Effects of Fluid Shear on Endothelial Cell Response to Inflammation.

Abstract

The endothelium is a thin monolayer of cells that regulates several important processes including maintaining blood pressure, clotting, angiogenesis, barrier function, and inflammation. Inflammation, a natural process by which foreign particles are eliminated from vascular tissue, is of considerable importance due its prevalent role in a number of disease pathologies. Endothelial response to inflammation results in differential expression of cell adhesion molecules, such as E-selectin, on the apical surface facing the bloodstream. Patterns and duration of adhesion molecule expression is critical to the balance between healthy and pathogenic inflammatory response. Chronic inflammation, due to endothelial dysfunction leads to a number of diseases, including neurological disorders, cancers and metastatic tumor growths, and cardiovascular diseases. Despite its prominent roles in disease pathogenesis, endothelial response has yet to be fully understood due to current in vitro models failing to fully replicate relevant endothelial inflammatory response under human physiological conditions. The influence of fluid shear on E-selectin expression due to inflammatory activation is investigated through simultaneous co-stimulation with fluid shear and interleukin-1β of naïve and preconditioned ECs using a novel laminar flow apparatus designed to study the broader time frame over which chronic inflammation is relevant. Naïve cells exposed to shear-cytokine activation display high E-selectin expression for up to 24 hr with peak expression occurring after 8-12 hr of activation contrary to the commonly observed 4-6 hr peak in statically activated cells. High shear preconditioned cells exhibited either elevated or muted E-selectin expression during acute and chronic time frames, respectively, depending on the preconditioning and subsequent shear-cytokine activation durations. The 8-12 hr peak E-selectin expression time in shear-cytokine activated cells coincides with the time frame observed for shear-exposed ECs to shift from a cobblestone to elongated morphology, highlighting a role for cell morphology determining EC response. Overall, the presented data suggest that high laminar shear enhances acute EC response to interleukin-1ß in naïve ECs as may be found in the pathological setting of ischemia/reperfusion injury while in preconditioned ECs, high laminar shear confers rapid E-selectin downregulation to protect against chronic inflammation. However, high laminar shear is protective against TNFα-induced acute and chronic inflammatory response.Ph.D.Chemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91577/1/rbhuang_1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/91577/2/rbhuang_2.pd