\316\2617 Nicotinic Acetylcholine Receptor Activity Modulates Lipopolysaccharide-Induced GSK3\316\262 Inhibition, Snail and VE-Cadherin Expression, and Pulmonary Endothelial Barrier Dysfunction
Loading...
Issue Date
2015
Authors
Liu, Jing '15
Degree
MS in Pharmaceutical Sciences
Advisor
Feleder, Carlos
Committee Members
Voigt, Jeffrey M.
Dearborn, Richard
Dearborn, Richard
Journal Title
Journal ISSN
Volume Title
Abstract
The pulmonary endothelium plays a critical role in coordinating the innate immune response through the regulation of vascular tone, leukocyte recruitment and transmigration, and hemostasis. The disruption of the endothelial hemostasis is partially characterized by pulmonary endothelial barrier dysfunction. Increased lung permeability is a major mechanism in pulmonary edema and lung dysfunction. Exposure to lipopolysaccharide (LPS), an endotoxin from gram negative bacteria, causes increased lung endothelial permeability to protein characteristic of the Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) which occurs during septic shock. In endothelial cells, exposure to LPS results in endothelial activation through Toll-like receptor 4 (TLR4). Endothelial barrier integrity is in large part dependent upon vascular endothelial cadherin (VE-cadherin), an essential component of adherens junctions, which connect adjoining endothelial cells. The transcription factor SNAI1 (Snail) is a known repressor of VE-cadherin gene expression. The regulation of Snail activity is primarily controlled by the activity of Glycogen synthase kinase 3\316\262 (GSK3\316\262), a serine threonine kinase which phosphorylates Snail resulting in Snail degradation. GSK3\316\262 is a known mediator of the inflammatory response; however the modulation of GSK3\316\262 in the lung microvessel endothelial response to LPS is unclear. In addition, it has been shown that increased activity of the \316\2617 nicotinic acetylcholine receptor (\316\2617nAChR) suppresses the lung response to LPS; however, the effect of \316\2617nAChR activity on the lung microvessel endothelial response to LPS integrated with the GSK3\316\262 / Snail / VE-cadherin promoter response is not known. The thesis identifies the modulation of GSK3\316\262 on Snail and VE-cadherin expression under LPS stimulation. The present study characterizes the Snail, GSK3\316\262, VE-cadherin-promoter and permeability response to LPS in rat pulmonary microvessel endothelial cell monolayers during stimulation of the \316\2617nAChR. The result shows that \316\2617nAChR significantly prevents LPS-induced GSK3\316\262 inhibition, Snail accumulation, decreased VE-cadherin expression and increased lung permeability.
Citation
Liu J. Alpha7 nicotinic acetylcholine receptor activity modulates lipopolysaccharide-induced GSK3? inhibition, snail and VE-cadherin expression, and pulmonary endothelial barrier dysfunction [thesis]. Ann Arbor (MI): Proquest/UMI; 2015. 70 p.
ACPHS Research Commons URI
Description
Click on the Resource Link to find this item in the ACPHS Library catalog.