Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis.
Clinical features, epidemiology, and therapy of lymphangioleiomyomatosis.
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DOI：
10.2147/clep.s50780
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发表时间：
2015
影响因子：
3.9
通讯作者：
Moss J
中科院分区：
文献类型：
--
作者：
Taveira-DaSilva AM;Moss J
淋巴管肌瘤病(LAM)是女性的一种多系统疾病，以异常的平滑肌样LAM细胞增殖为特征，导致肺囊肿、轴淋巴管内充满液体的囊性结构(如淋巴管肌瘤)和肾血管肌脂肪瘤。LAM是由TSC1或TSC2基因突变引起的，这两个基因分别编码Hamartin和Tuberin，这两种蛋白质在哺乳动物雷帕霉素靶标(MTOR)信号通路中起主要作用。LAM零星发生或与结节硬化症相关，结节硬化症是一种常染色体显性遗传综合征，以广泛的错构瘤病变为特征。LAM可表现为进行性呼吸困难、复发性气胸或乳糜胸。肺功能测试显示流速(第一秒用力呼气量)和弥散能力降低。运动试验可发现气体交换异常、呼吸受限和低氧血症。疾病的严重程度和进展可以通过肺组织学评分、计算机断层扫描量化、肺功能测试、6分钟步行试验、心肺运动试验和血清血管内皮生长因子D水平的测量来评估。西罗莫司和伊波利莫斯是两种mTOR抑制剂，在稳定肺功能和减少乳糜液、淋巴管肌瘤和血管肌脂肪瘤方面有效。然而，抑制mTOR复合体1会增加自噬，可能会提高LAM细胞的存活率。羟基氯喹联合西罗莫司抑制自噬是治疗LAM的一种可能方法。缺乏tuberin会导致RhoA GTPase活性增加和细胞存活，这一效应是通过mTOR复合体2信号介导的。由于西罗莫司和伊维洛莫司只影响mTOR复合体1的活性，针对RhoA GTP酶的辛伐他汀治疗正在研究中，辛伐他汀可以抑制Rho GTP酶并促进细胞凋亡。就像癌症一样，LAM可能最好使用多种药物来治疗，这些药物针对的是被认为在疾病发病机制中至关重要的信号通路。
Lymphangioleiomyomatosis (LAM) is a multisystem disease of women, characterized by proliferation of abnormal smooth muscle-like LAM cells, leading to the formation of lung cysts, fluid-filled cystic structures in the axial lymphatics (eg, lymphangioleiomyomas), and renal angiomyolipomas. LAM is caused by mutations of the TSC1 or TSC2 genes, which encode, respectively, hamartin and tuberin, two proteins with a major role in control of the mammalian target of rapamycin (mTOR) signaling pathway. LAM occurs sporadically or in association with tuberous sclerosis complex, an autosomal-dominant syndrome characterized by widespread hamartomatous lesions. LAM may present with progressive dyspnea, recurrent pneumothorax, or chylothorax. Pulmonary function tests show reduced flow rates (forced expiratory volume in the first second) and diffusion capacity. Exercise testing may reveal gas exchange abnormalities, ventilatory limitation, and hypoxemia. The severity and progression of disease may be assessed by lung histology scores, quantification of computed tomography, pulmonary function testing, 6-minute walk tests, cardiopulmonary exercise testing, and measurement of serum vascular endothelial growth factor D levels. Sirolimus and everolimus, two mTOR inhibitors, are effective in stabilizing lung function and reducing the size of chylous effusions, lymphangioleiomyo-mas, and angiomyolipomas. However, inhibition of mTOR complex 1 increases autophagy, possibly enhancing LAM cell survival. Inhibition of autophagy with hydroxychloroquine, in combination with sirolimus, has been proposed as a possible treatment for LAM. Deficiency of tuberin results in increased RhoA GTPase activity and cell survival, an effect that is mediated through mTOR complex 2 signaling. Because sirolimus and everolimus only affect the activity of mTOR complex 1, therapies targeting RhoA GTPases with simvastatin, which inhibits Rho GTPases and promotes apoptosis, are being investigated. As in the case of cancer, LAM may be best treated with multiple drugs targeting signaling pathways considered important in the pathogenesis of disease.