Thrombospondin-1/CD47 blockade following ischemia-reperfusion injury is tissue protective.

Abstract

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.

• Authors: Justin B Maxhimer, Hubert B Shih, Jeffrey S Isenberg, Thomas W Miller, David D Roberts
• Journal: Plastic and reconstructive surgery (Plast Reconstr Surg) Vol. 124 Issue 6 Pg. 1880-1889 (Dec 2009) ISSN: 1529-4242 [Electronic] United States
• PMID: 19952644 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• CD47 Antigen
• Nitric Oxide
• Malondialdehyde
• Interferon-gamma
• Cyclic GMP

Topics

• Analysis of Variance
• Animals
• Antibodies, Monoclonal (pharmacology)
• CD47 Antigen (drug effects, metabolism)
• Constriction
• Cyclic GMP (metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Immunohistochemistry
• Interferon-gamma (metabolism)
• Lipid Peroxidation
• Male
• Malondialdehyde (metabolism)
• Nitric Oxide (metabolism)
• Probability
• Random Allocation
• Rats
• Rats, Inbred F344
• Reperfusion Injury (drug therapy, pathology)
• Signal Transduction (drug effects, physiology)
• Surgical Flaps (blood supply)