Doctor of Philosophy (Ph.D.)
Degree Granting Department
Sarah Y. Yuan, Ph.D.
Jerome Breslin, Ph.D.
Thomas Taylor-Clark, Ph.D.
Burt Anderson, Ph.D.
sepsis, inflammation, endothelial cells, histones, hyperpermeability
Sepsis is a life-threatening inflammatory condition with high morbidity and mortality rates. Though improvements to diagnosis and management of sepsis have been made, the complexity of the disease process and an incomplete understanding of its endpoint mechanisms have prevented major breakthroughs for early diagnosis and treatment. Representing a common endpoint in a number of inflammatory injuries including sepsis, endothelial barrier dysfunction causes fluid leakage and leukocyte infiltration that leads to tissue damage and multiple organ failure. Therefore, elucidating mechanisms of endothelial barrier regulation is needed to further develop targeted therapies in inflammatory disease.
Sepsis is characterized by a hyperinflammatory response to infection that involves activation of many types of immune cells, especially neutrophils. Neutrophils release a number of pro-inflammatory mediators that can have damaging effects on surrounding tissues, including the microvascular endothelium. In this study, we investigated neutrophil-released products, specifically neutrophil extracellular traps (NETs), for their effects on microvascular endothelial barrier function. We utilized a number of in vitro and in vivo approaches to study endothelial barrier function in response to the release of NETs during sepsis. We found that histones, especially citrullinated histone 3 (H3Cit), have barrier-disrupting capabilities. In response to H3Cit, disruption of the endothelial barrier is characterized by opening of adherens junctions and reorganization of the actin cytoskeleton. These mechanisms do not seem to be dependent on the typical hyperpermeability signaling mediated by Rho, MLCK, PKC, Src, or FAK; however, the barrier-enhancing pharmacological agent forskolin can block the barrier dysfunction induced by H3Cit. These results provide evidence that targeting H3Cit may hold therapeutic potential to limit tissue injury during inflammatory conditions like sepsis.
Scholar Commons Citation
Meegan, Jamie E., "Neutrophil Extracellular Traps and Vascular Barrier Injury" (2018). Graduate Theses and Dissertations.