原理:结节病是一种原因不明的肉芽肿性疾病,值得注意的是血液和组织血管紧张素转换酶1(ACE1)水平和活性异常升高。ACE1调节肾素-血管紧张素-醛固酮系统(RAAS),其最终产物是醛固酮,选择性地参与盐皮质激素受体(MR)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的炎症反应。方法:使用建立的离体模型,我们首先确定了醛固酮是否由结节病肉芽肿产生,并验证了CYP11B2的存在,CYP11B2是其产生所需的酶.然后,我们评估了ACE1(卡托普利)的选择性抑制剂的作用,血管紧张素1型受体(氯沙坦)和MR(螺内酯,依普利酮)在肉芽肿形成上,由计算机图像分析反映的肉芽肿区域,和选定的细胞因子与结节病的发病机理有关。测量和主要结果:结节病PBMC自发产生醛固酮,在肉芽肿形成过程中,细胞内和细胞外水平均稳定增加。并行,PBMC显示在肉芽肿形成期间表达更多的CYP11B2。结节病肉芽肿和相关细胞因子的显著抑制(TNFα,IL-1β,IFNγ,观察到IL-10)对卡托普利预处理的反应,氯沙坦,螺内酯或依普利酮,与泼尼松相当。结论:RAAS在结节病肉芽肿中是完整的,并且在早期肉芽肿形成和相关的炎症介质反应中起重要作用,对临床治疗具有重要意义。
Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue angiotensin converting enzyme 1 (ACE1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors (MR) 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 MR (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 PBMCs, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, PBMCs 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.