Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

中文翻译：

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组胺信号传导和代谢确定淋巴管平滑肌瘤病的潜在生物标志物和治疗方法

抑制 mTOR 是淋巴管平滑肌瘤病 (LAM) 的标准治疗方法。然而，这种疗法具有不同的耐受性，尽管接受治疗，一些患者仍表现出肺功能进行性下降。由于症状的异质性和非侵入性测试的不足，LAM 诊断和监测也可能具有挑战性。在这里，我们提出单胺衍生的生物标志物，为新的治疗方法提供临床前证据。主要组胺衍生代谢物甲基咪唑乙酸 (MIAA) 在 LAM 血浆中相对丰富，且 MIAA 值与 VEGF-D 无关。较高水平的组胺与较差的肺功能和较大的疾病负担有关。分子和细胞分析以及代谢分析证实了活跃的组胺信号传导和代谢。使用已批准的针对单胺氧化酶 A/B（氯吉兰和雷沙吉兰）或组胺 H1 受体（氯雷他定）的药物可减少 LAM 肿瘤发生，并且氯雷他定与雷帕霉素具有协同作用。Maoa或Hrh1表达的缺失以及 L-组氨酸类似物的施用或低 L-组氨酸饮食也可以减少 LAM 肿瘤的发生。这些发现扩展了我们对 LAM 生物学的了解，并提出了改善疾病管理的可能方法。