Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1β, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.

中文翻译：

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肾素-血管紧张素-醛固酮系统调节结节病肉芽肿性炎症。


理由：结节病是一种原因不明的肉芽肿性疾病，以血液和组织 ACE1（血管紧张素转换酶 1）水平和活性异常升高为特征。 ACE1 调节肾素-血管紧张素-醛固酮系统 (RAAS)，该系统的最终产物是醛固酮，选择性地与盐皮质激素受体结合以促进炎症。目的：我们试图确定 RAAS 是否促进结节病肉芽肿形成和相关炎症反应。方法：使用已建立的离体模型，我们首先确定醛固酮是否由结节病肉芽肿产生，并验证其产生所需酶 CYP11B2 的存在。然后，我们评估了 ACE1（卡托普利）、血管紧张素 1 型受体（洛沙坦）和盐皮质激素受体（螺内酯、依普利酮）选择性抑制剂对肉芽肿形成的影响，这通过计算机图像分析生成的肉芽肿面积以及与结节病有关的选定细胞因子来反映发病。测量和主要结果：醛固酮由结节病外周血单核细胞自发产生，并且在肉芽肿形成过程中细胞内和细胞外水平稳定增加。与此同时，外周血单核细胞在肉芽肿形成过程中表达更多的 CYP11B2。卡托普利、氯沙坦、螺内酯或依普利酮预处理对结节病肉芽肿和相关细胞因子（TNFα、IL-1β、IFNγ、IL-10）的显着抑制作用与泼尼松相当。结论：结节病肉芽肿中的 RAAS 是完整的，对早期肉芽肿形成和相关炎症介质反应有显着贡献，对临床治疗具有重要意义。