Open AccessHistamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis
Author(s) -
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,
RevillaLópez Eva,
Saez Berta,
GómezOllés Susana,
Ancochea Julio,
Valenzuela Claudia,
Alonso Tamara,
Ussetti Piedad,
Laporta Rosalía,
Xaubet Antoni,
RodríguezPortal José A,
MontesWorboys Ana,
Machahua Carlos,
Bordas Jaume,
Menendez Javier A,
Cruzado Josep M,
Guiteras Roser,
Bontoux Christophe,
La Motta Concettina,
NogueraCastells Aleix,
Mancino Mario,
Lastra Enrique,
RigoBonnin Raúl,
Perales Jose C,
Viñals 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,
UgunKlusek Aslihan,
Billett Ellen,
Radzikowska Elżbieta,
Casanova Álvaro,
MolinaMolina María,
Roman Antonio,
Yanes Oscar,
Pujana Miquel A
Publication year - 2021
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202113929
Subject(s) - lymphangioleiomyomatosis , histamine , pharmacology , medicine , aprepitant , tolerability , biology , cancer research , bioinformatics , lung , antiemetic , vomiting , adverse effect
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.