Role of ZIP8 in first hand cigarette smoke exposure-mediated lung injury

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DESCRIPTION (provided by applicant): Cigarette smoke (CS) exposure is the most important risk factor for developing chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality in men and women in the United States. Importantly, the pathogenesis of CS-related lung disease remains unclear thereby creating a major obstacle to generate improved treatment strategies. Cadmium (Cd) is a major component of cigarette smoke and a leading environmental toxicant with a biological half-life of greater than 20 years. Cd significanty contributes to CS- induced lung disease but it is not known exactly how Cd enters the lung or how it mediates pathological manifestations once in. The long-term goal of this project is to determine the role of the human zinc transporter, ZIP8, a transporter of both zinc and Cd, in lung pathogenesis in the context of first hand (FHS) smoke exposure. Our central hypothesis is that inflammation driven by CS exposure will induce the expression of ZIP8 in lung epithelia thereby increasing Cd entry, immune dysfunction, and lung pathology. This hypothesis is predicated on recent published and preliminary observations by our group demonstrating that ZIP8 expression, not naturally abundant in lung epithelia, is up-regulated by NFkappaB (NF-?B), a key signaling pathway that is activated by CS exposure, and that increased ZIP8 expression enhances Cd uptake into lung epithelia which is further enhanced by zinc deficiency. The rationale for our approach is that establishment of the functional role of ZIP8 within the lung microenvironment in the context of CS exposure, immune activation, and dietary zinc intake, will improve our understanding of CS-related lung disease and foster innovative micronutrient surveillance and treatment strategies. Guided by strong preliminary evidence, this hypothesis will be tested by pursuing two specific aims that: 1) Evaluate the effects of FHS exposure on oxidative status and immune dysfunction in vivo relative to ZIP8 in BTZIP8 overexpressing mice (compared to wild-type matched controls); and 2) Determine the impact of zinc nutrition in vivo as a predisposing factor in ROS formation, immune dysfunction, and lung damage following prolonged FHS exposure. To accomplish the goals of aim 1 and 2 we will pursue novel studies in animal models that explore the role of ZIP8, redox status, immune dysfunction, and zinc nutrition in vivo. The research proposed in this application is innovative because it will for the first time critically evaluate the role of zinc metabolism in the setting of CS-related pathogenesi. This is important because it will define the functional significance of a novel pathway that regulates redox and immune function thereby revealing new molecular insight into CS-related lung disease that will lead to innovative strategies to prevent or better treat this lethal disease