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TitleDiesel exhaust particles alter endothelial tube permeability
NameChao, Ming-Wei (author), White, Lori (chair), Gordon, Marion (internal member), Gerecke, Donald (internal member), Laumbach, Robert (internal member), Svoboda, Kathy (outside member), Rutgers University, Graduate School - New Brunswick,
Degree Date2009-10
Date Created2009
SubjectToxicology,
Diesel motor exhaust gas--Physiological effect
DescriptionEpidemiological studies suggest that an increase of diesel exhaust particles (DEP) in ambient air corresponds to in an increase in hospital recorded myocardial infarctions within 48 hr after exposure. Among the many theories to explain this data are endothelial dysfunction and translocation of DEP into the vasculature. We hypothesized that translocation of DEP occurs because endothelial cells become permeable after exposure. To support this hypothesis, in vitro-assembled endothelial tubes were used to evaluate how DEP affected parameters influencing permeability, i.e., cell-cell junction integrity, and proinflammatory and oxidative stress-induced upregulation of Vascular Endothelial Growth Factor (VEGF, also known as Vascular Permeability Factor). Our first experiments demonstrated that the adherens junction molecule, VE-Cadherin, becomes redistributed from the membrane at cell-cell borders to the cytoplasm in response to DEP, separating the plasma membranes of adjacent cells. DEP were occasionally found in the endothelial cell cytoplasm and in the tube lumen. A second set of experiments demonstrated that DEP induced the generation of ROS, such as H2O2 in the HUVEC tube cells. Transcription factor Nrf2 was translocated to the cell nucleus and activated
transcription of the antioxidative enzyme HO-1. ELISA assays determined that DEP increased secretion of pro-inflammatory cytokines IL-6 and TNF-α. The oxidative and pro-inflammatory responses both induced secretion of VEGF, a factor known to enhance permeability. Usually, vascular permeability is associated with activation of the Akt pathway leading to increased cell survival. A third set of experiments found that DEP-induced permeability was instead associated with increased apoptosis. This was the associated with deactivation of the Akt pathway. These results suggest mechanisms for how DEP may affect in vivo capillaries.
transcription of the antioxidative enzyme HO-1. ELISA assays determined that DEP increased secretion of pro-inflammatory cytokines IL-6 and TNF-α. The oxidative and pro-inflammatory responses both induced secretion of VEGF, a factor known to enhance permeability. Usually, vascular permeability is associated with activation of the Akt pathway leading to increased cell survival. A third set of experiments found that DEP-induced permeability was instead associated with increased apoptosis. This was the associated with deactivation of the Akt pathway. These results suggest mechanisms for how DEP may affect in vivo capillaries.
NotePh.D.
NoteIncludes bibliographical references (p. 148-167)
Noteby Ming-Wei Chao
Genretheses
Persistent URLhttp://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051792
Languageeng
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work