Selective deletion of connective tissue growth factor attenuates experimentally-induced pulmonary fibrosis and pulmonary arterial hypertension.
Selective deletion of connective tissue growth factor attenuates experimentally-induced pulmonary fibrosis and pulmonary arterial hypertension.
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结缔组织生长因子的选择性缺失减弱实验诱导的肺纤维化和肺动脉高压。
DOI：
10.1016/j.biocel.2021.105961
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
Abraham DJ
中科院分区：
文献类型：
--
作者：
Tam AYY;Horwell AL;Trinder SL;Khan K;Xu S;Ong V;Denton CP;Norman JT;Holmes AM;Bou-Gharios G;Abraham DJ
CCN 2由TGF-β信号通路选择性且精确地诱导。CCN 2似乎介导TGF-β的许多活性特征。体外抑制CCN 2可降低TGF-β的许多功能性促纤维化活性。成纤维细胞特异性CCN 2缺失可减轻肺疾病模型中的间质纤维化和肺血管重塑结缔组织生长因子（CTGF，CCN 2）是一种基质细胞蛋白，在正常哺乳动物发育、组织稳态和修复中起关键作用。在病理条件下，失调的CCN 2与癌症、心血管疾病和组织纤维化有关。在这项研究中，CCN 2基因的遗传操作被用来研究CCN 2表达在体外和实验诱导的肺纤维化和肺动脉高压（PAH）模型中的作用。使用siRNA敲低CCN 2降低了来源于系统性硬化症患者的TGF-β处理的肺成纤维细胞中促纤维化标志物（纤连蛋白p <0.01，I型胶原p <0.05，α-SMA p < 0.0001，TIMP-1 p < 0.05和IL-6 p < 0.05）的表达。在两种肺部疾病模型中，使用以成纤维细胞特异性和时间依赖性方式靶向CCN 2的条件性基因缺失策略在小鼠中进行体内研究。如通过纤维化评分（野生型博来霉素3.733 ± 0.2667对CCN 2敲除（KO）博来霉素4.917 ± 0.3436，p < 0.05）和微CT评估的，CCN 2缺失显著减少博来霉素滴注后的肺间质瘢痕形成和纤维化。在已建立的慢性缺氧/Sugen肺动脉高压模型中，CCN 2基因缺失导致肺血管重塑显著减少，右心室肥大减少，PAH特征性血液动力学测量值降低（与缺氧/SU 5416条件下的WT小鼠相比，CCN 2 KO小鼠的RVSP和RV/LV + S显著降低（p < 0.05））。这些结果支持CCN 2在肺纤维化和PAH相关血管重塑中的重要作用。因此，旨在阻断CCN 2功能的疗法可能有益于几种形式的严重肺部疾病。
CCN2 is selectively and exquisitely induced by the TGF-β signalling pathway. CCN2 appears to mediate many of the activities characteristic of TGF-β. Inhibition of CCN2 in vitro reduces many of the functional pro-fibrotic activities of TGF-β. Fibroblast-specific deletion of CCN2 attenuates interstitial fibrosis and pulmonary vascular remodelling in models of lung diseases. Connective tissue growth factor (CTGF, CCN2) is a matricellular protein which plays key roles in normal mammalian development and in tissue homeostasis and repair. In pathological conditions, dysregulated CCN2 has been associated with cancer, cardiovascular disease, and tissue fibrosis. In this study, genetic manipulation of the CCN2 gene was employed to investigate the role of CCN2 expression in vitro and in experimentally-induced models of pulmonary fibrosis and pulmonary arterial hypertension (PAH). Knocking down CCN2 using siRNA reduced expression of pro-fibrotic markers (fibronectin p < 0.01, collagen type I p < 0.05, α-SMA p < 0.0001, TIMP-1 p < 0.05 and IL-6 p < 0.05) in TGF-β-treated lung fibroblasts derived from systemic sclerosis patients. In vivo studies were performed in mice using a conditional gene deletion strategy targeting CCN2 in a fibroblast-specific and time-dependent manner in two models of lung disease. CCN2 deletion significantly reduced pulmonary interstitial scarring and fibrosis following bleomycin-instillation, as assessed by fibrotic scores (wildtype bleomycin 3.733 ± 0.2667 vs CCN2 knockout (KO) bleomycin 4.917 ± 0.3436, p < 0.05) and micro-CT. In the well-established chronic hypoxia/Sugen model of pulmonary hypertension, CCN2 gene deletion resulted in a significant decrease in pulmonary vessel remodelling, less right ventricular hypertrophy and a reduction in the haemodynamic measurements characteristic of PAH (RVSP and RV/LV + S were significantly reduced (p < 0.05) in CCN2 KO compared to WT mice in hypoxic/SU5416 conditions). These results support a prominent role for CCN2 in pulmonary fibrosis and in vessel remodelling associated with PAH. Therefore, therapeutics aimed at blocking CCN2 function are likely to benefit several forms of severe lung disease.
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影响因子：
3.7
作者：
Doherty, Heather E.;Kim, Hyung-Suk;Maeda, Nobuyo
通讯作者：
Maeda, Nobuyo
影响因子：
13.3
作者：
Dziadzio, M;Usinger, W;Stratton, R
通讯作者：
Stratton, R
影响因子：
27.4
作者：
Khan, Korsa;Xu, Shiwen;Ong, Voon H.
通讯作者：
Ong, Voon H.
DOI：
10.1007/978-1-4939-6430-7_34
发表时间：
2017-01-01
期刊：
CCN PROTEINS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Leask, Andrew
通讯作者：
Leask, Andrew
DOI：
10.1007/978-1-4939-7113-8_10
发表时间：
2017-01-01
期刊：
FIBROSIS: METHODS AND PROTOCOLS
影响因子：
--
作者：
Li, Ian M. H.;Horwell, Amy L.;Bou-Gharios, George
通讯作者：
Bou-Gharios, George