Department of Dermatology, University of California San Francisco, 1700 Owens Street, San Francisco, California 94158, USA.
J Endocrinol. 2014 Mar 7;221(1):51-61. doi: 10.1530/JOE-13-0420. Print 2014 Apr.
Glucocorticoid (GC) excess inhibits wound healing causing increased patient discomfort and infection risk. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activates GCs (converting 11-dehydrocorticosterone to corticosterone in rodents) in many tissues including skin, where de novo steroidogenesis from cholesterol has also been reported. To examine the regulation of 11β-HSD1 and steroidogenic enzyme expression during wound healing, 5 mm wounds were generated in female SKH1 mice and compared at days 0, 2, 4, 8, 14, and 21 relative to unwounded skin. 11β-HSD1 expression (mRNA and protein) and enzyme activity were elevated at 2 and 4 days post-wounding, with 11β-HSD1 localizing to infiltrating inflammatory cells. 11β-HSD2 (GC-deactivating) mRNA expression and activity were undetectable. Although several steroidogenic enzymes displayed variable expression during healing, expression of the final enzyme required for the conversion of 11-deoxycorticosterone to corticosterone, 11β-hydroxylase (CYP11B1), was lacking in unwounded skin and post-wounding. Consequently, 11-deoxycorticosterone was the principal progesterone metabolite in mouse skin before and after wounding. Our findings demonstrate that 11β-HSD1 activates considerably more corticosterone than is generated de novo from progesterone in mouse skin and drives GC exposure during healing, demonstrating the basis for 11β-HSD1 inhibitors to accelerate wound repair.
糖皮质激素（GC）过多会抑制伤口愈合，增加患者不适和感染风险。11β-羟类固醇脱氢酶 1 型（11β-HSD1）在许多组织中激活 GC（在啮齿动物中将 11-脱氢皮质酮转化为皮质酮），包括皮肤，在皮肤中也有报道从胆固醇中重新合成类固醇。为了研究伤口愈合过程中 11β-HSD1 和类固醇生成酶表达的调节，在 SKH1 雌性小鼠中生成 5mm 伤口，并与未受伤皮肤相比，在第 0、2、4、8、14 和 21 天进行比较。11β-HSD1 的表达（mRNA 和蛋白质）和酶活性在伤口形成后 2 和 4 天升高，11β-HSD1 定位于浸润性炎症细胞中。11β-HSD2（GC 失活）mRNA 表达和活性不可检测。尽管几种类固醇生成酶在愈合过程中表现出不同的表达，但最后一种将 11-脱氧皮质酮转化为皮质酮所需的酶，即 11β-羟化酶（CYP11B1）的表达在未受伤皮肤和受伤后均缺乏。因此，11-脱氧皮质酮是小鼠皮肤在受伤前后孕激素的主要代谢物。我们的发现表明，在小鼠皮肤中，11β-HSD1 激活的皮质酮比从头从孕激素生成的皮质酮多得多，并在愈合过程中驱动 GC 暴露，这证明了 11β-HSD1 抑制剂加速伤口修复的基础。
