Role of Renin-Angiotensin-Aldosterone System during sarcoidosis granuloma formation

结节病是一种原因不明的肺部和全身肉芽肿性疾病。为了更好地理解 疾病机制，我们最近建立了一种新的体外人类肉芽肿模型，该模型具有许多 人类组织中疾病的结构和分子特征，为发病机制提供了新的见解 调节早期肉芽肿的形成。与先前的研究和临床经验相一致 结节病组织中血管紧张素转换酶(ACE)水平升高 结节病肉芽肿模型的特征表明巨噬细胞参与了结节病 肉芽肿的形成受肾素-血管紧张素-醛固酮系统(RAAS)的调节。我们的强者 初步数据显示，结节病巨噬细胞产生醛固酮，一种促进 炎症通过激活盐皮质激素受体(MRS)；我们进一步表明抑制 RAAS途径的抑制(例如，ACE抑制)或MRS的抑制可减少肉芽肿的形成。我们 假设RAAS通过以下途径促进结节病患者病理性肉芽肿的形成 激活MRS。本着R21筹资机制的精神，该项目具有很高的创新性，并具有 对增进我们对结节病发病机制的理解和对 提供新的治疗靶点和疾病生物标志物。目标一号将决定是否平衡 血管紧张素转换酶1和血管紧张素转换酶2(血管紧张素转换酶1介导的炎症抑制因子)调节结节病肉芽肿 通过控制血管紧张素II水平和相关的血管紧张素受体(ATR1)激活而形成。我们 推测血管紧张素转换酶和血管紧张素转换酶2的平衡影响结节病患者肉芽肿的形成。 AIM 2将确定醛固酮诱导的MR激活是否促进NRF2/HO-1/STAT3信号转导 促进结节病肉芽肿的形成，其特征是偏向CD163巨噬细胞。这些 研究将确定醛固酮是否促进巨噬细胞吞噬小体激活的信号通路 NRF2/HO-1/STAT3使巨噬细胞极化为表达CD163的表型 聚集并形成肉芽肿。目标3将是一项试验性研究，旨在确定醛固酮水平 在体外肉芽肿模型中获得的结果可以预测肺结节病疾病的进展。 目前，还没有可靠的预测结节病疾病进展的生物标志物来预测。 并指导治疗，而醛固酮是一个可行的候选者。这样做的短期目标是推进 对结节病的发病机制有基本的了解，并考虑相关的治疗目标。长期的 本项目的目标是解决目前结节病领域中与以下方面有关的不足 确定新的疾病特异性治疗方法(针对肉芽肿形成)，确定新的生物标记物 预测疾病的进展，并最终确定是否可以改变广泛可用的用途 RAAS调节药物(如血管紧张素转换酶、ATR1和MR抑制剂)用于治疗结节病。

Sarcoidosis is a pulmonary and systemic granulomatous disease of unknown cause. To better understand disease mechanisms, we have recently established a novel in vitro human granuloma model that shares many structural and molecular features of the disease in human tissues, yielding novel insights into mechanisms regulating early granuloma formation. In keeping with prior investigations and clinical experience linking sarcoidosis to elevated leves of angiotensin converting enzyme (ACE) in sarcoidosis tissues, molecular characterization of the sarcoidosis granuloma model indicates that macrophages participating in sarcoidosis granuloma formation are regulated by the renin-angiotensin-aldosterone system (RAAS). Our strong preliminary data shows that sarcoidosis macrophages produce aldosterone, a hormone that promotes inflammation through the activation of mineralocorticoid receptors (MRs); and we further show that suppression of the RAAS pathway (e.g., ACE inhibition) or inhibition of MRs attenuates granuloma formation. We hypothesize that RAAS promotes pathological granuloma formation in patients with sarcoidosis through activation of MRs. In the spirit of the R21 funding mechanisms, this project is highly innovative and has important beneficial implications for advancing our understanding of sarcoidosis disease mechanisms and for providing novel therapeutic targets and disease biomarkers. Aim 1 will determine if the balance between ACE1 and ACE2 (a suppressor of ACE1-mediated inflammation) regulates sarcoidosis granuloma formation by controlling angiotensin II levels and related angiotensin 1 receptor (ATR1) activation. We posit that the balance between ACE and ACE2 influences the formation of granulomas in sarcoidosis patients. Aim 2 will determine if aldosterone induced MR activation promotes NRF2/HO-1/STAT3 signaling to promote sarcoidosis granuloma formation, featuring polarization towards CD163 macrophages. These studies will determine if aldosterone promotes macrophage phagosome-activated signaling pathway NRF2/HO-1/STAT3 to polarize macrophages towards a CD163 expressing phenotype that is predisposed to aggregate and form granulomas. Aim 3 will be a pilot study designed to determine if aldosterone levels achieved in the in vitro granuloma model are predictive of pulmonary sarcoidosis disease progression. Currently, there are no reliable biomarkers predictive of sarcoidosis disease progression for prognostication and to guide therapy, and aldosterone is a viable candidate. The short-term goals of this are to advancing basic understanding of sarcoidosis disease mechanisms and to consider related therapeutic targets. Long-term aspirations of this project are to address current deficiencies in the field of sarcoidosis as relates to identifying novel disease-specific therapies (targeting granuloma formation), identifying novel biomarkers predictive of disease progression, and to ultimately determine if it is feasible to repurpose widely available RAAS modulating drugs (e.g., ACE, ATR1 and MR inhibitors) for the treatment of sarcoidosis.