Our hypothesis is that exposure to particulate matter containing heavy metals (Cd, As and Mn) leads to induction and activation of peptidyl arginine deiminase 2 (PAD2) in lung macrophages and citrullination of vimentin. Activation of TLR4 in airway fibroblasts by citrullinated vimentin leads to a pro-invasive, pro-fibrogenic phenotype, with subsequent airway remodeling and COPD.

Aim 1: Determine whether PAD2 and citrullinated vimentin, present in lung macrophages, BAL, plasma and EBC of a cohort of smokers and nonsmoker 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.

Aim 2: Determine the mechanisms by which HMs mediate activation of PAD2, with citrullination of vimentin in lung macrophages (LM’s) using a novel, selective pharmacologic inhibitor of PAD2 (AFM30a) as well as a pan PAD inhibitor (BB-Cl-amidine). We will also evaluate if citrullinated vimentin regulates airway fibroblast modulation into an invasive, apoptosis resistant phenotype through upregulation of TLR4.