THE DEVELOPMENT OF AN IN VITRO MODEL TO EXAMINE AND MODULATE HEPATIC ISCHEMIA AND REPERFUSION RESPONSES

Abstract

Transplantation is the optimal form of therapy for patients with end-stage liver disease; however, the use of organs with hepatic steatosis is often associated with increased risks for poor function and graft loss. In addition, ischemia reperfusion (IR) injury leads to cellular damage that can culminate in functional impairment and loss of graft. Furthermore, IR injury is aggravated by pre-existing steatosis and may involve additional mechanisms and mediators of cellular damage. Current models to study IR in vitro are not well defined and may overlook periods of injury that are involved in transplantation. In this thesis, I present an in vitro model for IR injury that includes multiple phases of injury and leads to the upregulation of heme oxygenase-1 (HO-1), and possibly enhances the expression of matrix metalloproteinase-9 (MMP-9). As graft HO-1 expression correlates positively with reduced injury, but MMP-9 expression is associated with increased injury, I therefore examined the utility of in vitro gene therapies to affect the expression of these proteins. We conclude that the in vitro model of ischemia and reperfusion is a promising tool to study the cellular response to IR and may provide a platform for the development of future therapies which could have clinical applications.