Abstract Rationale Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of mortality worldwide and a major contributor to chronic disability. Irreversible airway obstruction and progressive loss of lung function characterize COPD. Cadmium (Cd), a toxic environmental metal found in cigarette smoke and contaminated air, is increasingly recognized as a driver of COPD. Residents near the University of Alabama at Birmingham (UAB) Superfund site exhibit elevated Cd exposure, with higher prevalence of COPD than a control site. Vimentin, a cytoskeletal intermediate filament protein, undergoes citrullination following Cd exposure, promoting fibrosis. Sterol regulatory element-binding protein 1 (SREBP1) upregulates vimentin levels and is associated with lipogenic and profibrotic signaling. Sirtuin 6 (SIRT6) negatively regulates SREBP1 transcription, whereas SIRT6 deficiency enhances TGF-β-mediated fibrosis. Methods Bronchoalveolar lavage fluid (BALF) and lung tissue samples from COPD subjects (smokers and never-smokers, n = 15 each) residing in the UAB Superfund area and in non-contaminated control locations were analyzed to determine SIRT6 and SREBP1/SCD1 expression levels. A mouse model of Cd-induced COPD was employed to examine the regulatory role of Cd in modulating SIRT6 and SREBP1/SCD1 in airway epithelium and lung tissue. Low-dose Cd exposure in mice, replicated environmentally relevant conditions and produced airway fibrosis/narrowing, comparable to that observed in human COPD lungs. The effects of SIRT6 upregulation were evaluated through genetic overexpression of SIRT6 and pharmacological activation with the SIRT6 activator UBCS039. Subsequent molecular and histological analyses assessed changes in SREBP1/SCD1 expression, vimentin accumulation, collagen deposition, and airway structural remodeling following Cd exposure and SIRT6 modulation. Results COPD patients from the Superfund site were younger (under 50 years) than those from non-affected regions (over 50 years) and showed accelerated FEV1 decline. Histological analysis revealed airway wall thickening, luminal obstruction, and increased α-SMA and collagen deposition. Lung airways from these subjects exhibited reduced SIRT6 and elevated SREBP1 expression. In the Cd-induced COPD mouse model, CdCl2 exposure (0.458 mg/kg) produced lung Cd levels similar to those in human COPD tissue, replicating airway fibrosis and alveolar enlargement. Cd exposure decreased SIRT6 and upregulated SREBP1/SCD1, while SIRT6 activation, genetic or pharmacologic, normalized these proteins, reduced vimentin accumulation, and attenuated fibrotic remodeling. Conclusion These findings establish a mechanistic connection between cadmium exposure and the suppression of SIRT6, resulting in the activation of the SREBP1/SCD1 pathway and vimentin-mediated fibrotic remodeling. Restoring SIRT6 activity inhibits cadmium-induced airway structural changes, highlighting SIRT6 as a promising therapeutic target for COPD linked to environmental metal exposure. This abstract is funded by: NIEHS
Sinha et al. (Fri,) studied this question.