CD47 blockade reduces ischemia/reperfusion injury and improves survival in a rat liver transplantation model

Abstract

Orthotopic liver transplantation (OLT) remains the standard treatment option for nonresponsive liver failure. Because ischemia/reperfusion injury (IRI) is an important impediment to the success of OLT, new therapeutic strategies are needed to reduce IRI. We investigated whether blocking the CD47/thrombospondin-1 inhibitory action on nitric oxide signaling with a monoclonal antibody specific to CD47 (CD47mAb400) would reduce IRI in liver grafts. Syngeneic OLT was performed with Lewis rats. Control immunoglobulin G or CD47mAb400 was administered to the donor organ at procurement or to both the organ and the recipient at the time of transplant. Serum transaminases, histological changes of the liver, and animal survival were assessed. Oxidative stress, inflammatory responses, and hepatocellular damage were also quantified. A significant survival benefit was not achieved when CD47mAb400 was administered to the donor alone. However, CD47mAb400 administration to both the donor and the recipient increased animal survival afterward. The CD47mAb400-treated group showed lower serum transaminases, bilirubin, oxidative stress, terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling staining, caspase-3 activity, and proinflammatory cytokine expression of tumor necrosis factor α, interleukin-1β, and interleukin-6. Thus, CD47 blockade with CD47mAb400 administered both to the donor and the recipient reduced liver graft IRI in a rat liver transplantation model. This may translate to decreased liver dysfunction and increased survival of liver transplant recipients.

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

“…In liver and kidney I/R models, CD47 knockout mice were found to suffer less damage compared to control mice after periods of vascular occlusion followed by recanalization [13,17]. Administration of the CD47 monoclonal antibody similarly improved the survival of ischemic skin flaps and skin grafts, and both liver and kidney mouse I/R models [14,15,38,39].…”

“…Bauer et al reported that both TSP1 and CD47 are significantly upregulated in vascular cells during states of ischemia [12]. Blocking of the TSP1/CD47 signal using an anti-CD47 monoclonal antibody (CD47 mAb) in wild-type mice, or by generation of CD-47 knock-out mice, can mitigate kidney, liver, and tissue flap damage and improve tissue survival in I/R models [13][14][15][16][17]. However, the physiological function of CD47 in MIRI has yet to be elucidated.…”

Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia–reperfusion-induced hepatic injury in rats

“…Caspase-3 is the effector protease in the apoptotic cascade. It plays a significant role in IR-induced liver injury [44]. There are many processes implicated in activation of caspase-3 including TNF-α/TNF receptor, Fas/Fas ligand interaction, oxygen-free radical generation and nuclear factor-κB activation [8,10].…”

“…Rats were fed a standard rat chow diet and tap water and left to acclimatize for one week before the experiment. The experiment was conducted with adherence to the ethical standards Life Sciences 134 (2015) [42][43][44][45][46][47][48] approved by the faculty board committee of the Faculty of Medicine, Minia University, Egypt and in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for animal experiments.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…Mice (217) and rats (140) treated with CD47 antibodies sustained less injury after syngeneic renal transplantation, and in rats this was associated with increased blood flow 24 h post-transplantation. In healthy and steatotic rat liver transplantation ischemia-reperfusion models, pretreatment with a CD47 antibody (mAb400) was associated with improved animal survival, less organ injury, and lower superoxide levels, as characterized by dihydroethidium fluorescence of liver tissue sections (303,304).…”