# Project 2 Asthma in Children Exposed to Heavy Metals

> **NIH NIH P42** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $210,099

## Abstract

SUMMARY
 Environmental exposure of the lung to airborne particulate matter (PM) containing mixed heavy metals
contributes to development of chronic lung diseases, including asthma. These diseases are classically
associated with dysregulated epithelial-mesenchymal communication. PM with a particulate size of ≤2.5 µm
(PM2.5) contain high levels of heavy metals, including cadmium (Cd), arsenic (As), and manganese (Mn).
However, the mechanisms of how these heavy metals contribute to disease pathogenesis are unknown. In
support of this project, we detected elevated levels of heavy metals in the serum/urine of residents from the
Environmental Protection Agency (EPA) designated National Priorities List (NPL) Superfund site in North
Birmingham. Asthmatic children from this Affected Area have evidence of systemic heavy metals exposure, as
evidenced by higher urinary levels of arsenic. Bronchoalveolar lavage (BAL) fluid obtained by bronchoscopy of
asthmatic individuals from this Affected Area contain epithelial cell-derived exosomes that package
mitochondria. Additionally, BAL-derived exosomes from human asthmatic subjects are skewed towards a
higher concentration of anti-apoptotic sphingolipids (sphingosine-1-phoshate > ceramide) by SWATH-
lipidomics analysis. These exosomes are fibrogenic as they induce reprogramming of fibroblasts to an
apoptosis-resistant and fibrogenic phenotype. Animal studies demonstrate that intra-tracheal instillation of
heavy metals induces peribronchial fibrosis in mice, providing an opportunity to generate proof-of-concept pre-
clinical data in support of targeting pro-inflammatory and pro-fibrotic sphingolipid pathways in environmental
asthma.
 The hypothesis to be tested in this project is that heavy metal exposures in children induce airway
epithelium injury/activation that triggers the release of exosomal lipids to activate fibroblasts/smooth muscle
cells that contribute to airway hyper-responsiveness and remodeling in asthma. The specific aims are to: (1)
determine the mechanisms of heavy metal-induced exosomal lipid signaling that activates sub-epithelial
mesenchymal cells (SMCs/Fbs); (2) determine the role of lipid mediators/exosomes released by bronchial
epithelial cells in airway hyper-responsiveness and remodeling in mice exposed to heavy metals; and (3)
determine whether heavy metal exposures are associated with asthma severity and increased levels of
plasma, EBC and sputum lipid biomarkers in children residing in the North Birmingham NPL Superfund site.
 These studies will provide new insights into the impact of heavy metal exposure on asthma susceptibility
and severity; on novel mechanisms of epithelial-mesenchymal communication by fibrogenic exosomes; and
development of new therapeutic approaches to the treatment of chronic asthma associated with heavy metal
exposures.

## Key facts

- **NIH application ID:** 9840806
- **Project number:** 1P42ES027723-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Victor J. Thannickal
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $210,099
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840806

## Citation

> US National Institutes of Health, RePORTER application 9840806, Project 2 Asthma in Children Exposed to Heavy Metals (1P42ES027723-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840806. Licensed CC0.

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