In pig-to-primate models, antibodies directed at various targets (especially Gal 1,3 alpha Gal, or """"""""Gal"""""""") and complement are pivotal mediators of hyperacute rejection of the heart, lung, and other organs. However, we have consistently found that potent complement regulation coupled with efficient removal of anti-pig antibody is associated with dysfunction of lung xenografts. Notably, dysregulated coagulation features prominently in the early failure of hDAF transgenic pig lungs, even when anti-pig antibody is removed from the human blood and soluble complement receptor type 1 is added. Although we find that many features of hyperacute lung rejection (increased vascular resistance, capillary jeak) are attenuated in association with GalT KO lungs, intravascular coagulation remains a prominent histologic finding. ? ? During the term of this Award, we will use GalT KO pig lungs as the basis for novel mechanistic studies to evaluate the role of coagulation and complement in the HALR injury process in the context of lungs that do not express Gal. Using an ex vivo model of pig lung perfusion with human blood, several putative links between dysregulated coagulation, complement activation, and lung inflammation will be explored. We may identify new approaches or new therapeutic targets to promote physiologic function of pig lung in human blood environment. ? ? ?
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