Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis
Pharmacological targeting of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth in the mouse model of lymphangioleiomyomatosis
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DOI：
10.1152/ajplung.00262.2015
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发表时间：
2015-12-15
影响因子：
4.9
通讯作者：
Krymskaya, Vera P.
中科院分区：
文献类型：
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作者：
Atochina-Vasserman, Elena N.;Abramova, Elena;Krymskaya, Vera P.
肺淋巴管肌瘤病(LAM)是一种罕见的进行性肺部疾病，与结节性硬化症2(TSC2)肿瘤抑制基因突变相关，表现为LAM细胞肿瘤性生长，诱导囊性肺破坏和呼吸衰竭。LAM的严重程度与血清中促淋巴管生成血管内皮生长因子D(VEGF-D)的上调有关，这是LAM与其他囊性疾病的区别。我们研究的目的是确定TSC2缺乏是否上调了VEGF-D，以及食品和药物管理局批准的血管内皮生长因子受体(VEGFR)小分子抑制剂阿西替尼是否会减少LAM小鼠模型中TSC2缺失的肺病变的生长。我们的数据显示，在TSC2缺失的小鼠的血清和肺衬里中，血管内皮生长因子-D的表达上调。TSC2缺失病变的进行性生长诱导炎症细胞的募集和激活，并增加一氧化氮的产生。从TSC2缺失病变的小鼠肺衬里分离的招募细胞显示促血管生成VEGFA、促淋巴管生成FIGF和促炎NOS2、IL6和CCL2基因表达上调。重要的是，Axitinib是一种有效的抑制TSC2缺失性病变生长和炎性细胞募集的药物，这与血清和肺衬里中VEGF-D水平的降低有关。我们的数据表明，用Axitinib药物抑制VEGFR信号可以抑制TSC2缺失病变的生长，减弱炎症细胞的募集和激活，并降低全身和肺内血管内皮生长因子-D的水平。我们的研究表明，抑制VEGFR信号对LAM的治疗有潜在的治疗益处。
Pulmonary lymphangioleiomyomatosis (LAM), a rare progressive lung disease associated with mutations of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene, manifests by neoplastic growth of LAM cells, induction of cystic lung destruction, and respiratory failure. LAM severity correlates with upregulation in serum of the prolymphangiogenic vascular endothelial growth factor D (VEGF-D) that distinguishes LAM from other cystic diseases. The goals of our study was to determine whether Tsc2 deficiency upregulates VEGF-D, and whether axitinib, the Food and Drug Administration-approved small-molecule inhibitor of VEGF receptor (VEGFR) signaling, will reduce Tsc2-null lung lesion growth in a mouse model of LAM. Our data demonstrate upregulation of VEGF-D in the serum and lung lining in mice with Tsc2-null lesions. Progressive growth of Tsc2-null lesions induces recruitment and activation of inflammatory cells and increased nitric oxide production. Recruited cells isolated from the lung lining of mice with Tsc2-null lesions demonstrate upregulated expression of provasculogenic Vegfa, prolymphangiogenic Figf, and proinflammatory Nos2, Il6, and Ccl2 genes. Importantly, axitinib is an effective inhibitor of Tsc2-null lesion growth and inflammatory cell recruitment, which correlates with reduced VEGF-D levels in serum and lung lining. Our data demonstrate that pharmacological inhibition of VEGFR signaling with axitinib inhibits Tsc2-null lesion growth, attenuates recruitment and activation of inflammatory cells, and reduces VEGF-D levels systemically and in the lung lining. Our study suggests a potential therapeutic benefit of inhibition of VEGFR signaling for treatment of LAM.