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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Detalles Bibliográficos
Autores: Herranz, Carmen, Mateo González, Francesca, Baiges, Alexandra, Ruiz de Garibay, Gorka, Junza Martínez, Alexandra, Johnson, Simon R, Miller, Suzanne, García, Nadia, Capellades, Jordi, Gómez, Antonio, Vidal, August, Palomero, Luis, Espín, Roderic, Extremera, Ana I., Blommaert, Eline, Revilla López, Eva, Saez, Berta, Gómez Ollés, Susana, Ancochea, Julio, Valenzuela, Claudia, Alonso, Tamara, Ussetti, María Piedad, Laporta, Rosalía, Xaubet Mir, Antonio, Rodríguez Portal, Jose Antonio, Montes Worboys, Ana, Machahua, Carlos, Bordas Martínez, Jaume, Menendez, Javier A., Cruzado, Josep Ma., Guiteras, Roser, Bontoux, Christophe, La Motta, Concettina, Noguera Castells, Aleix, Mancino, Mario, Lastra, Enrique, Rigo Bonnin, Raúl, Perales, Jose C., Viñals Canals, Francesc, Lahiguera, Alvaro, Zhang, Xiaohu, Cuadras, Daniel, Moorsel, Coline H. M., Vis, Joanne J., Quanjel, Marian J. R., Filippakis, Harilaos, Hakem, Razq, Gorrini, Chiara, Ferrer, Marc, Ugun Klusek, Aslihan, Billett, Ellen, Radzikowska, Elżbieta, Casanova, Álvaro, Molina Molina, María, Roman, Antonio, Yanes, Oscar, Pujana Genestar, M. Ángel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/179910
Acceso en línea:https://hdl.handle.net/2445/179910
Access Level:acceso abierto
Palabra clave:Marcadors bioquímics
Histamina
Terapèutica
Biochemical markers
Histamine
Therapeutics
Descripción
Sumario: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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