Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.
Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.
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DOI：
10.15252/emmm.202113929
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发表时间：
2021-09-07
影响因子：
11.1
通讯作者：
Pujana MA
中科院分区：
文献类型：
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作者：
Herranz C;Mateo F;Baiges A;Ruiz de Garibay G;Junza A;Johnson SR;Miller S;García N;Capellades J;Gómez A;Vidal A;Palomero L;Espín R;Extremera AI;Blommaert E;Revilla-López E;Saez B;Gómez-Ollés S;Ancochea J;Valenzuela C;Alonso T;Ussetti P;Laporta R;Xaubet A;Rodríguez-Portal JA;Montes-Worboys A;Machahua C;Bordas J;Menendez JA;Cruzado JM;Guiteras R;Bontoux C;La Motta C;Noguera-Castells A;Mancino M;Lastra E;Rigo-Bonnin R;Perales JC;Viñals F;Lahiguera A;Zhang X;Cuadras D;van Moorsel CHM;van der Vis JJ;Quanjel MJR;Filippakis H;Hakem R;Gorrini C;Ferrer M;Ugun-Klusek A;Billett E;Radzikowska E;Casanova Á;Molina-Molina M;Roman A;Yanes O;Pujana MA
抑制mTOR是治疗淋巴管平滑肌瘤病（LAM）的标准方法。然而，这种疗法有不同的耐受性，一些患者尽管接受了治疗，但肺功能仍出现进行性下降。由于症状的异质性和非侵入性检查的不足，LAM的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。组胺衍生的主要代谢物甲基咪唑乙酸（MIAA）在LAM血浆中相对更丰富，且MIAA值与VEGF - D无关。较高水平的组胺与较差的肺功能和更大的疾病负担有关。分子和细胞分析以及代谢谱证实了活跃的组胺信号和代谢。经批准的靶向单胺氧化酶A/B（克洛吉林和雷沙吉兰）或组胺H1受体（氯雷他定）的药物可减少LAM的肿瘤发生，氯雷他定可与雷帕霉素协同作用。减少Maoa或Hrh1的表达，以及给予L -组氨酸类似物或低L -组氨酸饮食，也可以减少LAM的肿瘤发生。这些发现扩展了我们对LAM生物学的认识，并提出了改善疾病管理的可能方法。在这项研究中，淋巴血管平滑肌瘤病（LAM）以活跃的组胺代谢和信号传导为特征，这为推进疾病监测和/或治疗开辟了新的机会。
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. In this study, lymphangioleiomyomatosis (LAM) is characterized by active histamine metabolism and signaling, which opens new opportunities for advancing disease monitoring and/or treatment.