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

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 6; p. 948
• Main Authors: Becker, Felix, Kebschull, Linus, Rieger, Constantin, Mohr, Annika, Heitplatz, Barbara, Van Marck, Veerle, Hansen, Uwe, Ansari, Junaid, Reuter, Stefan, Strücker, Benjamin, Pascher, Andreas, Brockmann, Jens G, Castor, Trevor, Alexander, J Steve, Gavins, Felicity N E
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 10.03.2022; MDPI
• Subjects: Animals; Autografts; Bryostatin-1; Bryostatins - pharmacology; Cell activation; Cold storage; Cryopreservation; Endothelial cells; Endothelial Cells - metabolism; Experiments; Hypoxia; Immune response; Infiltration; Innate immunity; Ischemia; Ischemia - drug therapy; ischemia reperfusion injury; kidney transplant; Kidney transplantation; Kidney Transplantation - adverse effects; Kinases; Leukocytes (neutrophilic); Neutrophils; Neutrophils - metabolism; Permeability; Renal function; Reperfusion; Reperfusion Injury - metabolism; Swine; translational research; Transplants & implants; Tumor necrosis factor-TNF; Vascular endothelial growth factor; United States > US; kidney transplant; Bryostatin-1; ischemia reperfusion injury; translational research
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11060948

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.