Interleukin-6 overexpression induces pulmonary hypertension.
Interleukin-6 overexpression induces pulmonary hypertension.
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DOI：
10.1161/circresaha.108.182014
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发表时间：
2009-01-30
影响因子：
20.1
通讯作者：
Waxman AB
中科院分区：
文献类型：
--
作者：
Steiner MK;Syrkina OL;Kolliputi N;Mark EJ;Hales CA;Waxman AB
炎性细胞因子IL-6在肺动脉高压（PAH）患者的血清和肺中升高。PAH的几种动物模型引用了炎症介质的潜在作用。我们研究了IL-6在肺血管疾病发病机制中的作用。在肺特异性IL-6过表达转基因小鼠（Tg（+））中测量肺血管重塑指数，并与正常氧和慢性低氧条件下的野生型（Tg（-））对照进行比较。Tg（+）小鼠表现出右心室收缩压升高和右心室肥大，并伴有相应的肺血管病变，所有这些都因慢性缺氧而加重。IL-6过度表达增加近端动脉树的肌化，缺氧增强了这种作用。它还再现了PAH患者远端小动脉血管中观察到的肌化和增生性动脉病。后者的特征是形成闭塞性新生内膜血管增生性病变，该病变随着缺氧而恶化，由内皮细胞和T淋巴细胞组成。IL-6诱导的动脉病变变化伴随着促血管生成因子、血管内皮生长因子、促增殖激酶、ERK、促增殖转录因子c-MYC和MAX、抗凋亡蛋白生存素和Bcl-2的激活，以及生长抑制剂转化生长因子-β和促凋亡激酶JNK和p38的下调。这些结果表明，IL-6通过促增殖抗凋亡机制促进肺血管重塑和PAH的发展和进展。
Inflammatory cytokine IL-6 is elevated in the serum and lungs of patients with pulmonary artery hypertension (PAH). Several animal models of PAH cite the potential role of inflammatory mediators. We investigated IL-6’s role in the pathogenesis of pulmonary vascular disease. Indices of pulmonary vascular remodeling were measured in lung specific IL-6 over expression transgenic mice (Tg(+)) and compared to wild type (Tg(-)) controls in both normoxic and chronic hypoxic conditions. The Tg(+) mice exhibited elevated right ventricular systolic pressures and right ventricular hypertrophy with corresponding pulmonary vasculopathic changes, all of which were exacerbated by chronic hypoxia. IL-6 overexpression increased muscularization of the proximal arterial tree, and hypoxia enhanced this effect. It also reproduced the muscularization and proliferative arteriopathy seen in the distal arteriolar vessels of PAH patients. The latter was characterized by the formation of occlusive neointimal angioproliferative lesions that worsened with hypoxia and were composed of endothelial cells and T-lymphocytes. IL-6-induced arteriopathic changes were accompanied by activation of pro-angiogenic factor, vascular endothelial growth factor, the pro-proliferative kinase, ERK, pro-proliferative transcription factors c-MYC and MAX, the anti-apoptotic proteins survivin and Bcl-2, and down-regulation of the growth inhibitor transforming growth factor-β, and pro-apoptotic kinases JNK and p38. These findings suggest that IL-6 promotes the development and progression of pulmonary vascular remodeling and PAH through pro-proliferative anti-apoptotic mechanisms.