Div. of Pulmonary Medicine, Abramson Research Bldg., Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Am J Physiol Lung Cell Mol Physiol. 2012 Sep;303(5):L382-90. doi: 10.1152/ajplung.00125.2012. Epub 2012 Jul 6.
Endogenous glucocorticoid (GC) activation is regulated by the intracellular GC-activating and -inactivating enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD)1 and 11β-HSD2, respectively, that catalyze interconversion of inert cortisone and its bioactive metabolite cortisol. Because endogenous GCs are critically implicated in suppressing the asthmatic state, this study examined the roles of the 11β-HSD enzymes in regulating GC activation and bronchoprotection during proasthmatic stimulation. Airway hyperresponsiveness to methacholine and inflammation were assessed in rabbits following inhalation of the proasthmatic/proinflammatory cytokine IL-13 with and without pretreatment with the 11β-HSD inhibitor carbenoxolone (CBX). Additionally, IL-13-induced changes in 11β-HSD isozyme expression and GC metabolism were examined in epithelium-intact and -denuded tracheal segments and peripheral lung tissues. Finally, the effects of pretreatment with CBX or 11β-HSD2-targeted siRNAs were investigated with respect to cortisol prevention of IL-13-induced airway constrictor hyperresponsiveness and eotaxin-3 production by airway epithelial cells. IL-13-exposed rabbits exhibited airway hyperresponsiveness, inflammation, and elevated bronchoalveolar lung fluid levels of eotaxin-3. These responses were inhibited by pretreatment with CBX, suggesting a permissive proasthmatic role for 11β-HSD2. Supporting this concept, extended studies demonstrated that 1) IL-13-treated tracheal epithelium and peripheral lung tissues exhibit upregulated 11β-HSD2 activity, 2) the latter impairs cortisone-induced cortisol accumulation and the ability of administered cortisol to prevent both IL-13-induced heightened airway contractility and eotaxin-3 release from epithelial cells, and 3) these proasthmatic responses are prevented by cortisol administration in the presence of 11β-HSD2 inhibition. Collectively, these data demonstrate that the proasthmatic effects of IL-13 are enabled by impaired endogenous GC activation in the lung that is attributed to upregulation of 11β-HSD2 in the pulmonary epithelium.
内源性糖皮质激素（GC）的激活受细胞内 GC 激活和失活酶 11β-羟类固醇脱氢酶（11β-HSD）1 和 11β-HSD2 分别调节，它们催化无活性的可的松与其生物活性代谢产物皮质醇的相互转化。由于内源性 GCs 在抑制哮喘状态中具有重要作用，因此本研究探讨了 11β-HSD 酶在调节 GC 激活和支气管保护中的作用在哮喘前刺激期间。在吸入哮喘/炎症前细胞因子白细胞介素-13（IL-13）后，通过气道高反应性测定兔气道高反应性和炎症，并用 11β-HSD 抑制剂 carbenoxolone（CBX）预处理。此外，在完整和去上皮的气管段和外周肺组织中检查了 IL-13 诱导的 11β-HSD 同工酶表达和 GC 代谢的变化。最后，研究了 CBX 预处理或 11β-HSD2 靶向 siRNA 预处理对皮质醇预防 IL-13 诱导的气道收缩性高反应性和气道上皮细胞产生嗜酸性粒细胞趋化因子-3 的影响。暴露于 IL-13 的兔子表现出气道高反应性、炎症和升高的支气管肺泡肺液中嗜酸性粒细胞趋化因子-3 水平。这些反应被 CBX 预处理抑制，表明 11β-HSD2 在哮喘前具有允许作用。支持这一概念，扩展研究表明：1）IL-13 处理的气管上皮和外周肺组织表现出上调的 11β-HSD2 活性，2）后者损害皮质酮诱导的皮质醇积累，以及给予皮质醇预防 IL-13 诱导的气道收缩性增高和嗜酸性粒细胞趋化因子-3 从上皮细胞释放的能力，3）在存在 11β-HSD2 抑制的情况下，皮质醇给药可预防这些哮喘前反应。总的来说，这些数据表明，IL-13 的哮喘前效应是通过肺内内源性 GC 激活受损而产生的，这归因于肺上皮中 11β-HSD2 的上调。
