Superfund Research Program
Heavy Metal Induced Airway Remodeling and COPD
Project Summary (2020-2025)
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 U.S. The prevalence of COPD is twice as high in the affected area in Birmingham, Alabama, where the 35th Avenue Superfund site is located, 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. The researchers' 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. The researchers are examining this hypothesis in the following specific aims:
- They are using a novel, selective pharmacologic inhibitor of PAD2 (AFM30a), as well as a pan PAD inhibitor (BB-Cl-amidine) to evaluate whether this leads to inhibition of citrullination of vimentin.
- 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 blocks the development of COPD. The researchers are using TLR4-/- mice to evaluate whether citrullinated vimentin directly causes airway remodeling and COPD as well as an invasive pro-fibrogenic phenotype of fibroblasts using 3D lung pulmospheres.
- 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 is being conducted in a validation cohort of COPD subjects in parallel with plasma and exhaled breath condensate (EBC) measurements. Early biomarkers of COPD in exhaled breath condensate may help the researchers 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.