Deciphering Occupational Asthma Pathogenesis Caused by Isocyanate

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 DESCRIPTION (provided by applicant): This grant application focuses on occupational asthma caused by isocyanate chemicals, which are respiratory toxins needed to make polyurethane and commonly used in the manufacturing, construction and transportation industry sectors. Isocyanates' health hazards are widely recognized and workplace airborne levels are restricted by local governmental regulatory agencies, however, isocyanates remain a leading cause of occupational asthma throughout the world. Substantial knowledge gaps in our understanding of the mechanisms underlying isocyanate asthma and potential differences compared with other types of extrinsic asthma contribute to disease persistence. We have developed an exciting new hypothesize for the pathogenesis of isocyanate asthma and begun to decipher a dynamic biochemical pathway involving multiple host molecules. We have identified glutathione (GSH) as an important primary "self" reaction target for isocyanate and shown that GSH-isocyanate reaction products can transfer isocyanate to (transcarbamoylate) other self molecules, creating antigenic changes in the process. Serum antibodies from occupationally exposed workers specifically bind albumin transcarbamoylated by GSH-isocyanate. In animal studies, GSH-isocyanate reaction products cause asthma-like airway inflammation with significant eosinophilia and mucus production in immune sensitized hosts. The airway inflammation elicited by GSH-isocyanate resembles the prototypical TH2-type response to common protein allergens, but occurs without measurable increases in IL-4 or IL-13. Instead selective increases are observed in the shared beta subunit of IL-12/IL-23, chitinases (YM-1/YM-2), RELMα/Fizz-1, and other markers of alternatively activated macrophages. The data begin to define a new paradigm for isocyanate asthma pathogenesis, which explain the diseases puzzling features and suggest novel approaches for surveillance, prevention, and treatment. We propose to elucidate the distinct pathways through which GSH mediates isocyanate-induced airway inflammatory responses, thus, providing insight necessary to develop new intervention strategies, and to identify biomarkers applicable to exposure surveillance and disease prevention. Specifically, we propose the following three aims: AIM 1. Determine the influence of endogenous GSH levels on isocyanate immune sensitization and exposure induced airway inflammation. AIM 2. Elucidate the isocyanate-stimulated cell types, cytokines, and signal transduction cascades critical to immune sensitization and exposure-induced airway pathology. AIM 3. Identify biomarkers of isocyanate exposure and disease. The studies are relevant to NORA Construction and Manufacturing Sectors, and will provide insight into the Respiratory, and Immune and Dermal Disease Co-Sectors.