# Impact of particle and ozone inhalation co-exposure on alveolar epithelial regeneration

> **NIH NIH R01** · WEST VIRGINIA UNIVERSITY · 2022 · $636,145

## Abstract

PROJECT SUMMARY/ABSTRACT
Environmental inhalation exposures are inherently mixed (gases and particles), yet environmental regulations
are still based on single toxicant exposures. Developing and studying the co-exposure scenario in a standardized
and controlled fashion will enable a better mechanistic understanding of how environmental exposures result in
adverse outcomes. The impact of co-exposures is poorly studied, especially in susceptible populations such as
individuals with acute lung injury (ALI). In the absence of such knowledge on environmental co-exposures, it will
be very difficult, if not impossible, to reduce the burden of environmental disease and develop effective as well
as realistic exposure limits to safeguard public health. The goal of this proposal is to elucidate mechanisms of
carbon black (CB; surrogate of the carbon core of ultrafine particles) and ozone (O3) inhalation co-exposure-
induced lung injury and modulation of epithelial regeneration in mice following ALI. We will further mechanistically
characterize the role of mitochondrial nucleotide-binding oligomerization domain-like Receptor X1 (NLRX1) in
these responses. We hypothesize that co-exposure to CB and O3 synergistically increases pulmonary damage
by oxidizing the particle surfaces, causing NLRX1 mediated mitochondrial dysfunction and microbial dysbiosis,
leading to reprogramming of the alveolar progenitor (AT2) cells for altered alveolar regeneration. Our research
plan exclusively combines state of the art inhalation co-exposures, unique mouse models, and 3-D organoid
cultures to elucidate the mechanisms of co-exposure induced pulmonary damage in healthy and injured lungs
(a susceptibility model). Our preliminary studies demonstrate that O3 and CB inhalation co-exposures
synergistically exacerbates lung injury, oxidative stress, inflammation, lung function decline, lung permeability,
mitochondrial oxidative phosphorylation, and lung microbial dysbiosis compared to individual exposures. Mice
lacking NLRX1 exhibit significantly aggravated inflammatory response after co-exposure. Alveolar type 2 (AT2)
cells (alveolar progenitor cells) show significant apoptosis, mitochondrial damage, and impaired ability to form
3-D alveolar organoids after co-exposure. Bleomycin (BLM)-induced lung epithelial injury is significantly
increased, while epithelial proliferation is impaired after co-exposure. Our specific aims are 1) to determine
synergistic biological activity and mechanisms of lung inflammation after co-exposure, 2) to identify how the
altered mechanisms of alveolar injury and alveolar progenitor cell dysfunction contribute to progression and
outcome of ALI, and 3) to characterize microbiome-alveolar progenitor cell cross-talk during co-exposure with or
without ALI. These studies will delineate genetic (NLRX1) and cellular mechanisms (alveolar progenitor
mitochondrial dysfunction and microbial dysbiosis) through which environmental exposures impact ALI
outcomes. These ...

## Key facts

- **NIH application ID:** 10356885
- **Project number:** 5R01ES031253-03
- **Recipient organization:** WEST VIRGINIA UNIVERSITY
- **Principal Investigator:** Salik Hussain
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $636,145
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356885

## Citation

> US National Institutes of Health, RePORTER application 10356885, Impact of particle and ozone inhalation co-exposure on alveolar epithelial regeneration (5R01ES031253-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10356885. Licensed CC0.

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