Histamine signaling and metabolism identify potential biomarkers and therapies for lymphangioleiomyomatosis

Inhibition of mTOR is the standard of care for lymphangioleiomy-omatosis (LAM). However, this therapy has variable tolerability andsome patients show progressive decline of lung function despitetreatment. LAM diagnosis and monitoring can also be challengingdue to the heterogeneity of symptoms and insufficiency of non-invasive tests. Here, we propose monoamine-derived biomarkersthat provide preclinical evidence for novel therapeutic approaches.The major histamine-derived metabolite methylimidazoleaceticacid (MIAA) is relatively more abundant in LAM plasma, and MIAAvalues are independent of VEGF-D. Higher levels of histamine areassociated with poorer lung function and greater disease burden.Molecular and cellular analyses, and metabolic profiling confirmedactive histamine signaling and metabolism. LAM tumorigenesis isreduced using approved drugs targeting monoamine oxidases A/B(clorgyline and rasagiline) or histamine H1 receptor (loratadine),and loratadine synergizes with rapamycin. Depletion of Maoa orHrh1 expression, and administration of an L-histidine analog, or alow L-histidine diet, also reduce LAM tumorigenesis. These findingsextend our knowledge of LAM biology and suggest possible ways ofimproving disease management.