Cardiovascular Research

Targeting of intragraft reactive oxygen species by APP-103, a novel polymer product, mitigates ischemia/reperfusion injury and p

Authors: Koichiro Minami|||Soochan Bae|||Hirofumi Uehara|||Chen Zhao|||Dongwon Lee|||Jasper Iske|||Michael W Fanger|||Jake Reder|||Ian Morrison|||Haruhito Azuma|||Astrid Wiens|||Edward Van Keuren|||Brandy Houser|||Abdala ElKhal|||Peter M Kang|||Stefan G Tullius

Affiliations: + Expand

Abstract

Inflammatory responses associated with ischemia/reperfusion injury (IRI) play a central role in alloimmunity and transplant outcomes. A key event driving these inflammatory responses is the burst of reactive oxygen species (ROS), with hydrogen peroxide (H O ) as the most abundant form that occurs as a result of surgical implantation of the donor organ. Here, we used a syngeneic rat renal transplant and IRI model to evaluate the therapeutic properties of APP-103, a polyoxalate-based copolymer molecule containing vanillyl alcohol (VA) that exhibits high sensitivity and specificity toward the production of H O . We show that APP-103 is safe, and that it effectively promotes kidney function following IRI and survival of renal transplants. APP-103 reduces tissue injury and IRI-associated inflammatory responses in models of both warm ischemia (kidney clamping) and prolonged cold ischemia (syngeneic renal transplant). Mechanistically, we demonstrate that APP-103 exerts protective effects by specifically targeting the production of ROS. Our data introduce APP-103 as a novel, nontoxic, and site-activating therapeutic approach that effectively ameliorates the consequences of IRI in solid organ transplantation.

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Chemical List

Polymers|||Reactive Oxygen Species

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