Prevention of initial perfusion failure during xenogeneic ex vivo liver perfusion by selectin inhibition

Background. Endothelial cell activation triggered by xenoreactive antibodie s and complement products is the main feature of discordant xenograft rejec tion. The contribution of early cell-mediated mechanisms to this rejection process is poorly understood, and the function of adhesion molecules in xen ogeneic: cell interactions in vivo is unclear. The aim of the study was to investigate the role of selectins in mediating cell-dependent initial perfu sion failure and functional restrictions in xenoperfused guinea pig (GP) li vers, Methods. Isolated GP livers were hemoperfused in a flow-constant, recircula ting perfusion system via the portal vein. Microhemodynamic parameters such as sinusoidal perfusion rate and leukocyte flux were analyzed using intrav ital fluorescence microscopy. Hepatic oxygen consumption and bile productio n, as well as liver enzymes, potassium level, and numbers of white blood ce lls and platelets in the perfusate, were determined. The GP livers were per fused either with GP blood (control perfusion), with unmodified rat blood ( xenoperfusion), or with rat blood treated with the selectin-blocking polysa ccharide Fucoidin, Results. A significant sinusoidal perfusion failure was observed in the xen operfusion group, which was accompanied by distinct signs of a functional r estriction-like reduced oxygen consumption, bile production, and increased perfusion pressure. However, there were significantly fewer impairments in the Fucoidin group. Furthermore, fewer platelets were trapped and a smaller number of stagnant leukocytes were observed in this group. Conclusion. Fucoidin did not suppress complement activation during xenoperf usion. Considering that Fucoidin inhibits the selectin-dependent interactio ns among white blood cells, platelets, and sulfate-containing proteoglycans on the surface of vascular endothelium, these findings suggest an importan t role for early cellular interactions in the development of organ failure during xenogeneic rejection.