# Project 1 Heavy Metal Induced Airway Remodeling and COPD

> **NIH NIH P42** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $213,201

## Abstract

The lung is a major portal for respirable environmental toxicants including heavy metals such as arsenic
(As), cadmium (Cd), and manganese (Mn), all of which are recognized to cause chronic obstructive pulmonary
disease (COPD). COPD is the third largest cause of mortality in the US. The prevalence of COPD is twice
as high in the Affected Area in Birmingham, Alabama where the Superfund site is located when compared to
the Control Area. Peptidyl arginine deiminase-2 enzyme (PAD2) in lung macrophages is activated by heavy
metals in a calcium dependent manner and induces deimination (citrullination) of vimentin to citrullinated vimentin
by the irreversible alteration of the arginine residue to the non-coded citrulline residue. Our hypothesis is that
exposure to particulate matter containing heavy metals (As, Cd and Mn) leads to induction and activation of
peptidyl arginine deiminase 2 in lung macrophages and deimination of vimentin. Activation of TLR4 in airway
fibroblasts by deiminated(citrullinated) vimentin leads to a pro-invasive, pro-fibrogenic phenotype, with
subsequent airway remodeling and COPD. We will examine this hypothesis in the following specific aims:
Aim 1: We will use a novel, selective pharmacologic inhibitor of PAD2 (AFM30a) as well as a pan PAD inhibitor
(BB-Cl-amidine) to evaluate if this leads to inhibition of citrullination of vimentin. We will also evaluate if
citrullinated vimentin modulates airway fibroblast into an invasive, phenotype in 3D lung pulmospheres through
upregulation of TLR4 in vitro. Aim 2: Determine whether heavy metal exposure leads to airway remodeling in a
murine model of COPD and is associated with the activation of PAD2, the citrullination and secretion of vimentin
and an invasive profibrotic phenotype of lung fibroblast. Pharmacologic or genetic inhibition of PAD2 will block
the development of COPD. We will use TLR4-/- mice to evaluate if citrullinated vimentin directly causes airway
remodeling and COPD as well as an invasive pro-fibrogenic phenotype of fibroblasts using 3D lung
pulmospheres. Aim 3: Determine whether PAD2 and citrullinated vimentin, present in lung macrophages, BAL,
plasma and EBC of a cohort of subjects from the Affected Area are biomarkers for COPD. Existing biospecimens
have been tested in a discovery cohort of subjects and prospective testing will be conducted in a validation cohort
of COPD subjects in parallel with airway fractal dimension (AFD) on CT scans, plasma and exhaled breath
condensate (EBC) measurements. Early biomarkers of COPD in exhaled breath condensate may help us
recognize disease susceptibility. Importantly, these studies may provide novel therapeutic strategies to
block the effects of PAD2 in patients with chronic lung disease such as COPD.

## Key facts

- **NIH application ID:** 9840805
- **Project number:** 1P42ES027723-01A1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Veena B. Antony
- **Activity code:** P42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $213,201
- **Award type:** 1
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840805

## Citation

> US National Institutes of Health, RePORTER application 9840805, Project 1 Heavy Metal Induced Airway Remodeling and COPD (1P42ES027723-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840805. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*