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Local blockade of glucocorticoid activation reverses stress‐ and glucocorticoid‐induced delays in cutaneous wound healing
Author(s) -
Youm JongKyung,
Park Kyungho,
Uchida Yoshikazu,
Chan Aegean,
Mauro Theodora M.,
Holleran Walter M.,
Elias Peter M.
Publication year - 2013
Publication title -
wound repair and regeneration
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.847
H-Index - 109
eISSN - 1524-475X
pISSN - 1067-1927
DOI - 10.1111/wrr.12083
Subject(s) - blockade , glucocorticoid receptor , glucocorticoid , antiglucocorticoid , pharmacology , 11β hydroxysteroid dehydrogenase type 1 , receptor , antagonist , chemistry , endocrinology , medicine , enzyme , dehydrogenase , biochemistry
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, R u‐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.