Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dubé syndrome.
Haploinsufficiency of the folliculin gene leads to impaired functions of lung fibroblasts in patients with Birt-Hogg-Dubé syndrome.
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DOI：
10.14814/phy2.13025
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发表时间：
2016-11
影响因子：
2.5
通讯作者：
Seyama K
中科院分区：
文献类型：
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作者：
Hoshika Y;Takahashi F;Togo S;Hashimoto M;Nara T;Kobayashi T;Nurwidya F;Kataoka H;Kurihara M;Kobayashi E;Ebana H;Kikkawa M;Ando K;Nishino K;Hino O;Takahashi K;Seyama K
Birt-Hogg-Dubé综合征（BHDS）是由FLCN基因的种系突变引起的常染色体显性遗传疾病，其特征在于皮肤纤维毛囊瘤、多发性肺囊肿、自发性气胸和肾肿瘤。肺部表现经常比其他器官受累更早出现，提示BHDS的诊断。但是，肺囊肿的形成机制和气胸的发病机制尚未阐明。成纤维细胞分离自BHDS患者（n = 12）和作为对照的肺癌患者（n = 10）的肺组织。通过对纤连蛋白的趋化性和三维（3-D）凝胶收缩试验评价这些肺成纤维细胞的功能能力。与对照组相比，BHDS患者的成纤维细胞趋化性降低。当通过qPCR评估时，BHDS成纤维细胞中纤连蛋白和TGF-β1的表达显著降低。在BHDS肺成纤维细胞培养基中加入TGF-β1可显著恢复这些细胞的趋化和凝胶收缩能力。当FLCN表达被敲低时，人胎肺成纤维细胞（HFL-1）表现出减少的趋化性和3-D凝胶收缩。相反，当野生型FLCN过表达时，对纤连蛋白的趋化活性显着增加，而突变FLCN的转导对趋化性没有影响。我们的结果表明FLCN与肺成纤维细胞的趋化性有关。连同BHDS肺成纤维细胞的TGF-β1表达减少，FLCN单倍不足状态可能导致肺成纤维细胞功能障碍，从而损害组织修复。这可能揭示了BHDS患者肺囊肿形成和气胸发生的机制之一。
Birt–Hogg–Dubé syndrome (BHDS) is an autosomal dominant inherited disorder caused by germline mutations in the FLCN gene, and characterized by skin fibrofolliculomas, multiple lung cysts, spontaneous pneumothorax, and renal neoplasms. Pulmonary manifestations frequently develop earlier than other organ involvements, prompting a diagnosis of BHDS. However, the mechanism of lung cyst formation and pathogenesis of pneumothorax have not yet been clarified. Fibroblasts were isolated from lung tissues obtained from patients with BHDS (n = 12) and lung cancer (n = 10) as controls. The functional abilities of these lung fibroblasts were evaluated by the tests for chemotaxis to fibronectin and three‐dimensional (3‐D) gel contraction. Fibroblasts from BHDS patients showed diminished chemotaxis as compared with fibroblasts from controls. Expression of fibronectin and TGF‐β1 was significantly reduced in BHDS fibroblasts when assessed by qPCR. Addition of TGF‐β1 in culture medium of BHDS lung fibroblasts significantly restored these cells' abilities of chemotaxis and gel contraction. Human fetal lung fibroblasts (HFL‐1) exhibited reduced chemotaxis and 3‐D gel contraction when FLCN expression was knocked down. To the contrary, a significant increase in chemotactic activity toward to fibronectin was demonstrated when wild‐type FLCN was overexpressed, whereas transduction of mutant FLCN showed no effect on chemotaxis. Our results suggest that FLCN is associated with chemotaxis in lung fibroblasts. Together with reduced TGF‐β1 expression by BHDS lung fibroblasts, a state of FLCN haploinsufficiency may cause lung fibroblast dysfunction, thereby impairing tissue repair. These may reveal one mechanism of lung cyst formation and pneumothorax in BHDS patients.