Alternative erythropoietin-mediated signaling prevents secondary microvascular thrombosis and inflammation within cutaneous burns

Stefan Bohr, Suraj J. Patel, Keyue Shen, Antonia G. Vitalo, Michael Brines, Anthony Cerami, Francois Berthiaume, Martin L. Yarmush

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Alternate erythropoietin (EPO)-mediated signaling via the heteromeric receptor composed of the EPO receptor and the β-common receptor (CD131) exerts the tissue-protective actions of EPO in various types of injuries. Herein we investigated the effects of the EPO derivative helix beta surface peptide (synonym: ARA290), which specifically triggers alternate EPO-mediated signaling, but does not bind the erythropoietic EPO receptor homodimer, on the progression of secondary tissue damage following cutaneous burns. For this purpose, a deep partial thickness cutaneous burn injury was applied on the back of mice, followed by systemic administration of vehicle or ARA290 at 1, 12, and 24 h postburn. With vehicle-only treatment, wounds exhibited secondary microvascular thrombosis within 24 h postburn, and subsequent necrosis of the surrounding tissue, thus converting to a full-thickness injury within 48 h. On the other hand, when ARA290 was systemically administered, patency of the microvasculature was maintained. Furthermore, ARA290 mitigated the innate inflammatory response, most notably tumor necrosis factor-alpha-mediated signaling. These findings correlated with long-term recovery of initially injured yet viable tissue components. In conclusion, ARA290 may be a promising therapeutic approach to prevent the conversion of partial- to full-thickness burn injuries. In a clinical setting, the decrease in burn depth and area would likely reduce the necessity for extensive surgical debridement as well as secondary wound closure by means of skin grafting. This use of ARA290 is consistent with its tissue-protective properties previously reported in other models of injury, such as myocardial infarction and hemorrhagic shock.

Original languageEnglish (US)
Pages (from-to)3513-3518
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number9
DOIs
StatePublished - Feb 26 2013
Externally publishedYes

Keywords

  • Cell adhesion molecules
  • Hypoxia
  • Leukocyte infiltration
  • Oxidative stress
  • Thermal injury

ASJC Scopus subject areas

  • General

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