A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis.
A model of human lung fibrogenesis for the assessment of anti-fibrotic strategies in idiopathic pulmonary fibrosis.
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DOI：
10.1038/s41598-017-18555-9
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发表时间：
2018-01-10
影响因子：
4.6
通讯作者：
Bradding P
中科院分区：
文献类型：
--
作者：
Roach KM;Sutcliffe A;Matthews L;Elliott G;Newby C;Amrani Y;Bradding P
特发性肺纤维化（IPF）是一种进行性间质性肺病，治疗选择有限。KCa3.1离子通道在人肺肌成纤维细胞TGFβ1依赖性促纤维化反应中起关键作用。我们的目的是建立一个人肺实质纤维化模型，并测试选择性KCa3.1阻滞剂senicapoc的疗效。将2 mm 3的人肺实质片在DMEM ± TGFβ1（10 ng/ml）中培养7天，并通过RT-PCR、免疫组织化学和胶原分泌来检测促纤维化途径。在与TGFβ1培养7天后，41个IPF和纤维化相关基因显著上调。免疫组织化学染色显示TGFβ1刺激后ECM蛋白和成纤维细胞特异性蛋白表达增加。TGFβ1刺激后胶原分泌显著增加。这些促纤维化反应被senicapoc减弱，但不是由地塞米松。这种人肺纤维化的7天离体模型重现了IPF中明显的促纤维化事件，并且对KCa 3.1通道抑制敏感。通过维持人体组织复杂的细胞-细胞和细胞-基质相互作用，并消除跨物种异质性，该模型可以更好地预测临床试验中的药物疗效，并加速IPF药物开发。KCa3.1通道是治疗IPF的有希望的靶点。
Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with limited therapeutic options. KCa3.1 ion channels play a critical role in TGFβ1-dependent pro-fibrotic responses in human lung myofibroblasts. We aimed to develop a human lung parenchymal model of fibrogenesis and test the efficacy of the selective KCa3.1 blocker senicapoc. 2 mm3 pieces of human lung parenchyma were cultured for 7 days in DMEM ± TGFβ1 (10 ng/ml) and pro-fibrotic pathways examined by RT-PCR, immunohistochemistry and collagen secretion. Following 7 days of culture with TGFβ1, 41 IPF- and fibrosis-associated genes were significantly upregulated. Immunohistochemical staining demonstrated increased expression of ECM proteins and fibroblast-specific protein after TGFβ1-stimulation. Collagen secretion was significantly increased following TGFβ1-stimulation. These pro-fibrotic responses were attenuated by senicapoc, but not by dexamethasone. This 7 day ex vivo model of human lung fibrogenesis recapitulates pro-fibrotic events evident in IPF and is sensitive to KCa3.1 channel inhibition. By maintaining the complex cell-cell and cell-matrix interactions of human tissue, and removing cross-species heterogeneity, this model may better predict drug efficacy in clinical trials and accelerate drug development in IPF. KCa3.1 channels are a promising target for the treatment of IPF.
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DOI：
10.1165/ajrcmb.10.5.8179909
发表时间：
1994-05-01
影响因子：
6.4
作者：
BRADDING, P;ROBERTS, JA;HOLGATE, ST
通讯作者：
HOLGATE, ST
DOI：
10.1165/ajrcmb/5.2.155
发表时间：
1991-08-01
影响因子：
6.4
作者：
KHALIL, N;OCONNOR, RN;GREENBERG, AH
通讯作者：
GREENBERG, AH
影响因子：
7.7
作者：
Huang C;Shen S;Ma Q;Chen J;Gill A;Pollock CA;Chen XM
通讯作者：
Chen XM
影响因子：
158.5
作者：
Brightling, CE;Bradding, P;Pavord, ID
通讯作者：
Pavord, ID
DOI：
10.1513/pats.201203-023aw
发表时间：
2012-07-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Fernandez, Isis E;Eickelberg, Oliver
通讯作者：
Eickelberg, Oliver