Sirolimus Decreases Circulating Lymphangioleiomyomatosis Cells in Patients With Lymphangioleiomyomatosis
Sirolimus Decreases Circulating Lymphangioleiomyomatosis Cells in Patients With Lymphangioleiomyomatosis
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DOI：
10.1378/chest.13-1071
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发表时间：
2014-01-01
期刊：
影响因子：
9.6
通讯作者：
Moss, Joel
中科院分区：
文献类型：
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作者：
Cai, Xiong;Pacheco-Rodriguez, Gustavo;Moss, Joel
背景：淋巴管肌瘤病(LAM)是散发性或女性结节性硬化症(TSC)，以囊性肺破坏、淋巴管受累(如乳糜性胸腔积液、淋巴管肌瘤)和肾血管肌脂肪瘤(AML)为特征。LAM的多系统表现似乎是由于LAM细胞的转移性扩散所致，该细胞携带肿瘤抑制基因TSC1或TSC2的失活突变或杂合性丢失(LOH)，从而导致哺乳动物靶标雷帕霉素的过度激活。西罗莫司可以减缓肺功能的下降，减少乳糜液，并缩小AML的大小。本研究的目的是确定西罗莫司对循环LAM细胞的影响。方法：采用密度梯度分离系统从血液中分离细胞，通过离心法从尿液和乳糜液中分离细胞。血细胞与抗CD45-异硫氰酸荧光素(FITC)和抗CD235a-R-藻红蛋白(PE)抗体孵育，尿液和乳糜液细胞与抗CD44v6-FITC和抗CD9-R-PE抗体孵育。结果：治疗前100%的患者血液和75%的尿液标本中均检出伴有TSC2杂合性缺失的LAM细胞。在平均2.2+/-0.4年的西罗莫司治疗期间，LAM细胞在血液(P<；.001)和尿液(P=.003)中的检出率分别显著下降至25%和8%。治疗后，绝经后患者的循环LAM细胞丢失更多(P=0.025)。结论：接受西罗莫司治疗的患者循环LAM细胞的进行性丢失与治疗时间和绝经状态有关。
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.