Transplant Reperfusion Associated Inflammation

Reperfusion-associated microcirculatory dysfunction involves the activation of distinct humoral, cellular, and molecular systems. In contrast to warm ischemia-reperfusion, after cold ischemia (preservation) and transplantation (reperfusion) the nonparenchymal cell population, including the microvascular endothelial cells, has to be considered as a major target for the manifestation of injury and thus graft failure [7]. Nonetheless, the nature of the microcirculatory dysfunction is similar when compared with that observed after warm ischemia. In vivo studies with orthotopic rat liver transplantation showed both sinusoidal no-reflow- (perfusion failure) and reflow-paradox-associated events (leukocyte and platelet accumulation and adherence) as determinants in the development of primary graft dysfunction. Leukocyte-endothelial cell interaction seems to be mediated classically by involvement of P-selectin in leukocyte rolling and Mac-1 and ICAM-1 in leukocyte firm adhesion, because blockade of selectins, ß2-integrins, and ICAM-1 has been shown effective in reducing post-transplant leukocyte adhesion. In parallel, platelet recruitment within the microvasculature seems to strongly involve P-selectin, because mice lacking P-selectin showed a reduction of platelet-endothelial cell interaction and improvement of survival after warm ischemia-reperfusion. Accordingly, the application of a soluble P-selectin glycoprotein ligand in a cold ischemia-reperfusion kidney transplantation model has been proven able to protect against blood flow perturbations and parenchymal injury.

A large number of recent experimental studies brought evidence that an imbalance of the nitric oxide-endothelin system contributes to the manifestation of both no-reflow and reflow-paradox in post-transplant reperfusion injury. Endothelin-1 seems to be the "bad guy" in this scenario. This view is supported by the fact that endothelin-1 and big-endothelin concentrations are elevated in liver graft tissue during cold storage and reperfusion, and that the cold storage-induced endothelin-1 release is associated with an increase in portal pressure at the time of reperfusion. In parallel, a considerable number of studies could demonstrate that the blockade of the endothelin A receptor results in an attenuation of post-transplant microcirculatory perfusion failure and leukocyte adhesion in liver, pancreas, and small intestine [8]. In line with this, inhibition of nitric oxide by using the nitric oxide synthase inhibitor L-NAME aggravates hepatic microcirculatory ischemia-reperfusion injury, while nitric oxide donors, such as L-arginine or FK409, improve post-transplant microcirculation and reduce leukocyte adhesion and microvascular permeability in pancreas and small-bowel transplants.

Apart from the imbalance of the nitric oxide-endothelin system, a considerable number of other inflammatory mediators contribute to the intravascular leukocyte accumulation in cold ischemia reperfusion, including oxygen radicals, nuclear factor kappa B-related cytokines, complement, phospholipase A2, leukotrienes, thromboxane, and platelet-activating factor. Kupffer cells have to be considered as the source of these inflammatory mediators. In fact, there is substantial evidence from liver transplantation experiments that cold ischemia-reperfusion markedly activates Kupffer cells and that this activation is associated with depressed hepatocellular function post-transplantation. As a consequence, blockade or elimination of Kupffer cells by methyl palmi-tate or liposome-encapsulated dichloromethylene diphos-phonate attenuates sinusoidal endothelial cell damage and improves post-transplant survival. Whether oxygen radicals produced after onset of reperfusion trigger the activation of Kupffer cells is not yet clear. Treatment with the antioxidant ^-acetylcysteine did not affect Kupffer cell phagocytotic activity, although it reduced the leukocytic response after liver transplantation. In contrast, UW solution and in particular Carolina rinse, both containing a whole armamentarium of antioxidants, have been shown to be effective in reducing Kupffer cell activation. In addition, the source of postis-chemic radical production is still a matter of controversy. Whereas some studies with cold ischemia-reperfusion indicate that hepatocytes may serve as a major site of reactive oxygen species generation, triggered through Kupffer cell-independent mechanisms, others have shown that microcir-culatory failure after rat liver transplantation is related to Kupffer cell-derived oxidant stress.

Little is known as to whether pericytes and hepatic stellate cells are also involved in mediating microcirculatory dysfunction after cold preservation and transplantation. Stellate cells regulate sinusoidal vascular tone via endothe-lin and nitric oxide action. In conditions associated with ischemia-reperfusion an imbalance toward endothelin may result in sinusoidal narrowing and thus microvascular perfusion failure. Accordingly, a recent study has demonstrated in warm ischemia-reperfusion as well as after orthotopic liver transplantation that the inhibition of stellate cell contraction by a rock inhibitor can prevent postischemic hepatic micro-circulatory disruption and, by this means, can improve post-transplant survival.

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