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Xenotransplantation

Beneficial effect of a nitric oxide donor in an exxa0vivo model of pig-to-human pulmonary xenotransplantation.


PMID 26381495

Abstract

Nitric oxide (NO) can reduce platelet adhesion and vascular resistance. Tempol can scavenge the reactive oxygen species (ROS) that induce tissue injury. As xenograft rejection attenuates endogenous NO production and generates ROS, we evaluated the potential effect of an NO donor (SIN-1, 3-morpholinosydnonimine) and tempol on hyperacute xenograft dysfunction using an exxa0vivo porcine lung perfusion model. For the evaluation of von Willebrand factor (vWF) secretion, human endothelial cells were stimulated with thrombin. Porcine lungs were perfused with either fresh human whole blood (unmodified control group [nxa0=xa04]), SIN-1 (nxa0=xa04), or SIN and tempol (nxa0=xa04). SIN-1 and tempol significantly inhibited vWF secretion from endothelial cells inxa0vitro. However, they did not suppress xenogeneic complement activation. In an exxa0vivo pulmonary perfusion model, SIN-1 improved pulmonary xenograft function by reducing pulmonary vascular resistance (PVR), inhibiting complement activation, and inhibiting thrombin generation. Combined treatment with tempol and SIN-1 potentiated PVR reduction, but slightly enhanced complement activation. An NO donor is expected to improve pulmonary xenograft function through inhibition of vWF secretion, vasoconstriction, thrombin generation, and indirectly through inhibition of complement activation. The additional effects of tempol on an NO donor were not considered significant in an exxa0vivo xenograft system.