Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis
Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis
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DOI：
10.1111/bph.13947
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发表时间：
2017-10-01
影响因子：
7.3
通讯作者：
Karmouty-Quintana, Harry
中科院分区：
文献类型：
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作者：
Collum, Scott D.;Chen, Ning-Yuan;Karmouty-Quintana, Harry
背景和目的III组肺动脉高压(PH)是一种高度致命性和广泛性的肺部疾病，是特发性肺纤维化(IPF)的常见并发症，被认为是唯一最重要的死亡率预测因子。虽然在IPF患者中观察到了透明质酸水平的升高，但与IPF相关的透明质酸介导的血管重构和透明质酸介导的促进PH的机制尚不完全清楚。此外，采用肺纤维化和PH的实验模型，检测透明质酸合成酶抑制剂4-甲基优贝利酮(4MU)对PH的抑制作用。利用人肺血管平滑肌细胞(PASMC)研究了透明质酸导致肺纤维化相关肺高压发生的机制。结果发现，肺纤维化和肺纤维化患者肺组织透明质酸水平升高，透明质酸合成酶基因表达增加。有趣的是，我们还报告了IPF和IPF合并PH患者的透明质酸酶水平升高。值得注意的是，我们的数据还表明，在我们的模型中，4MU能够预防或治疗地抑制PH，而不影响纤维化。对透明质酸特异性机制的研究表明，透明质酸片段以一种RhoA依赖的方式导致PASMC僵硬和增殖增加，但细胞运动性降低。结论结合我们的结果，我们的结果显示了在肺纤维化背景下导致肺高压的独特机制的证据。
BACKGROUND AND PURPOSEGroup III pulmonary hypertension (PH) is a highly lethal and widespread lung disorder that is a common complication in idiopathic pulmonary fibrosis (IPF) where it is considered to be the single most significant predictor of mortality. While increased levels of hyaluronan have been observed in IPF patients, hyaluronan-mediated vascular remodelling and the hyaluronan-mediated mechanisms promoting PH associated with IPF are not fully understood.EXPERIMENTAL APPROACHExplanted lung tissue from patients with IPF with and without a diagnosis of PH was used to identify increased levels of hyaluronan. In addition, an experimental model of lung fibrosis and PH was used to test the capacity of 4-methylumbeliferone (4MU), a hyaluronan synthase inhibitor to attenuate PH. Human pulmonary artery smooth muscle cells (PASMC) were used to identify the hyaluronan-specific mechanisms that lead to the development of PH associated with lung fibrosis.KEY RESULTSIn patients with IPF and PH, increased levels of hyaluronan and expression of hyaluronan synthase genes are present. Interestingly, we also report increased levels of hyaluronidases in patients with IPF and IPF with PH. Remarkably, our data also show that 4MU is able to inhibit PH in our model either prophylactically or therapeutically, without affecting fibrosis. Studies to determine the hyaluronan-specific mechanisms revealed that hyaluronan fragments result in increased PASMC stiffness and proliferation but reduced cell motility in a RhoA-dependent manner.CONCLUSIONS AND IMPLICATIONSTaken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis.