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dc.contributor.advisorWheatley, Antony
dc.contributor.authorKillilea, Marykate
dc.description.abstractStress is a key regulator of homeostasis in the body. However, aberrant activation of the stress response has been implicated in predisposing to, and exacerbating processes that underlie a variety of pathological conditions including mood disorders (anxiety/depression), cardiovascular disease, gastrointestinal disease and liver disease. Accumulating evidence demonstrates that the endocannabinoid system may play a significant role in modulating liver injury and represents an important therapeutic target in the treatment of liver diseases. Therefore, one of the main objectives of this thesis was to enhance our understanding of the impact of physical and psychological stress on LPS/GalN-induced acute liver injury. The data herein demonstrate for the first time that the genetically stress-sensitive Wistar Kyoto (WKY) rat exhibits a heightened inflammatory response and overall liver injury when compared to normo-stress sensitive Sprague Dawley (SD) rats in response to LPS/GalN. Further studies were conducted to determine if physical restraint stress in addition to LPS/GalN administration could potentiate liver injury. Although data from a previous study demonstrated that restraint stress (RS) alone could not cause liver injury, RS exposure prior to LPS/GalN resulted in an exacerbated liver injury similar to that seen in the WKY rat exposed to LPS/GalN alone. Furthermore, the data demonstrated that at WKY rats exhibit a heightened endocrine and inflammatory response to LPS/GalN compared to SD rats, and this effect was not potentiated further by RS. Further studies investigated the changes in hepatic microcirculatory changes in the WKY rat strain following LPS/GalN. The data indicates that WKY rats display similar leukocyte-endothelial interactions despite a heightened inflammatory response to LPS/GalN. Furthermore, WKY rats exhibit an increased sinusoidal perfusion failure and hepatocellular injury in early phase LPS/GalN-induced liver injury. A further objective was to investigate the potential role of the hepatic endocannabinoid system in LPS/GalN-induced liver injury and if endocannabinoid modulation of such responses could be further altered in the presence of stress. The data indicate that WKY rats display an increase in hepatic levels of the endocannabinoids anandamide (AEA) and 2-AG with concomitant decreases in degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). The data also indicated a decrease in CB1 and CB2 receptor expression following LPS/GalN. Although studies in the literature indicate a hepatoprotective and anti-inflammatory roles for CB1 antagonism and CB2 agonism in liver injury, a subsequent study identified that there was no effect of CB1 antagonism with AM6545 or CB2 agonism with JWH133 on LPS/GalN-induced liver injury. Taken together, the data demonstrate that stress (physical or genetic susceptibility) exacerbated LPS/GalN-induced liver injury. Furthermore, the stress sensitive WKY strain display an altered hepatic endocannabinoid system in response to LPS/GalN. Although the data indicate that targeting classical cannabinoid receptors failed to attenuate LPS/GalN-induced liver injury in this model, this does not rule out alternative receptor or non-receptor targets. In conclusion, the data herein in this thesis provides novel evidence for a role of stress in the exacerbation of acute liver injury induced by LPS/GalN. Importantly, either a genetic susceptibility to stress or a physical stress can potentiate acute liver injury. Furthermore, the data demonstrate that there is a possible role for the hepatic endocannabinoid system in modulation these effects.en_IE
dc.publisherNUI Galway
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 Ireland
dc.subjectAcute liver injuryen_IE
dc.subjectWistar Kyotoen_IE
dc.subjectMedicine, Nursing and Health Sciencesen_IE
dc.titleStress-induced exacerbation of LPS/GalN liver injuryen_IE
dc.contributor.funderCollege of Medicine, Nursing and Health Sciences, National University of Ireland, Galwayen_IE
dc.local.noteStress has been identified as a major contributor in the development and exacerbation of several disease states. This thesis examined whether the prior exposure to a physical or genetic susceptibility to stress could result in an aggravated acute liver injury.en_IE

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Attribution-NonCommercial-NoDerivs 3.0 Ireland
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