| Chronic obstructive pulmonary disease (COPD) is a complex respiratory disease primarily caused by cigarette smoking. Cadmium (Cd), a toxic metal abundantly present in cigarette smoke, has been implicated in the development of disease, and accumulates in the bodies of smokers. It was recently discovered that a zinc (Zn) transporter, SLC39A8 (ZIP8), is responsible for the primary import of Cd into cells. Our lab discovered ZIP8 is under the transcriptional regulation of the central inflammatory NF-kappaB pathway. We hypothesize that inflammation in the lung created by smoke exposure increases the expression of ZIP8 thereby facilitating Cd uptake and pathology associated with COPD.;The first aim of our work addressed the role of ZIP8 in Cd-mediated epithelial cell toxicity using the adenocarcinomic alveolar epithelial A549 cell line. Cd-induced toxicity was enhanced by TNF-alpha in an NF-kappaB-dependent manner, which stimulated expression of ZIP8. Use of an NF-kappaB (p65) inhibitor (Bay11-7082) or ZIP8 siRNA resulted in a significant decrease in cell toxicity. Cell death was also reversible with increasing concentrations of the micronutrient Zn. Immunohistochemical analysis of primary human upper airway epithelial cells revealed preferential ZIP8 expression on the environmentally-facing apical membrane. Analysis of lung tissue from GOLD stage 0 cigarette smokers and non-smoking controls revealed ZIP8 mRNA and protein to be significantly increased in the lungs of smokers.;We translated these findings into a mouse model of chronic cigarette smoke exposure using a transgenic ZIP8 overexpressing mouse line. ZIP8 overexpression dramatically increased emphysematic pathology, compared to smoke exposed C57/Bl6 control mice. In line with previous studies, our epidemiologic analysis of the 2011-2012 National Health and Nutrition Examination Survey revealed blood Cd levels of smokers correlated with lower Zn serum levels. Based on our findings, we contend ZIP8 is a potential mediator of COPD pathogenesis by creating an imbalance of the toxicant Cd and micronutrient Zn.;Lastly, we investigated the contribution of Cd to macrophage dysfunction in COPD. We found Cd to significantly reduce a macrophages ability to respond to an endotoxin challenge, specifically by inhibiting NF-kappaB activity, an effect not observed in monocytes, a closely related cell type. Atomic absorption spectroscopy revealed a greater accumulation of Cd within macrophages than monocytes, suggesting fundamental differences in Cd metabolism. We postulate this may be an important mechanism by which Cd contributes to impaired immune responses observed in COPD patients. Taken together, this novel body of work suggests Zn metabolism may inadvertently contribute to COPD pathogenesis by facilitating cadmium import and thereby lung pathology. |
