Bryostatin-1 limits neutrophil transmigration following ischemia- reperfusion injury and prevents delayed renal graft function in a porcine autotransplant model: UKM

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Abstract: Bryostatin-1 limits neutrophil transmigration following ischemia- reperfusion injury and prevents delayed renal graft function in a porcine autotransplant model

In kidney IRI, renal endothelial cells (EC) are the first site of graft injury, while neutrophils are the first line of host defense after reperfusion. The degree of renal EC damage within the graft predicts the severity of neutrophil transendothelial migration (TEM), with neutrophils in turn acting as the gate-keeper cell population by their ability to orchestrate the influx of subsequent waves of leukocytes into the graft. Therefore, EC integrity and neutrophil TEM represent one of the most promising targets to attenuate IRI and thus to ameliorate DGF (Fig 1).

Given the clinical impact of DGF, new strategies are urgently needed to ameliorate the unavoidable IRI in kidney transplantation, with Bryostatin-1 (a protein kinase C delta blocker PKCδ)) being a most promising candidate. Bryostatin-1 has been initially described as an anti-cancer drug and since then its safety, efficiency and therapeutic potential have been repeatedly proven in a variety experimental studies as well as clinical Phase I and Phase II trials. Recently, our collaborators described an additional mechanism of action for Bryostatin-1, which is a near complete blockade of in vitro neutrophil TEM through activation of the EC second messenger PKCδ.

For this novel ‘partners-across-campus` project, we and our international collaborators are transferring the newly obtained results of Bryostatin-1 as a potent inhibitor of neutrophil TEM for the field of transplant medicine, using both relevant in vitro as well as translational in vivo models. This project will validate protective effects of Bryostatin-1 in the continuum of renal IRI in a preclinical model of kidney autotransplantation.

Research Group Leader

MD Felix Becker
E-Mail: felix.becker(at)ukmuenster(dot)de Publikationen