Wednesday, April 24, 2024
4/24/2024
The lung is a major portal for respirable environmental toxicants including heavy metals such as cadmium (Cd), which is recognized to cause chronic obstructive pulmonary disease (COPD). COPD is the third largest cause of mortality in the US. Airway remodeling with loss of the lumen of small airways and airflow obstruction precede airspace enlargement and emphysema. Airway remodeling is associated with a profusion of airway fibroblasts and an increase in extracellular matrix proteins. Vimentin is an intracellular type 3 filament that can trigger peribronchial fibrosis. The prevalence of COPD is twice as high in a zip code where a Superfund site is located in Birmingham, Alabama when compared to a control zip code with similar demographics and smoking prevalence. We postulate that chronic low dose cadmium (Cd) exposure induces alterations in vimentin-mitochondrial dynamics that results in mitochondrial dysfunction and aberrant activation of peribronchiolar fibroblasts leading to bronchiolar luminal narrowing and subsequent COPD. We will examine this hypothesis in the following specific aims: (1) Determine whether exposure to Cd in a cohort of smokers and never-smokers from a Birmingham community predicts susceptibility to airway remodeling and COPD. (2) Determine the mechanisms by which Cd mediates alterations in vimentin-mitochondrial dynamics to regulate fibroblast activation. (3) Determine whether low dose Cd, or pSer39Vim induced airway remodeling and airspace enlargement in a mouse model of COPD is associated with fibroblast invasion, ECM deposition and apoptosis resistance. These studies will directly address a significant gap in our understanding of how cadmium contributes to the pathogenesis of COPD and the role of vimentin filaments in mitochondrial homeostasis. Early biomarkers of COPD in exhaled breath condensate may help us recognize disease susceptibility. Importantly, these studies may provide novel therapeutic strategies in patients with COPD.
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