Bryostatin-1 Attenuates Ischemia-Elicited Neutrophil Transmigration and Ameliorates Graft Injury after Kidney Transplantation.

Felix Becker,Junaid Ansari,Trevor Castor,Jens G Brockmann,Linus Kebschull,Veerle Van Marck,Uwe Hansen,Andreas Pascher,Benjamin Strücker,Barbara Heitplatz,Constantin Rieger,Annika Mohr,Felicity N E Gavins,Stefan Reuter,J Steve Alexander

doi:10.3390/cells11060948

Abstract

Ischemia reperfusion injury (IRI) is a form of sterile inflammation whose severity determines short- and long-term graft fates in kidney transplantation. Neutrophils are now recognized as a key cell type mediating early graft injury, which activates further innate immune responses and intensifies acquired immunity and alloimmunity. Since the macrolide Bryostatin-1 has been shown to block neutrophil transmigration, we aimed to determine whether these findings could be translated to the field of kidney transplantation. To study the effects of Bryostatin-1 on ischemia-elicited neutrophil transmigration, an in vitro model of hypoxia and normoxia was equipped with human endothelial cells and neutrophils. To translate these findings, a porcine renal autotransplantation model with eight hours of reperfusion was used to study neutrophil infiltration in vivo. Graft-specific treatment using Bryostatin-1 (100 nM) was applied during static cold storage. Bryostatin-1 dose-dependently blocked neutrophil activation and transmigration over ischemically challenged endothelial cell monolayers. When applied to porcine renal autografts, Bryostatin-1 reduced neutrophil graft infiltration, attenuated histological and ultrastructural damage, and improved renal function. Our novel findings demonstrate that Bryostatin-1 is a promising pharmacological candidate for graft-specific treatment in kidney transplantation, as it provides protection by blocking neutrophil infiltration and attenuating functional graft injury.

Highlights

Organ shortage remains the cardinal problem in transplant medicine, and the use of organs with extended ischemia time is becoming routine, reflecting decreasing numbers of donated organs in contrast to increasing numbers of patients on the waiting list
Ischemia reperfusion injury (IRI) produces an inflammatory state that leads to acute kidney injury (AKI) and a high susceptibility to subsequent delayed graft function (DGF), a form of acute post-transplant graft dysfunction, which correlates with ischemia reperfusion injury (IRI) severity [3,4]
When compared to control conditions, hypoxia elicited a significant increase in the permeability of human umbilical vein endothelial cell (HUVEC) monolayers, irrespective of the molecular weight (Figure 2A)

Summary

Introduction

Organ shortage remains the cardinal problem in transplant medicine, and the use of organs with extended ischemia time is becoming routine, reflecting decreasing numbers of donated organs in contrast to increasing numbers of patients on the waiting list. Neutrophils represent the primary mediators of early host-induced tissue injury and act as the ‘gatekeeper’ cell, reflecting their ability to orchestrate the influx of subsequent waves of leukocytes into the graft This is an important concept in transplantation because limitation of initial neutrophil infiltration may reduce subsequent recruitment of additional inflammatory cells and more extensive, later phases of tissue damage [11]. In keeping with this concept, experimental strategies depleting neutrophils or inhibiting their early infiltration have been effective in reducing IRI and improving graft function and survival [10–15]. These strategies are largely confined to the treatment of the organ recipient following graft implantation

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