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.