3. This study employed unique approaches to identify and characterize "self" targets of HDI reactivity in the lower airways. Anesthetized rabbits free breathed through a tracheostomy tube connected to chambers containing either, O2, or O2 plus ∼200 ppb HDI vapors. Following 60 minutes of exposure, the airways were lavaged and the fluid was analyzed by LC-MS and LC-MS/MS. 4. The low-molecular weight (<3 kDa) fraction of HDI exposed, but not control rabbit bronchoalveolar lavage (BAL) fluid identified 783.26 and 476.18 m/z [M+H]+ ions with high energy collision-induced dissociation (HCD) fragmentation patterns consistent with bis glutathione (GSH)-HDI and mono(GSH)-HDI. Proteomic analyses of the high molecular weight (>3 kDa) fraction of exposed rabbit BAL fluid identified HDI modification of specific lysines in uteroglobin (aka clara cell protein) and albumin. 5. In summary, this study utilized a unique approach to chemical vapor exposure in rabbits, to identify HDI reaction products with "self" molecules in the lower airways.

Keywords: Exposure; glutathione; hexamethylene diisocyanate; tracheostomy.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Body Fluids / metabolism
  • Chromatography, Liquid
  • Isocyanates / pharmacology*
  • Lung / drug effects*
  • Male
  • Mass Spectrometry
  • Models, Molecular
  • Molecular Weight
  • Peptides / chemistry
  • Rabbits
  • Tracheostomy*
  • Volatilization

Substances

  • Isocyanates
  • Peptides
  • 1,6-hexamethylene diisocyanate