Cadmium (Cd), a toxic heavy metal and carcinogen that is abundantly present in cigarette smoke, is a cause of smoking-induced lung disease. SLC39A8 (ZIP8), a zinc transporter, is a major portal for Cd uptake into cells. We have recently identified that ZIP8 expression is under the transcriptional control of the NF-κB pathway. On the basis of this, we hypothesized that cigarette-smoke induced inflammation would increase ZIP8 expression in lung epithelia, thereby enhancing Cd uptake and cell toxicity. Herein we report that ZIP8 is a central mediator of Cd-mediated toxicity. TNF-α treatment of primary human lung epithelia and A549 cells induced ZIP8 expression, resulting in significantly higher cell death attributable to both apoptosis and necrosis following Cd exposure. Inhibition of the NF-κB pathway and ZIP8 expression significantly reduced cell toxicity. Zinc (Zn), a known cytoprotectant, prevented Cd-mediated cell toxicity via ZIP8 uptake. Consistent with cell culture findings, a significant increase in ZIP8 mRNA and protein expression was observed in the lung of chronic smokers compared with nonsmokers. From these studies, we conclude that ZIP8 expression is induced in lung epithelia in an NF-κB-dependent manner, thereby resulting in increased cell death in the presence of Cd. From this we contend that ZIP8 plays a critical role at the interface between micronutrient (Zn) metabolism and toxic metal exposure (Cd) in the lung microenvironment following cigarette smoke exposure. Furthermore, dietary Zn intake, or a lack thereof, may be a contributing factor in smoking-induced lung disease.

Sepsis rapidly activates the host inflammatory response and acute phase response. Severe sepsis, complicated by multiple organ failure, is associated with overwhelming inflammation and high mortality. We previously observed that zinc (Zn) deficiency significantly increases mortality in a mouse model of polymicrobial sepsis due to over-activation of the inflammatory response. In order to identify potential mechanisms that account for Zn-responsive effects, we generated whole exome expression profiles from the lung tissue of septic mice that were maintained on Zn modified diets. Based on systems analysis, we observed that Zn deficiency enhances the acute phase response and particularly the JAK-STAT3 pathway, resulting in increased serum amyloid A production. In vitro studies of primary hepatocytes and HepG2 cells substantiated that Zn-deficiency augments serum amyloid A production through up-regulation of the JAK-STAT3 and NF-κB pathways. In contrast, Zn inhibited STAT3 activation through the up-regulation of SHP1 activity. Collectively, these findings demonstrate that Zn deficiency enhances the acute phase response through up-regulation of the JAK-STAT3 pathway, thereby perpetuating increased inflammation that may lead to increased morbidity and mortality in response to sepsis.

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Tobacco smoke is the primary cause of chronic obstructive pulmonary disease (COPD) in the U.S. Immune dysfunction in the lung of chronic smokers increases the risk of respiratory infections. IL-1β is a vital cytokine in host defense and its expression is decreased in the lungs of these patients. Cadmium (Cd) is abundant in cigarette smoke and a major contributor to smoking-related lung disease. The purpose of this investigation is to determine whether Cd suppresses IL-1β in monocytes. THP-1 cells were differentiated into macrophages using PMA and then treated overnight with Cd, followed by combined LPS and ATP stimulation. Primary human monocytes were isolated from blood using CD14+ positive selection and subject to similar exposures. Analysis of THP-1 and monocyte cultures revealed that Cd suppresses IL-1β release following stimulation with LPS and ATP. Additionally, there was a decrease in IL-1β mRNA in Cd-treated LPS stimulated macrophages. We observed a decrease in phospho-p65 translocation into the nucleus of Cd-treated macrophages after LPS stimulation. Consistent with this, using a cell-free system, we observed that Cd inhibits IKKβ kinase activity (IC50 of ~100 nM). From these studies we conclude that Cd acts as an inhibitor of the canonical NF-κB pathway and inhibits IL-1β production. Accordingly, Cd may play a critical role in COPD pathogenesis by impairing monocyte immune function.

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