One of the least understood aspects of orthotopic liver transplantation (OLT) is the post-transplant function of the hepatic reticuloendothelial system (RES). Our ability to accurately assess RES function, which is relevant to host immunity and resistance to sepsis, has also been limited. this project seeks to better understand the mechanisms of two distinct components of hepatic RES function (phagocytosis and phagocytic killing), specifically focusing on the role of reactive oxygen intermediates (ROI) in each component. The central hypothesis of this research proposal is that the hepatic RES function is significantly altered following OLT, due in large measure to activation or injury inflicted by ROI at the time of organ reperfusion. Such alterations may be manifest by a modification or reprioritization of the RES functional repertoire in the perioperative period. We propose that paradoxically, phagocytosis and killing by resident macrophages of the RES are, to a finite and quantifiable degree, dependent upon the initial generation of superoxide and other toxic oxygen metabolites. As a corollary, we believe modification of the hepatic RES phagocytic and degradative capacity has a central role in both graft and host survival. We propose to study the role of ROI in hepatic RES function utilizing a double- labeled bacteria clearance model that allows us to quantitatively discriminate phagocytosis from phagocytic killing. These in vivo observations will then be correlated in vitro by determination of the ROI contribution to Kupffer cell microbial phagocytosis and killing capacity. Using a rat OLT model the posttransplant phagocytic and degradative capacities of the RES will be assessed, and the impact of altered graft RES upon protection of the host from invasive pathogens will be delineated.
