Details:

Alternative Title:
Chem Res Toxicol
Publisher's site:
http://dx.doi.org/10.1021/tx5005002
Personal Author:
Wisnewski, Adam V. ; Liu, Jian ; Colangelo, Christopher M.
Wisnewski, Adam V. ; Liu, Jian ; Colangelo, Christopher M. Less -
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-23β (but not α) 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-23β, 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.
Subject:
[+]
Allergens
Animals
Bronchoalveolar Lavage Fluid
Eosinophils
Glutathione
Humans
Infant
Inflammation
Isocyanates
Macrophage Activation
Mice
Mice, Inbred BALB C
Trachea

Source:
Chem Res Toxicol. 28(4):729-737.
Pubmed ID:
25635619
Pubmed Central ID:
PMC4667722
Document Type:
Journal Article
Funding:
OH010438/OH/NIOSH CDC HHS/United States ; OH010494/OH/NIOSH CDC HHS/United States ; R21 OH010438/OH/NIOSH CDC HHS/United States ; R21 OH010494/OH/NIOSH CDC HHS/United States
OH010438/OH/NIOSH CDC HHS/United States ; OH010494/OH/NIOSH CDC HHS/United States ; R21 OH010438/OH/NIOSH CDC HHS/United States ; R21 OH010494/OH/NIOSH CDC HHS/United States Less -
Collection(s):
CDC Public Access
Main Document Checksum:
[+]
urn:sha256:35680e03dbca8cf068d2a39241c819cf5fe48c5bbf7939d7aff196eeea044bc2
File Type:

Supporting Files

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