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Local blockade of glucocorticoid activation reverses stress- and glucocorticoid-induced delays in cutaneous wound healing

Authors

  • Jong-Kyung Youm PhD,

    1. Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
    2. Northern California Institute for Research and Education, University of California, San Francisco, California
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  • Kyungho Park PhD, MD,

    1. Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
    2. Northern California Institute for Research and Education, University of California, San Francisco, California
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  • Yoshikazu Uchida PhD,

    1. Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
    2. Northern California Institute for Research and Education, University of California, San Francisco, California
    3. Department of Dermatology, University of California, San Francisco, California
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  • Aegean Chan MD,

    1. Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
    2. Northern California Institute for Research and Education, University of California, San Francisco, California
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  • Theodora M. Mauro MD,

    1. Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
    2. Northern California Institute for Research and Education, University of California, San Francisco, California
    3. Department of Dermatology, University of California, San Francisco, California
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  • Walter M. Holleran PharmD,

    1. Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
    2. Northern California Institute for Research and Education, University of California, San Francisco, California
    3. Department of Dermatology, University of California, San Francisco, California
    4. Department of Pharmacuetical Chemistry, University of California, San Francisco, California
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  • Peter M. Elias MD

    Corresponding author
    1. Northern California Institute for Research and Education, University of California, San Francisco, California
    2. Department of Dermatology, University of California, San Francisco, California
    • Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California
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Reprint requests:

Prof. P. M. Elias, Dermatology Service (190), VA Medical Center, 4150 Clement Street, San Francisco, CA, USA.

Tel: +1 415 750 2091;

Fax: +1 415 750 2106;

Email: eliasp@derm.ucsf.edu

Abstract

Stress slows cutaneous wound healing (WH) in an endogenous glucocorticoid (GC)-dependent fashion. We investigated whether stress/GC-induced delays in WH require further intracutaneous activation of endogenous GC; and whether blockade or down-regulation of peripheral activation normalizes WH in the face of stress. Delayed WH in our motion-restricted murine model of stress could be attributed to elevated systemic GC, because blockade of GC production (using corticotropin-releasing factor inhibitor, antalarmin), or of peripheral binding to the GC receptor [GCr], with an antagonist, Ru-486, normalized WH. We next investigated whether local blockade or down-regulation of the peripheral GC-activating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), accelerates cutaneous WH. Topical applications of nonspecific (carbenoxolone) as well as an isoform-specific 11β-HSD1 inhibitor overcame stress and exogenous GC-induced delays in WH. Moreover, two liver X receptor ligands, TO901317 and GW3695, down-regulated expression of 11β-HSD1, attenuating stress-induced delays in WH. Combined inhibitor and liver X receptor ligand applications accelerated WH in the face of stress/systemic GC. Thus: (1) intracutaneous conversion of inactive-to-active GC accounts for stress (GC)-induced delays in WH; and (2) blockade or down-regulation of 11β-HSD1 and/or GCr normalize cutaneous WH in the face of stress/GC. Local blockade or down-regulation of cutaneous GC activation could help enhance WH in various clinical settings.

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