Chest
Original ResearchDiffuse Lung DiseaseSirolimus Decreases Circulating Lymphangioleiomyomatosis Cells in Patients With Lymphangioleiomyomatosis
Section snippets
Study Design
Twenty-three patients with LAM were enrolled between 2007 and 2012 at the National Institutes of Health (NIH) Clinical Center in clinical protocols (95-H-0186; 96-H-0100) approved by the National Heart, Lung, and Blood Institute Institutional Review Board. The diagnosis of LAM was based on clinical, radiographic, and histopathologic findings. Patients with only high-resolution CT scan-compatible cystic disease were not judged to have LAM, unless a biopsy specimen was obtained or the patients
Results
Twenty-three patients with LAM who fit the study inclusion criteria were enrolled between 2007 and 2012 at the NIH Clinical Center. Baseline demographic and clinical characteristics are shown in Table 1. Samples of blood, urine, and chylous effusions were collected at NIH before and during sirolimus therapy. Sirolimus was prescribed by local physicians and the dose adjusted to maintain serum levels between 5 and 15 ng/mL. Cells from blood, chylous effusions, and urine were sorted on the basis
Discussion
We studied the effect of sirolimus on phenotypically distinct circulating LAM cells. Patients treated with sirolimus had a decrease in circulating LAM cells in blood, chylous effusions, and urine that depended on time of treatment and the hormonal status of the patient. The LAM cells were identified by LOH in the tumor suppressor gene TSC2. This assay was used because nucleotide polymorphisms flanking the tumor suppressor gene, which were the basis for the LOH determinations, were shown
Acknowledgments
Author contributions: Drs Cai, Pacheco-Rodriguez, Stylianou, and Moss had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Dr Cai: contributed to carrying out the research, analyzing the data, and writing the manuscript.
Dr Pacheco-Rodriguez: contributed to the research design, sample preparation, and writing of the manuscript.
Ms Haughey: contributed to the patient recruitment, data analysis, and review of the
References (18)
- et al.
Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM)
J Biol Chem
(2002) - et al.
mTOR signaling in growth control and disease
Cell
(2012) - et al.
TOR, a central controller of cell growth
Cell
(2000) - et al.
The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment
Am J Respir Crit Care Med
(2006) - et al.
Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis
Proc Natl Acad Sci U S A
(2000) - et al.
The TSC1-TSC2 complex: a molecular switchboard controlling cell growth
Biochem J
(2008) - et al.
Rapamycin passes the torch: a new generation of mTOR inhibitors
Nat Rev Drug Discov
(2011) - et al.
Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis
N Engl J Med
(2008) - et al.
Efficacy and safety of sirolimus in lymphangioleiomyomatosis
N Engl J Med
(2011)
Cited by (35)
Genetic diffuse cystic lung disease in adults
2024, Revue des Maladies RespiratoiresLymphangioleiomyomatosis
2023, Presse MedicalePulmonary Langerhans Cell Histiocytosis and Lymphangioleiomyomatosis Have Circulating Cells With Loss of Heterozygosity of the TSC2 Gene
2022, ChestCitation Excerpt :This study was approved by the Institute’s Institutional Review Board, and written informed consent was obtained from each subject prior to enrollment in the study (CE/CE/85/2014/LDC Prot.141/2014). Blood and, when available, urine samples were collected the same day and processed as previously described.12,24 Blood samples were processed within 2 h after collection using OncoQuick (Greiner Bio-One) columns per the manufacturer’s recommendations.
A More Hopeful Path to the Future in Lymphangioleiomyomatosis Patients: Sirolimus
2020, Open Respiratory ArchivesQuantitative analysis of computed tomography of the lungs in patients with lymphangioleiomyomatosis treated with sirolimus
2020, HeliyonCitation Excerpt :Hyperactivated mTOR pathways result in plumpy and large cells. On the other hand, sirolimus impedes lymphangiogenesis and inhibits function of lymphatic endothelial cells [26], and also has been reported to decrease circulating LAM cells in blood and serum VEGF-D concentrations [5, 27]. These actions of sirolimus seem to clear lymphatic congestion in the lungs [28], reduce or eliminate chylous effusion [4, 29], and shrink lymphangioleiomyomas [29].
Dr Cai is currently at the School of Pharmaceutical Sciences, Nanjing University of Chinese Medicine (Nanjing, Jiangsu, China).
Funding/Support: This study was funded in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute [to Dr Moss], and R01-AR062080 [to Dr Darling].
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.