Environmental Cadmium, persistent inflammation and airways disease

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Environmental pollutants can contribute to the unresolved or impaired resolution of inflammation which is one of the critical mechanisms for developing chronic diseases. Cadmium (Cd), an environmental pollutant, is one of the top ten hazardous chemical pollutants that negatively impacts human health and increases the burden of disease. One real-life example of environmental Cd pollution-related negative health impacts is the North Birmingham Superfund site. It is established that Superfund Site at N. Birmingham has high environmental Cd contamination due to being near coke and steel plants in the area. Our laboratory is associated with the Superfund Research Center at UAB and works closely with the community at the Birmingham Superfund Site. In our research with the biological samples from the superfund site community, we have found that residents from Superfund Site (Affected Area) have two times more incidence of chronic airway diseases. Environmental exposure to Cd can induce dysregulated resolution pathways related to persistent inflammation which can be one of the reasons for the increased incidences of airway diseases. The lung tissue and AMs from these residents demonstrate higher levels of Cd than normal levels. The macrophages also demonstrated decreased efferocytosis ability, presence of increased PAD4 and citrullinated CaMKII. We will be investigating Cd toxicity mediated effects of PAD4 related downstream pathways for the impaired efferocytosis and airway remodeling. We have 3 specific aims to test our hypothesis that Cd inhibits efferocytosis by AMs through PAD4 which leads to continued inflammation and airway remodeling. Our specific aims are: (1) determine the mechanisms of Cd induced PAD4 activity on efferocytosis by AMs in vitro and determine the impact of AMs with dysfunctional efferocytosis previously described 3D ex-vivo pulmospheres model. (2) Determine if Cd exposure mediated PAD4 dependent dysfunctional efferocytosis is associated with airway disease in vivo. (3) Determine if association of environmental exposure of Cd and decreased efferocytosis, and lung function in the residents from North Birmingham Superfund Site.