Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis.
Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis.
复制标题
DOI：
10.1186/s12931-018-0876-y
复制
发表时间：
2018-09-15
影响因子：
5.8
通讯作者：
Königshoff M
中科院分区：
文献类型：
--
作者：
Lehmann M;Buhl L;Alsafadi HN;Klee S;Hermann S;Mutze K;Ota C;Lindner M;Behr J;Hilgendorff A;Wagner DE;Königshoff M
特发性肺纤维化（IPF）是一种致死性间质性肺病。肺上皮的重复性损伤和重编程被认为是疾病进展的关键驱动因素，有助于成纤维细胞活化、细胞外基质重塑以及随后的肺结构和功能丧失。到目前为止，吡非尼酮和尼莫地平是已知的唯一获批的减缓疾病进展的药物，然而，这些药物是否以及如何影响肺上皮细胞功能，在很大程度上仍未探索。我们用吡非尼酮或NATRA处理鼠和人3D离体肺组织培养物（3D-LTC;由精密切割肺切片（PCLS）产生）以及原代鼠肺泡上皮II型（pmATII）细胞。鼠3D-LTC或pmATII细胞来源于纤维化的博来霉素模型。早期纤维化的变化诱导人3D-LTC的混合物的促纤维化因子。通过qPCR、蛋白质印迹、免疫荧光染色和ELISA测定上皮细胞和间充质细胞功能。在鼠和人3D-LTC以及pmATII细胞中，低μM浓度的Nursing（1 μM）和mM浓度的吡非尼酮（2.5 mM）降低了纤维化基因表达，包括胶原1a 1和纤连蛋白。值得注意的是，在pmATII细胞以及鼠和人3D-LTC中，NCLs稳定远端肺上皮细胞标志物，特别是表面活性剂蛋白C的表达。吡非尼酮和尼莫地平对小鼠和人上皮细胞表现出不同的作用，这可能有助于其抗纤维化作用。人3D-LTC代表了评估用于治疗IPF患者的潜在药物的抗纤维化机制的有价值的工具。本文的在线版本（10.1186/s12931-018-0876-y）包含补充材料，可供授权用户使用。
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. Low μM concentrations of Nintedanib (1 μM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients. The online version of this article (10.1186/s12931-018-0876-y) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
5.3
作者：
Li LF;Kao KC;Liu YY;Lin CW;Chen NH;Lee CS;Wang CW;Yang CT
通讯作者：
Yang CT
影响因子：
5.8
作者：
Hostettler KE;Zhong J;Papakonstantinou E;Karakiulakis G;Tamm M;Seidel P;Sun Q;Mandal J;Lardinois D;Lambers C;Roth M
通讯作者：
Roth M
DOI：
10.1073/pnas.1107559108
发表时间：
2011-06-28
影响因子：
11.1
作者：
Lawson, William E.;Cheng, Dong-Sheng;Blackwell, Timothy S.
通讯作者：
Blackwell, Timothy S.
影响因子：
7.3
作者：
Datta A;Scotton CJ;Chambers RC
通讯作者：
Chambers RC
DOI：
10.1165/rcmb.2017-0096st
发表时间：
2017-05-01
影响因子：
6.4
作者：
Jenkins, R. Gisli;Moore, Bethany B.;White, Eric S.
通讯作者：
White, Eric S.