Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

Autor: Carmen Herranz, Francesca Mateo, Alexandra Baiges, Gorka Ruiz de Garibay, Alexandra Junza, Simon R Johnson, Suzanne Miller, Nadia García, Jordi Capellades, Antonio Gómez, August Vidal, Luis Palomero, Roderic Espín, Ana I Extremera, Eline Blommaert, Eva Revilla‐López, Berta Saez, Susana Gómez‐Ollés, Julio Ancochea, Claudia Valenzuela, Tamara Alonso, Piedad Ussetti, Rosalía Laporta, Antoni Xaubet, José A Rodríguez‐Portal, Ana Montes‐Worboys, Carlos Machahua, Jaume Bordas, Javier A Menendez, Josep M Cruzado, Roser Guiteras, Christophe Bontoux, Concettina La Motta, Aleix Noguera‐Castells, Mario Mancino, Enrique Lastra, Raúl Rigo‐Bonnin, Jose C Perales, Francesc Viñals, Alvaro Lahiguera, Xiaohu Zhang, Daniel Cuadras, Coline H M vanMoorsel, Joanne J van derVis, Marian J R Quanjel, Harilaos Filippakis, Razq Hakem, Chiara Gorrini, Marc Ferrer, Aslihan Ugun‐Klusek, Ellen Billett, Elżbieta Radzikowska, Álvaro Casanova, María Molina‐Molina, Antonio Roman, Oscar Yanes, Miquel A Pujana
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 13, Iss 9, Pp n/a-n/a (2021)
Druh dokumentu: article
ISSN: 1757-4684
1757-4676
20211392
DOI: 10.15252/emmm.202113929
Popis: Abstract 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.
Databáze: Directory of Open Access Journals
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