Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.
Electrophilic PPARγ ligands inhibit corneal fibroblast to myofibroblast differentiation in vitro: a potentially novel therapy for corneal scarring.
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亲电PPARγ配体在体外抑制角膜成纤维细胞对肌纤维细胞分化：一种潜在的新型角膜疤痕疗法。
DOI：
10.1016/j.exer.2011.11.018
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发表时间：
2012-01
影响因子：
3.4
通讯作者：
Phipps, R. P.
中科院分区：
文献类型：
--
作者：
Kuriyan, A. E.;Lehmann, G. M.;Kulkarni, A. A.;Woeller, C. F.;Feldon, S. E.;Hindman, H. B.;Sime, P. J.;Huxlin, K. R.;Phipps, R. P.
角膜瘢痕形成的一个关键组成部分是TGFβ诱导的角膜角膜细胞分化为肌成纤维细胞。这种分化的抑制剂是角膜瘢痕形成的潜在治疗剂。在这项研究中，我们测试了两种亲电子过氧化物酶体增殖物激活受体γ（PPARγ）配体：氰基-3，12-二氧杂环戊烯-1，9-二烯-28-酸甲酯（CDDO-Me）和15-脱氧-Δ-12，14-前列腺素J2（15 d-PGJ 2）在体外抑制TGFβ诱导的肌成纤维细胞分化的相对有效性和作用机制。TGFβ用于诱导培养的原代人角膜成纤维细胞中的肌成纤维细胞分化。将CDDO-Me和15 d-PGJ 2加入培养物中以测试它们抑制该过程的能力。通过测量肌成纤维细胞特异性蛋白（αSMA、胶原I和纤连蛋白）和mRNA（αSMA和胶原III）的表达来评估肌成纤维细胞分化。在遗传和细胞培养操作的细胞中检测了这些药物抑制成肌纤维细胞分化中PPARγ的作用。最后，我们通过Western印迹和免疫荧光检测了亲电性在这些药物对TGFβ诱导的αSMA表达的作用中的重要性。两种亲电性PPARγ配体（CDDO-Me和15 d-PGJ 2）均有效抑制TGFβ诱导的肌成纤维细胞分化，但任一试剂均仅部分需要PPARγ抑制肌成纤维细胞分化。亲电性PPARγ配体能够比非亲电性PPARγ配体更有效地抑制肌成纤维细胞分化，表明亲电性在该过程中起重要作用。CDDO-Me和15 d-PGJ 2是TGFβ诱导的角膜成纤维细胞向肌成纤维细胞分化的强抑制剂，表明这类药物作为角膜瘢痕形成的潜在新疗法，在临床前动物模型中进行进一步研究。
A critical component of corneal scarring is the TGFβ-induced differentiation of corneal keratocytes into myofibroblasts. Inhibitors of this differentiation are potentially therapeutic for corneal scarring. In this study, we tested the relative effectiveness and mechanisms of action of two electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) ligands: cyano-3,12-dioxolean-1,9-dien-28-oic acid-metheyl ester (CDDO-Me) and 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) for inhibiting TGFβ-induced myofibroblast differentiation in vitro. TGFβ was used to induce myofibroblast differentiation in cultured, primary human corneal fibroblasts. CDDO-Me and 15d-PGJ2 were added to cultures to test their ability to inhibit this process. Myofibroblast differentiation was assessed by measuring the expression of myofibroblast-specific proteins (αSMA, collagen I, and fibronectin) and mRNA (αSMA and collagen III). The role of PPARγ in the inhibition of myofibroblast differentiation by these agents was tested in genetically and pharmacologically manipulated cells. Finally, we assayed the importance of electrophilicity in the actions of these agents on TGFβ-induced αSMA expression via Western blotting and immunofluorescence. Both electrophilic PPARγ ligands (CDDO-Me and 15d-PGJ2) potently inhibited TGFβ-induced myofibroblast differentiation, but PPARγ was only partially required for inhibition of myofibroblast differentiation by either agent. Electrophilic PPARγ ligands were able to inhibit myofibroblast differentiation more potently than non-electrophilic PPARγ ligands, suggesting an important role of electrophilicity in this process. CDDO-Me and 15d-PGJ2 are strong inhibitors of TGFβ-induced corneal fibroblast to myofibroblast differentiation in vitro, suggesting this class of agents as potential novel therapies for corneal scarring warranting further study in pre-clinical animal models.
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影响因子：
5
作者：
Kawai, Toru;Masaki, Takao;Yorioka, Noriaki
通讯作者：
Yorioka, Noriaki
影响因子：
3.4
作者：
Jester, JV;Huang, JY;Cavanagh, HD
通讯作者：
Cavanagh, HD
影响因子：
11.2
作者：
Brookes, Paul S.;Morse, Kimberly;Bernstein, Steven H.
通讯作者：
Bernstein, Steven H.
影响因子：
64.5
作者：
KLIEWER, SA;LENHARD, JM;LEHMANN, JM
通讯作者：
LEHMANN, JM
影响因子：
4.8
作者：
Guo, Naxin;Woeller, Collynn F.;Phipps, Richard P.
通讯作者：
Phipps, Richard P.