Sepsis and the associated multiple organ dysfunction syndrome (MODS) continue to have significant morbidity and mortality in infants and children. Despite data suggesting that prolonged inflammation results from an overabundance of pro-inflammatory mediators, therapeutic innovations aimed at reducing individual inflammatory mediators have failed to significantly improve clinical outcome. The low-density lipoprotein receptor-related protein (LRP) is a multi-functional scavenger receptor located on hepatocytes, monocytes, and macrophages. The diverse biologic role of LRP includes regulation of proteolytic activity, lipid metabolism, fibrinolysis, and cellular migration. Many of these activities are disrupted and contribute to the pathophysiology of sepsis and MODS. Specifically, clearance of cytokines and proteases is hypothesized to be an important mechanism for preventing the inflammatory response from becoming systemic and promoting the resolution of inflammation. In addition, inhibition of leukocyte migration toward an inflammatory stimulus may result in abnormal immune defense. The potential importance of LRP is exemplified by knockout studies, in which loss of LRP is uniformly fatal embryologically. Due to the lethality of the LRP knockout, conditional inactivation techniques have been utilized to examine mechanisms of LRP function. We hypothesize that loss of hepatic LRP will result in abnormal clearance of cytokines, proteinases, and proteinase-complexes, resulting in exaggerated inflammation. The proposed studies will induce sepsis via cecal ligation and perforation in a well-described murine model of conditional LRP inactivation and measure organ dysfunction using histopathology, organ specific inflammatory gene upregulation, serum cytokine measurements, and intravital microscopy. We also hypothesize that loss of leukocyte LRP will result in decreased cellular migration. The studies will use conditional LRP inactivation at the level of the leukocyte with immunohistochemistry and in vitro analysis to examine cellular migration. These studies are proposed to examine the mechanisms of LRP's involvement in the development of systemic inflammation in sepsis and MODS in hopes that these clinical entities may be prevented and treated in critically ill infants and children.
