PM exposure and changes in respiratory host defense responses

Project Summary
It is well established that both acute and chronic exposure to PM significantly affects human health, causing 7 million
premature deaths worldwide. It is becoming increasingly evident that PM modifies respiratory host defense responses, which
would affect groups of all ages and could have significant implications for children with developing immune systems or
susceptible individuals with pre-existing respiratory conditions. The host defense responses of the respiratory tract include
innate resident immune cells, such as monocytes/macrophages, and epithelial cells, which provide the first line of defense
in the airways against invading pollutants or pathogens. Pollutant-induced modifications of either or both of these
components of respiratory host defense will have significant effects on the ability of the host airway to fight infections.
While epidemiological studies have demonstrated the association between ambient PM exposure and enhanced
susceptibility to infection, a critical knowledge gap exists regarding the mechanistic link between PM-induced immune
dysfunction of epithelial cells and airway immune cells and in vivo evidence of respiratory immune health effects. The
objective of this proposal is to address how PM modifies cellular mechanisms that are integral to maintaining respiratory
immune function homeostasis and link these to observations made in humans in vivo. We hypothesize that PM samples
collected during high (vs low) air pollution periods in China will 1) suppress respiratory immune function when tested in
vitro (UNC), and 2) show similar deleterious effects when examined in vivo in exposed individuals in China (China
collaborators). SA 1 will determine the effects of PM from China on epithelial cell immune and antiviral host defense
function and identify the mechanisms mediating these responses. These studies will use our well-established system of
differentiated human nasal epithelial cells, which will be exposed to PM collected in China and examined for changes in
host defense function and bioenergetic modifications. SA 2 will determine PM-induced modifications of innate immune
cell phenotype and functions and the mechanisms mediating these responses. These studies will use sputum and
bronchoalveolar lavage macrophages acquired from healthy volunteers, and exposed to PM ex vivo, and examined for
changes in immune cell phenotype and function. The role of PM-induced changes in bioenergetics will also be examined.
The in vitro studies in SA1 and SA2 will be linked to human in vivo studies proposed in SA3. In SA3, one hundred volunteers
from Xinxiang Medical University will be personal air samplers and undergo collection of nasal mucosal samples and
induced sputum samples during high and low air pollution periods. Innate immune endpoints as described in SA1 and SA2
will be measured on the collected nasal and sputum samples in SA3.The data derived from these studies will yield important
mechanistic information on PM-induced health effects to support current epidemiological associations. Furthermore, these
data will address a clinical knowledge gap regarding global health implications for highly polluted and populated countries
around the world.