Lymphangioleiomyomatosis (LAM) is a rare lung disease, linked to Tuberous Sclerosis Complex (TSC) or occurring sporadically, and involves abnormal mTORC1 activation. LAM cells are neoplastic, and recent focus has turned to extracellular vesicles (EVs), which mediate tumor progression and may serve as biomarkers. This study, conducted at the Pulmonology Unit of ASST Santi Paolo e Carlo and the Pharmacology Laboratory of the University of Milan, will analyze the characteristics of serum EVs in patients with LAM and TSC. During scheduled outpatient visits, clinical and functional data and blood samples will be collected. Plasma will be separated, and EVs will be isolated via centrifugation. EVs will be analyzed for size, concentration, and molecular content (proteins, lipids, nucleic acids). The results obtained will be collected and correlated with the clinical and functional data.
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Female participants aged ≥18 years with a confirmed diagnosis of tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), followed at the Pulmonology Unit of ASST Santi Paolo e Carlo, Milan, and able to provide written informed consent.
Other
Cross-sectional
Pulmonary Function Test
Diagnostic testSpirometry, Plethysmography, Diffusing capacity of the lungs for carbon monoxide (DLCO), and Six-minute walk test (6MWT).
Analysis of Extracellular Vesicles
Diagnostic testFrom the venous blood sample, plasma will be separated, and extracellular vesicles (EVs) will be isolated through serial centrifugation steps. The EVs will be analyzed to assess their concentration (particles/mL) and size (nanometers, nm). Additionally, omics analyses will be performed to study the molecular content of the EVs, including nucleic acids, proteins, and lipids.
To compare the number and morphological characteristics of Extracellular Vesicles (EVs) in women with S-LAM, TSC-LAM, TSC without pulmonary involvement, and healthy controls
The concentration (particles/mL) and the size (nm) of EVs isolated from the plasma of 3 groups of patients (sporadic LAM, LAM associated to TSC, TSC without pulmonary involvement) and of 1 healthy control group will be assessed through Nanoparticle Tracking Analysis.
To evaluate the content of EVs (miRNA, lipids, proteins, metabolites) through omics analyses in women with S-LAM, TSC-LAM, TSC without pulmonary involvement, and healthy controls
The content of EVs isolated from the plasma of 3 groups of patients (plasma of 3 groups of patients (sporadic LAM, LAM associated to TSC, TSC without pulmonary involvement) and of 1 healthy control group will be assessed through -omics analyses.
Effect of mTOR-inhibitor therapy on EVs count
The concentration (particles/mL) of extracellular vesicles (EVs) in patients with LAM treated with mTOR inhibitor therapy (sirolimus or everolimus) compared with patients not receiving mTOR inhibitor therapy will be assessed using Nanoparticle Tracking Analysis (NTA).
Effect of mTOR-inhibitor therapy on EVs morphology
The size (nanometers, nm) of extracellular vesicles (EVs) in patients with LAM treated with mTOR inhibitor therapy (sirolimus or everolimus) compared with patients not receiving mTOR inhibitor therapy will be assessed using Electron Microscopy (EM).
Association between EVs characteristics and disease severity
The concentration (particles/mL) and size (nanometers, nm) of extracellular vesicles (EVs) isolated from the plasma of patients with S-LAM, TSC-LAM, and TSC without pulmonary involvement will be analyzed for their association with disease severity, as assessed by the number of systemic manifestations of TSC and the presence of pulmonary disease.
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