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, Francesca, Baiges, Alexandra, Ruiz de Garibay, Gorka, Junza, 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, Sáez, Berta, Gómez-Ollés, Susana, Ancochea, Julio, Valenzuela, Claudia, Alonso, Tamara, Ussetti, Piedad, Laporta, Rosalía, Xaubet, Antoni, Rodríguez-Portal, José A., Montes-Worboys, Ana, Machahua, Carlos, Bordas, Jaume, Menéndez, Javier A., Cruzado, Josep M., Guiteras, Roser, Bontoux, Christophe, La Motta, Concettina, Noguera-Castells, Aleix, Mancino, Mario, Lastra, Enrique, Rigo-Bonnin, Raúl, Perales, José C., Viñals, Francesc, Lahiguera, Álvaro, Zhang, Xiaohu, Cuadras, Daniel, Moorsel, Coline H. M. van, Vis, Joanne J. van der, Quanjel, Marian J. R., Filippakis, Harilaos, Hakem, Razq, Gorrini, Chiara, Ferrer, Marc, Ugun-Klusek, Aslihan, Billett, Ellen, Radzikowska, Elżbieta, Casanova, Álvaro, Molina-Molina, María, Román, Antonio, Yanes, Óscar, Pujana, Miguel Ángel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/265901
Acceso en línea:http://hdl.handle.net/10261/265901
Access Level:acceso abierto
Palabra clave:Biomarkers
Histamine
Lymphangioleiomyomatosis
mTOR
Therapy
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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