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Thrombospondin-1/CD47 Blockade following Ischemia-Reperfusion Injury Is Tissue Protective

Maxhimer, Justin B., M.D.; Shih, Hubert B., B.S.; Isenberg, Jeffrey S., M.D., M.P.H.; Miller, Thomas W., Ph.D.; Roberts, David D., Ph.D.

Plastic and Reconstructive Surgery: December 2009 - Volume 124 - Issue 6 - p 1880-1889
doi: 10.1097/PRS.0b013e3181bceec3

Background: Nitric oxide has prosurvival effects that can limit ischemia-reperfusion injuries. However, the matrix glycoprotein thrombospondin-1 is induced following ischemia-reperfusion injury and limits nitric oxide signaling by engaging its cell surface receptor CD47. In this article, the authors examine whether postinjury blocking of this inhibitory signal can protect from ischemia-reperfusion injury in a rat flap model.

Methods: A total of 40 tissue flaps were created in rats based solely on the deep inferior epigastric vessels. Microvascular clamps were used to create 45 minutes of ischemia time to the flaps. The flaps were then treated using a monoclonal antibody to CD47 or an isotype-matched control immunoglobulin G1 5 or 30 minutes after clamp removal. Twenty-four or 72 hours postoperatively, the necrotic area of the flap was determined, and serum, deep inferior epigastric vessels, and flaps were harvested for analysis from five rats in each respective group.

Results: Treatment with a CD47 antibody 5 minutes after reperfusion significantly reduces flap necrosis compared with immunoglobulin G1 control (9 percent versus 43 percent; p < 0.01). The protective effect is even more dramatic when treatment is delayed until 30 minutes after reperfusion (10 percent versus 88 percent for control; p < 0.01). Markers of neutrophil and endothelial cell activation along with total leukocytes are reduced in CD47 antibody–treated flaps, as are tissue malondialdehyde levels. Levels of cyclic guanosine monophosphate are elevated 72 hours postoperatively in the CD47 antibody–treated deep inferior epigastric vessels versus the control flaps.

Conclusions: Therapies targeting the thrombospondin-1 receptor CD47 offer potential for increasing tissue survival in ischemia-reperfusion injuries. The ability to protect when given after ischemia-reperfusion injury enables a broader clinical applicability.

Bethesda and Baltimore, Md.; and Pittsburgh, Pa.

From the Laboratory of Pathology, National Cancer Institute, National Institutes of Health; the Department of Surgery, The Johns Hopkins Medical Institutions; the Howard Hughes Medical Institute–National Institutes of Health Research Scholar Program; and the Division of Pulmonary, Allergy, and Critical Care Medicine and Vascular Medicine Institute, University of Pittsburgh School of Medicine.

Received for publication April 6, 2009; accepted June 19, 2009.

Presented in part at the 54th Annual Meeting of the Plastic Surgery Research Council, in Pittsburgh, Pennsylvania, May 27 through 30, 2009.

Disclosure:J.S.I. is a founder and scientific advisor of Vasculox, Inc., St. Louis, Mo. None of the other authors has any commercial associations that might pose or create a conflict of interest with information presented in this article.

David D. Roberts, Ph.D.; National Institutes of Health; Building 10, Room 2A33; 10 Center Drive, MSC1500; Bethesda, Md. 20892-1500;

©2009American Society of Plastic Surgeons