On CXC Chemokines in Endotoxin-Induced Liver Injury

Abstract: Leukocyte recruitment is a rate-limiting step in endotoxemic liver injury. Leukocyte extravasation is a multistep process, supported by multiple combinations of adhesion molecules and chemokine receptors. This thesis examined the mechanisms of activation, adhesion and extravascular infiltration of leukocytes in endotoxin-induced liver injury. It was found that leukocyte adhesion in postsinusoidal venules is predominately mediated by lymphocyte function antigen-1 (LFA-1). This conclusion was supported by the use of LFA-1-deficient mice, immunoneutralization of LFA-1 and treatment with a statin-based inhibitor of LFA-1 (LFA703). Moreover, it were found that activation of leukocytes and expression of CXC chemokines (MIP-2 and KC) in endotoxemic livers were dependent on the generation of reactive oxygen species. The detailed role of these CXC chemokines were examined and this thesis demonstrates that CXC chemokines are critical in the actual extravasation process of leukocytes in the liver. Linomide has been demonstrated to exert a beneficial effect against endotoxin-induced liver injury although the mechanism has remained elusive. Herein, it was shown that the protective effect of Linomide is mediated via up-regulation of IL-10, which, in turn, downregulates the hepatic expression of CXC chemokines in endotoxemic animals. Taken together, this work points to central pathways in the inflammatory processes of endotoxin-induced liver damage, which are not only important for a deeper understanding of the pathophysiology, but also critical in the development of more effective and specific therapies against septic liver injury.