Local blockade of glucocorticoid activation reverses stress- and glucocorticoid-induced delays in cutaneous wound healing.
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.
Department of Dermatology, Veterans Affairs Medical Center, San Francisco, California; Northern California Institute for Research and Education, University of California, San Francisco, California.
Jong-Kyung
JK
Youm
Kyungho
K
Park
Yoshikazu
Y
Uchida
Aegean
A
Chan
Theodora M
TM
Mauro
Walter M
WM
Holleran
Peter M
PM
Elias
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D013315:Stress, Psychological / Q000378:metabolism*; D014945:Wound Healing / Q000187:drug effects
D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1