Expression of HIF-1A/VEGF/ING-4 Axis in Pulmonary Sarcoidosis
Expression of HIF-1A/VEGF/ING-4 Axis in Pulmonary Sarcoidosis
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DOI：
10.1007/5584_2015_144
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发表时间：
2015-01-01
期刊：
影响因子：
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通讯作者：
Brzezianska-Lasota, E.
中科院分区：
文献类型：
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作者：
Piotrowski, W. J.;Kiszalkiewicz, J.;Brzezianska-Lasota, E.
缺氧诱导因子-1A（HIF-1A）/血管内皮生长因子（VEGF）/生长蛋白抑制因子-4（ING-4）轴调控的血管生成/血管抑制可能对结节病的病程和预后至关重要。血管生成因子的过度表达（通过HIF-1A激活VEGF）可能易患慢性病程和肺纤维化，而免疫血管抑制（与抑制性ING-4的过度表达有关）可能参与早期结节病炎症的肉芽肿形成，或肉芽肿的持续或复发形成。在这项工作中，我们调查了HIF-1A，VEGF和ING-4的基因表达在支气管肺泡液（BALF）细胞和外周血（PB）淋巴细胞的结节病患者（n = 94），以更好地了解疾病的机制，并寻找其生物标志物。通过qPCR分析相对基因表达水平（RQ值）。根据是否存在肺实质受累（放射学I期与II-IV期）、急性与隐匿性发作、肺功能检查、钙代谢参数、BALF中淋巴细胞百分比（BALL %）和BAL CD 4（+）/CD 8（+）、年龄和性别对结果进行评价。在BALF细胞中，ING-4和VEGF RQ值增加，而HIF-1A表达减少。在PB淋巴细胞中，所有研究的基因都过表达。肺功能异常患者外周血淋巴细胞、肺容量受限患者BALF细胞中HIF-1A表达增高，肺功能异常患者BALF细胞中VEGF基因表达增高。这些发现与以前关于HIF-1A/VEGF/ING-4轴在结节病发病机制中的作用的数据一致。HIF-1A和VEGF基因的上调与公认的负性免疫反应有关。
Angiogenesis/angiostasis regulated by hypoxia inducible factor-1A (HIF-1A)/vascular endothelial growth factor (VEGF)/inhibitor of growth protein 4 (ING-4) axis may be crucial for the course and outcome of sarcoidosis. Overexpression of angiogenic factors (activation of VEGF through HIF-1A) may predispose to chronic course and lung fibrosis, whereas immunoangiostasis (related to an overexpression of inhibitory ING-4) may be involved in granuloma formation in early sarcoid inflammation, or sustained or recurrent formation of granulomas. In this work we investigated gene expression of HIF-1A, VEGF and ING-4 in bronchoalveolar fluid (BALF) cells and in peripheral blood (PB) lymphocytes of sarcoidosis patients (n = 94), to better understand mechanisms of the disease and to search for its biomarkers. The relative gene expression level (RQ value) was analyzed by qPCR. The results were evaluated according to the presence of lung parenchymal involvement (radiological stage I vs. II-IV), acute vs. insidious onset, lung function tests, calcium metabolism parameters, percentage of lymphocytes (BALL %) and BAL CD4(+)/CD8(+) in BALF, age, and gender. In BALF cells, the ING-4 and VEGF RQ values were increased, while HIF-1A expression was decreased. In PB lymphocytes all studied genes were overexpressed. Higher expression of HIF-1A in PB lymphocytes of patients with abnormal spirometry, and in BALF cells of patients with lung volume restriction was found. VEGF gene expression in BALF cells was also higher in patients with abnormal spirometry. These findings were in line with previous data on the role of HIF-1A/VEGF/ING-4 axis in the pathogenesis of sarcoidosis. Up-regulated HIF-1A and VEGF genes are linked to acknowledged negative prognostics.