Epidemiological studies have demonstrated an association between fine particulate matter (PM2.5) and acute cardiovascular events. While the precise mechanism(s) that result in transduction of responses to inhaled PM2.5 in the vasculature are currently not well understood, it is clear that these responses can occur within a few weeks of exposure. To investigate the mechanisms by which PM2.5may modulate inflammation and vascular tone with short-term exposure, the researchers will investigate these responses in relevant animal models using real world ambient PM2.5 exposure. Accordingly, they hypothesize that exposure to ambient PM2.5 for 8 weeks induces systemic microvascular inflammation and dysfunction through monocyte/macrophage NAD(P)H dependent reactive oxygen species (ROS) generation and that endothelial nitric oxide plays a pivotal role in modulation of these responses. The investigators plan to examine this hypothesis systematically in appropriate animal model systems that will include genetically modified and tissue-specific conditional gene knockout mice via Cre-lox technology using a versatile ambient exposure system. In the first specific aim, they will investigate the effect of 8-week exposure to PM2.5 in FVBN mice and endothelial nitric oxide synthase (eNOS) knockout mice and examine leukocyte and vascular responses and superoxide production in cremasteric microcirculation. In the second specific aim, the investigators will determine the activation of monocyte/macrophage NAD(P)H oxidase in mice expressing enhanced yellow fluorescent protein (YFP) under the control of c-fms promoter after PM2.5 exposure by flow cytometry, intravital microscopy, and real time PCR. In the final specific aim, they will investigate the effect of PM2.5 exposure on NAD(P)H oxidase derived ROS-mediated monocyte response in the microcirculation in the mice deficient in a critical cytosolic component of NAD(P)H oxidase (p47phox-/- or gp91phox-/-) and tissue specific (endothelium or monocyte/macrophage lineage), conditional gene knockout mice models. Principal component analysis of PM2.5 will also be performed to elucidate which source-related components are most closely associated with biological responses. This study is expected to provide the link between PM2.5 exposure and systemic inflammatory response, and will provide a cellular and molecular basis for the association of adverse cardiovascular effects with air pollution exposure.
Showing the most recent 10 out of 31 publications
