Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis.
Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis.
复制标题
DOI：
10.3389/fphar.2021.679388
复制
发表时间：
2021
影响因子：
5.6
通讯作者：
Bradding P
中科院分区：
文献类型：
--
作者：
Roach KM;Castells E;Dixon K;Mason S;Elliott G;Marshall H;Poblocka MA;Macip S;Richardson M;Khalfaoui L;Bradding P
简介：特发性肺纤维化（IPF）是一种进行性、致死性肺部疾病，预后不良，发病率增加。吡非尼酮和尼达尼布是唯一获批的IPF治疗药物，但疗效有限，其作用机制尚不清楚。在此，我们检查了吡非尼酮和尼达尼布在人类肺纤维化模型中的作用，并将其与推定的抗纤维化化合物脂氧素A4（LXA 4）和senicapoc（一种KCa 3.1离子通道阻滞剂）进行了比较。 方法：使用TGFβ1、±吡非尼酮、尼达尼布或LXA 4在培养的人肺实质中诱导早期纤维化7天。通过RT-PCR、免疫组化和可溶性胶原分泌检测促纤维化反应。 结果如下：在检测的84个IPF和纤维化相关基因中，有36个基因在人肺实质中被TGFβ1显著上调，且≥0.5 log 2FC（n = 32）。Nursing（n = 13）降低了14个纤维化相关基因的mRNA表达，包括MMP（MMP 1，−4，−13，−14），整合素α2，CXCR 4和PDGFB，但上调α-平滑肌肌动蛋白（αSMA）。吡非尼酮仅降低MMP 3和MMP-13的mRNA表达。Senicapoc（n = 11）先前减弱了28种纤维化相关基因的表达，包括αSMA、几种生长因子、III型胶原和αV/β6整合素。吡非尼酮和尼达尼布可显著抑制组织内TGFβ1诱导的成纤维细胞增殖，但与senicapoc不同，吡非尼酮和尼达尼布均未阻止组织αSMA表达增加。LXA 4无效。 结论：吡非尼酮和尼达尼布显示出适度的抗纤维化作用，并为新药在人肺组织中的抗纤维化活性提供了基准。基于这些数据，我们预测KCa3.1阻滞剂senicapoc在IPF中的获益将大于这些许可药物。
Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker. Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion. Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,−4,−13,−14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and −13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective. Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.
登录
查看更多内容
影响因子：
5.8
作者：
Lehtonen ST;Veijola A;Karvonen H;Lappi-Blanco E;Sormunen R;Korpela S;Zagai U;Sköld MC;Kaarteenaho R
通讯作者：
Kaarteenaho R
影响因子：
5.8
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
通讯作者：
Königshoff M
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：
10.1084/jem.20162152
发表时间：
2017-08-07
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Misharin AV;Morales-Nebreda L;Reyfman PA;Cuda CM;Walter JM;McQuattie-Pimentel AC;Chen CI;Anekalla KR;Joshi N;Williams KJN;Abdala-Valencia H;Yacoub TJ;Chi M;Chiu S;Gonzalez-Gonzalez FJ;Gates K;Lam AP;Nicholson TT;Homan PJ;Soberanes S;Dominguez S;Morgan VK;Saber R;Shaffer A;Hinchcliff M;Marshall SA;Bharat A;Berdnikovs S;Bhorade SM;Bartom ET;Morimoto RI;Balch WE;Sznajder JI;Chandel NS;Mutlu GM;Jain M;Gottardi CJ;Singer BD;Ridge KM;Bagheri N;Shilatifard A;Budinger GRS;Perlman H
通讯作者：
Perlman H
影响因子：
6.5
作者：
Ataga, Kenneth I.;Reid, Marvin;Stocker, Jonathan W.
通讯作者：
Stocker, Jonathan W.