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J. Biol. Chem., Vol. 281, Issue 30, 21225-21235, July 28, 2006

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-Adrenergic Receptor Antagonists Accelerate Skin Wound Healing

EVIDENCE FOR A CATECHOLAMINE SYNTHESIS NETWORK IN THE EPIDERMIS^*

Christine E. Pullar¹, Amilcar Rizzo, and R. Rivkah Isseroff

From the Department of Dermatology, School of Medicine, University of California, Davis, California 95616 and Dermatology Service, Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655

The skin is our primary defense against noxious environmental agents. Upon injury, keratinocytes migrate directionally into the wound bed to initiate re-epithelialization, essential for wound repair and restoration of barrier integrity. Keratinocytes express a high level of 2-adrenergic receptors (2-ARs) that appear to play a role in cutaneous homeostasis as aberrations in either keratinocyte 2-AR function or density are associated with various skin diseases. Here we report the novel finding that -AR antagonists promote wound re-epithelialization in a "chronic" human skin wound-healing model. -AR antagonists increase ERK phosphorylation, the rate of keratinocyte migration, electric field-directed migration, and ultimately accelerate human skin wound re-epithelialization. We demonstrate that keratinocytes express two key enzymes required for catecholamine (-AR agonist) synthesis, tyrosine hydroxylase and phenylethanolamine-N-methyl transferase, both localized within keratinocyte cytoplasmic vesicles. Finally, we confirm the synthesis of epinephrine by measuring the endogenously synthesized catecholamine in keratinocyte extracts. Previously, we have demonstrated that -AR agonists delay wound re-epithelialization. Here we report that the mechanism for the -AR antagonist-mediated augmentation of wound repair is due to 2-AR blockade, preventing the binding of endogenously synthesized epinephrine. Our work describes an endogenous -AR mediator network in the skin that can temporally regulate skin wound repair. Further investigation of this network will improve our understanding of both the skin repair process and the multiple modes of action of one of the most frequently prescribed class of drugs, hopefully resulting in a new treatment for chronic wounds.

Received for publication, February 2, 2006 , and in revised form, April 3, 2006.

^* This work was supported in part by National Institutes of Health Grants AR 48827 (to C. E. P.) and AR 44518 (to R. R. I.) and Shriners Hospital for Children Grant 06-NCA-004 (to R. R. I.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Dermatology, School of Medicine, University of California, Davis, TB 192, One Shields Ave, Davis, CA 95616. Tel.: 530-752-1713; Fax: 530-752-9766; E-mail: cepullar{at}ucdavis.edu.

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