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Original Research: Diffuse Lung Disease |

Sirolimus Decreases Circulating Lymphangioleiomyomatosis Cells in Patients With LymphangioleiomyomatosisSirolimus Decreases Circulating LAM Cells

Xiong Cai, PhD; Gustavo Pacheco-Rodriguez, PhD; Mary Haughey, RN, BSN; Leigh Samsel, MS; Suowen Xu, PhD; Hai-Ping Wu, BS; J. Philip McCoy, PhD; Mario Stylianou, PhD; Thomas N. Darling, MD, PhD; Joel Moss, MD, PhD, FCCP
Author and Funding Information

From the Cardiovascular and Pulmonary Branch (Drs Cai, Pacheco-Rodriguez, Xu, and Moss and Mss Haughey and Wu), Flow Cytometry Core Facility (Ms Samsel and Dr McCoy), and Office of Biostatistics Research, Division of Cardiovascular Science (Dr Stylianou), National Heart, Lung, and Blood Institute, National Institutes of Health; and the Department of Dermatology (Dr Darling), Uniformed Services University of the Health Sciences, Bethesda, MD.

Correspondence to: Joel Moss, MD, PhD, FCCP, Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bldg 10, Room 6D05, MSC-1590, 9000 Rockville Pike, Bethesda, MD 20892-1590; e-mail: mossj@nhlbi.nih.gov


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.


Chest. 2014;145(1):108-112. doi:10.1378/chest.13-1071
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Background:  Lymphangioleiomyomatosis (LAM), sporadic or in women with tuberous sclerosis complex (TSC), is characterized by cystic lung destruction, lymphatic involvement (eg, chylous pleural effusions, lymphangioleiomyomas), and renal angiomyolipomas (AMLs). The multisystem manifestations of LAM appear to result from metastatic dissemination of LAM cells bearing inactivating mutations or having loss of heterozygosity (LOH) of the tumor suppressor genes TSC1 or TSC2, which leads to hyperactivation of the mammalian target of rapamycin. Sirolimus slows the decline of lung function, reduces chylous effusions, and shrinks the size of AMLs. The purpose of this study was to determine the effect of sirolimus on circulating LAM cells.

Methods:  Cells from blood were isolated by a density-gradient fractionation system and from urine and chylous effusions by centrifugation. Blood cells were incubated with anti-CD45-fluorescein isothiocyanate (FITC) and anti-CD235a-R-phycoerythrin (PE) antibodies, and urine and chylous effusion cells were incubated with anti-CD44v6-FITC and anti-CD9-R-PE antibodies. Cells were sorted and analyzed for TSC2 LOH.

Results:  LAM cells with TSC2 LOH were identified in 100% of blood specimens and 75% of urine samples from patients before therapy. Over a mean duration of 2.2 ± 0.4 years of sirolimus therapy, detection rates of LAM cells were significantly decreased to 25% in blood (P < .001) and 8% in urine (P = .003). Following therapy, a greater loss of circulating LAM cells was seen in postmenopausal patients (P = .025).

Conclusions:  Patients receiving sirolimus had a progressive loss of circulating LAM cells that depended on time of treatment and menopausal status.

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