KLF4 is a therapeutically tractable brake on fibroblast activation that promotes resolution of pulmonary fibrosis.
KLF4 is a therapeutically tractable brake on fibroblast activation that promotes resolution of pulmonary fibrosis.
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KLF4是一种可在成纤维细胞激活上进行治疗的制动器，可促进肺纤维化的分辨率。
DOI：
10.1172/jci.insight.160688
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发表时间：
2022-08-22
期刊：
影响因子：
8
通讯作者：
Peters-Golden, Marc
中科院分区：
文献类型：
--
作者：
Penke, Loka R.;Speth, Jennifer M.;Huang, Steven K.;Fortier, Sean M.;Baas, Jared;Peters-Golden, Marc
关于推动组织纤维化的成纤维细胞激活的潜在分子刹车的信息很少。转录因子Krüppel-like factor4(KLF4)被认为是细胞干细胞的决定因素和肿瘤抑制因子。我们发现它在纤维化肺成纤维细胞中的表达减弱。功能获得和功能丧失的研究表明，KLF4抑制成纤维细胞的增殖、胶原合成和向肌成纤维细胞的分化，同时恢复其对凋亡的敏感性。在一过性纤维化模型中，有条件地从成纤维细胞中删除KLF4增强了肺纤维化的峰值程度，并取消了随后的自发消退。KLF4的小分子诱导剂能够恢复其在纤维化成纤维细胞中的表达，并在以临床上更相关的持续性肺纤维化为特征的实验模型中诱导消退。这些数据表明KLF4是成纤维细胞激活的关键刹车，它的诱导代表了一种治疗肺和其他器官纤维化的方法。
There is a paucity of information about potential molecular brakes on the activation of fibroblasts that drive tissue fibrosis. The transcription factor Krüppel-like factor 4 (KLF4) is best known as a determinant of cell stemness and a tumor suppressor. We found that its expression was diminished in fibroblasts from fibrotic lung. Gain- and loss-of-function studies showed that KLF4 inhibited fibroblast proliferation, collagen synthesis, and differentiation to myofibroblasts, while restoring their sensitivity to apoptosis. Conditional deletion of KLF4 from fibroblasts potentiated the peak degree of pulmonary fibrosis and abrogated the subsequent spontaneous resolution in a model of transient fibrosis. A small molecule inducer of KLF4 was able to restore its expression in fibrotic fibroblasts and elicit resolution in an experimental model characterized by more clinically relevant persistent pulmonary fibrosis. These data identify KLF4 as a pivotal brake on fibroblast activation whose induction represents a therapeutic approach in fibrosis of the lung and perhaps other organs.
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影响因子：
11.2
作者：
Farrugia MK;Vanderbilt DB;Salkeni MA;Ruppert JM
通讯作者：
Ruppert JM
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：
27.4
作者：
Malaab M;Renaud L;Takamura N;Zimmerman KD;da Silveira WA;Ramos PS;Haddad S;Peters-Golden M;Penke LR;Wolf B;Hardiman G;Langefeld CD;Medsger TA;Feghali-Bostwick CA
通讯作者：
Feghali-Bostwick CA
DOI：
10.1165/rcmb.2012-0224oc
发表时间：
2013-07-01
影响因子：
6.4
作者：
Ajayi, Iyabode O.;Sisson, Thomas H.;Horowitz, Jeffrey C.
通讯作者：
Horowitz, Jeffrey C.
DOI：
10.1164/ajrccm/144.5.1080
发表时间：
1991-11-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
BOROK, Z;GILLISSEN, A;CRYSTAL, RG
通讯作者：
CRYSTAL, RG