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Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator

Abstract

Impaired wound healing, as it occurs in diabetes mellitus or long-term corticoid treatment, is commonly associated with disability, diminished quality of life, and high economic costs. Selective agonists of the A2A receptor subtype of adenosine, an endogenous regulator of inflammation, promote tissue repair in animal models, both healthy and with impaired healing. Plasmin-mediated proteolysis of fibrin and other matrix proteins is essential for cell migration at sites of injury. Since adenosine A2A receptor activation increases plasminogen activator release from macrophages and mast cells, we studied the effect of a selective agonist, CGS-21680, on full-thickness excisional wound closure in wild-type, urokinase plasminogen activator (uPA)-deficient, and tissue plasminogen activator (tPA)-deficient mice. Wound closure was impaired in tPA- and uPA-deficient mice as compared with wild-type mice, and topical application of CGS-21680 significantly increased the rate at which wounds closed in wild-type mice and uPA-deficient mice, but not in tPA-deficient mice. Immunostaining of tissue sections showed that tPA was present in endothelial cells and histiocytes by day 3 post-wound and also by day 6. In contrast, uPA was more prominent in these cell types only by day 6 post-wound. Our results confirm that plasminogen activation contributes to wound repair and are consistent with the hypothesis that adenosine A2A receptor activation promotes wound closure by a mechanism that depends upon tPA, but not uPA. Moreover, our results suggest that topical adenosine A2A receptor agonists may be useful in promotion of wound closure in patients with impaired wound healing.

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Abbreviations

CGS-21680:

2-p-[2-Carboxyethyl] phenethyl-amino-5′-N-ethylcarboxamido-adenosine

PBS:

Phosphate-buffered saline

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Acknowledgments

We thank Dr. Richard Shapiro for the donation of the tissue plasminogen activator (tPA)-deficient, urokinase plasminogen activator (uPA)-deficient, and matching C57BL6 control mice. We thank Dr. Luis Chiriboga, Director of the Immunohistochemistry Service at NYU Langone Medical Center, New York, for the histological procedures and analysis.

Sources of Support

This work was supported by grants to BNC from the National Institutes of Health (AR54897, AR56672), the NYU-HHC Clinical and Translational Science Institute (1UL1RR029893), OSI Pharmaceuticals and the Vilcek Foundation and grants to MCM from the Instituto de Salud Carlos III of Spain (FIS 05/1659), and the Spanish Ministry of Economy and Competitiveness-FEDER (SAF2009-10347 and RETICEF RD06/0013/2001).

Conflict of Interest

Dr. Cronstein holds or has filed applications for patents on the use of adenosine A2A receptor agonists to promote wound healing and the use of A2A receptor antagonists to inhibit fibrosis, the use of adenosine A1 receptor antagonists to treat osteoporosis and other diseases of bone, the use of adenosine A1 and A2B receptor antagonists to treat fatty liver, and the use of adenosine A2A receptor agonists to prevent prosthesis loosening. He is a consultant (within the past 2 years) for King Pharmaceuticals (licensee of patents on wound healing and fibrosis above), CanFite Biopharmaceuticals, Savient Pharmaceuticals, Bristol-Myers Squibb, Roche Pharmaceuticals, Cellzome, Tap (Takeda) Pharmaceuticals, Prometheus Laboratories, Regeneron (Westat, DSMB), Sepracor, Amgen, Endocyte, Protalex, Allos, Inc., Combinatorx, Kyowa Hakka, received honoraria from Tap (Takeda) Pharmaceuticals, and holds stock in CanFite Biopharmaceuticals received for membership in Scientific Advisory Board.

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Correspondence to M. Carmen Montesinos.

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Montesinos, M.C., Desai-Merchant, A. & Cronstein, B.N. Promotion of Wound Healing by an Agonist of Adenosine A2A Receptor Is Dependent on Tissue Plasminogen Activator. Inflammation 38, 2036–2041 (2015). https://doi.org/10.1007/s10753-015-0184-3

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  • DOI: https://doi.org/10.1007/s10753-015-0184-3

KEY WORDS

  • adenosine A2A receptors
  • plasminogen activator
  • wound healing
  • animal models