# Deciphering Occupational Asthma Pathogenesis Caused by Isocyanate

> **NIH ALLCDC R01** · YALE UNIVERSITY · 2024 · $652,908

## Abstract

Diisocyanates are crucial ingredients in many important products and industries (i.e. construction,
automotive, aerospace, medical, military/civilian). Recognized in 1951 as occupational allergens, progress in
understanding diisocyanate asthma has lagged behind that of environmental asthma. Gaps in understanding
diisocyanate asthma pathogenesis impede almost all aspects of disease control; exposure surveillance and
prevention, disease screening and diagnosis, and prophylactic or post-exposure therapeutics or treatments.
Differences between diisocyanate asthma and common environmental asthma are especially critical to
screening and clinical workup, notably the lack of antigen (e.g. chemical)-specific IgE in affected workers.
Individuals that continue to work with diisocyanates after developing “hypersensitivity” face long-term adverse
pulmonary health outcomes, and in rare cases have died.
 In a prior R01 we developed a novel approach for delivering diisocyanate to the lower airways in mice
(overcoming upper airway “scrubbing” that hampered prior studies) to help understand pathogenic responses
and identify new exposure biomarkers useful for exposure surveillance. Our novel mouse diisocyanate asthma
model has provided substantial insight into the immune responses triggered by exposure, particularly
differences between pathogenic responses in immune sensitized hosts vs. non-pathogenic responses in non-
sensitized hosts and differences in chemical (MDI) asthma vs. environmental asthma (see preliminary data).
Importantly, the data highlight innate immune responses that differentiate “self” from “non-self” as a critical
aspect of pathogenesis and identify candidate genes and molecular targets that mediate this process.
 The present investigation proposes to complete the elucidation of pathogenic mechanisms triggered by
diisocyanate using our animal model and to translate promising preliminary findings in mice on biomarkers to
clinical samples from exposed workers. We hypothesize that we can utilize our mouse model of diisocyanate
asthma, taking advantage of genetic manipulation and experimental drugs that focus on specific molecular
targets, to better understand the mechanisms that differentiate pathogenic from non-pathogenic responses.
We further hypothesize that exposure biomarkers from animal studies, including di-lysine-diisocyanate recently
discovered by our laboratory, can translate to humans and serve as an effective basis for biomonitoring
workplace exposures. The Specific Aims are: Aim 1. Identify and characterize the dendritic cell(s) that initiates
pathologic systemic immune sensitization to diisocyanate. Aim 2. Identify and characterize the effector cells
and molecules in the lungs that mediate asthma pathology following respiratory tract exposure. Aim 3. Identify,
validate, and translate biomarkers of diisocyanate exposure and sensitivity/disease. The application is relevant
to Construction, Manufacturing, and Transportation NORA sectors ...

## Key facts

- **NIH application ID:** 10942178
- **Project number:** 1R01OH012726-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** ADAM WISNEWSKI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** ALLCDC
- **Fiscal year:** 2024
- **Award amount:** $652,908
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942178

## Citation

> US National Institutes of Health, RePORTER application 10942178, Deciphering Occupational Asthma Pathogenesis Caused by Isocyanate (1R01OH012726-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10942178. Licensed CC0.

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