# Extracellular vesicles as mediators of injury in inhaled exposures to toxic chemicals.

> **NIH NIH R56** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $445,500

## Abstract

Project Summary
Sulfur mustard (SM) and chlorine have reemerged as a potential threat to both military and civilian populations.
Inhaled exposures to sulfur mustard (SM) and chlorine cause acute lung injury, which can lead to respiratory
failure, multiorgan dysfunction and death. Mechanisms by which pulmonary toxicity contributes to systemic injury
are not clear. Our studies with inhaled halogens (chlorine and bromine) have demonstrated serious cardiac and
neuronal injury. We have previously identified circulating adducts of halogens that form in the pulmonary bed
and contribute towards distant organ damage and disease pathogenicity. In our inhaled SM models of injury, we
demonstrated that circulating factors such as nucleic acids released from pulmonary tissues and cells can
contribute significantly to lung damage and that scavenging the nucleic acids can alleviate injury and rescue
from mortality. Therefore, circulating factors are critical to pulmonary and systemic injuries. Growing evidence
suggests that several such factors are carried as cargo in exosomes a type of extracellular vesicles (EV). Studies
have shown that EV/exosomes could be pathogenic. Our preliminary data shows that the composition of cargoes
from the bronchoalveolar lavage fluid (BALF) of chlorine exposed rats are distinct from the exosomal cargo
obtained from the BALF of control animals. Further, we demonstrate that exosomes isolated from the BALF of
animals exposed to CEES (2-chloroethyl ethylsulfide, aka: half mustard), an analog of SM, when added to cells
in culture dose-dependently increased inflammatory cytokines and procoagulation genes, important components
in the pathogenesis of SM-induced and CEES-induced injuries. In our in vivo studies the SM BALF exosome
content correlated with the BALF protein, a marker of leaky alveolar barrier. These studies led us to hypothesize
that toxic chemical exposures result in the release of pathogenic exosomes that causes activation of the
inflammatory and coagulation pathways and that blocking their biogenesis or uptake can mitigate injury and
protect from acute morbidity and mortality. Accordingly, we will (a) characterize EV/exosomes derived from the
BALF and plasma of rats exposed to Cl2 and CEES, (b) identify mechanisms by which EV/exosomes from these
toxic chemical-exposed animals cause injury, and (c) evaluate pathogenicity of EV/exosomes derived from toxic
chemical-exposed animals are test efficacy or biogenesis or uptake inhibitors. These studies will delineate
mechanisms by which EV/exosomes influence pulmonary injury/disease severity and resolution and also
determine whether exosomes can serve as potential therapeutic targets in mitigating organ injury caused by
inhaled toxic chemicals.

## Key facts

- **NIH application ID:** 10887268
- **Project number:** 1R56ES034423-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Aftab Ahmad
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2023-08-17 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10887268

## Citation

> US National Institutes of Health, RePORTER application 10887268, Extracellular vesicles as mediators of injury in inhaled exposures to toxic chemicals. (1R56ES034423-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10887268. Licensed CC0.

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