Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis.

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...

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Detalhes bibliográficos
Autores: 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
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2021
País:España
Recursos:Fundació Sant Joan de Déu
Repositório:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p19959
Acesso em linha:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=19959
Access Level:Acceso aberto
Palavra-chave:*biomarker
*histamine
*lymphangioleiomyomatosis
*mTOR
*therapy
Descrição
Resumo: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.

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