On leukocyte recruitment in endotoxemic liver injury

Sammanfattning: Leukocyte recruitment is a key feature of liver injury associated with endotoxemia and systemic inflammation. The aim of this thesis was to define the adhesive mechanisms underlying leukocyte endothelial cell interactions, and the therapeutic potential of interference with specific adhesion molecules in endotoxemic liver damage. Moreover, the causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand was investigated. For these purposes, intravital fluorescence microscopy of the liver microcirculation was adopted. It was found that TNF-alpha- and LPS-induced leukocyte rolling in hepatic postsinusoidal venules is primarily mediated by P-selectin, and not by E- nor L-selectin. This initial P-selectin-dependent leukocyte rolling was found to be a prerequisite for subsequent firm adhesion in postsinusoidal venules of the liver. Firm adhesion of leukocytes was found to be dependent on CD18/CD11a (LFA-1). Notably, inhibition of P-selectin and LFA-1 function protected against septic liver injury. For example, leukocyte recruitment, perfusion failure, hepatocellular injury and apoptosis were nearly abolished. In contrast, sinusoidal sequestration of leukocytes was not found to be a major determinant in endotoxemic liver injury. Moreover, the immunomodulator Linomide exerted potent protection against liver damage associated with endotoxemia. Taken together, this thesis indentifies fundamental adhesive mechanisms of leukocyte recruitment in septic liver injury, and defines a causal relationship between leukocyte recruitment in postsinusoidal venules and hepatic injury and apoptosis in endotoxemia. The beneficial effect of Linomide in endotoxemic liver injury demonstrated herein warrants further studies in clinical settings. Finally, it is suggested that P-selectin and LFA-1 constitute potential pharmacological targets against pathological inflammation in the liver.