Treatment of liver ischemia-reperfusion injury by limiting thrombospondin-1/CD47 signaling.
BACKGROUND
Ischemia-reperfusion (I/R) injury remains a primary complication of transplant surgery, accounting for about 80% of liver transplant failures, and is a major source of morbidity in other pathologic conditions. Activation of endothelium and inflammatory cell recruitment are central to the initiation and promulgation of I/R injury, which can be limited by the bioactive gas nitric oxide (NO). The discovery that thrombsospondin-1 (TSP1), via CD47, limits NO signaling in vascular cells and ischemic injuries in vivo suggested that I/R injury could be another important target of this signaling pathway.


METHODS
Wild-type, TSP1-null, and CD47-null mice underwent liver I/R injury. Wild-type animals were pretreated with CD47 or control antibodies before liver I/R injury. Tissue perfusion via laser Doppler imaging, serum enzymes, histology, and immunohistology were assessed.


RESULTS
TSP1-null and CD47-null mice subjected to subtotal liver I/R injury showed improved perfusion relative to wild-type mice. Null mice subjected to liver I/R had decreased liver enzyme release and less histologic evidence of injury. Elevated TSP1 expression in liver tissue after I/R injury suggested that preventing its interaction with CD47 could be protective. Thus, pretreatment of wild-type mice using a blocking CD47 antibody improved recovery of tissue perfusion and preserved liver integrity after I/R injury.


CONCLUSIONS
Tissue survival and perfusion after liver I/R injury are limited by TSP1 and CD47. Targeting CD47 before I/R injury enhances tissue survival and perfusion in a model of liver I/R injury and suggests therapeutics for enhancing organ survival in transplantation surgery.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. isenberj@mail.nih.gov
Maxhimer
Justin B
JB
Powers
Perlita
P
Tsokos
Maria
M
Frazier
William A
WA
Roberts
David D
DD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D051928:CD47 Antigen / Q000502:physiology*; D005260:Female; D007155:Immunologic Factors / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism / Q000601:surgery*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020127:Recovery of Function; D015427:Reperfusion Injury / Q000209:etiology* / Q000378:metabolism / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology*; D019700:Thrombospondin 1 / Q000502:physiology*
D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D007155:Immunologic Factors; D019700:Thrombospondin 1