Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells
Inhibition of p38MAP kinase suppresses fibrotic reaction of retinal pigment epithelial cells
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DOI：
10.1038/labinvest.3700294
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发表时间：
2005-07-01
影响因子：
5
通讯作者：
Ooshima, A
中科院分区：
文献类型：
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作者：
Saika, S;Yamanaka, O;Ooshima, A
增生性玻璃体视网膜病变(PVR)是视网膜脱离手术失败的主要原因之一。其发病机制包括视网膜色素上皮和其他视网膜来源的非神经细胞的纤维化反应，导致分离的视网膜固定。我们检测了p38丝裂原活化蛋白激酶(MAPK)在转化生长因子(TGF)-β2依赖的人视网膜色素上皮细胞系ARPE-19促纤维化反应中的作用，并评价了p38MAPK基因转移抑制p38MAPK在PVR小鼠模型中的治疗效果。外源性转化生长因子-β2激活ARPE-19细胞p38MAPK。它也抑制细胞增殖，但这不受p38MAPK抑制剂SB202190的影响。SB202190干扰依赖于转化生长因子-β2的细胞迁移和I型胶原和纤维连接蛋白的产生，但对这些活性的基础水平没有影响。虽然SB202190不影响Smads2/3 C末端的磷酸化，但它确实抑制了Smads3/4的转录活性，报告基因CAGA12-Luc表明。DN-p38MAPK基因转移可减轻小鼠视网膜脱离后视网膜色素上皮的纤维化反应，支持其防治PVR的有效性。
Proliferative vitreoretinopathy ( PVR) is one of the major causes of the failure of retinal detachment surgery. Its pathogenesis includes a fibrotic reaction by the retinal pigment epithelium and other retina-derived non-neural cells, leading to fixation of the detached retina. We examined the role of p38 mitogen-activated protein kinase ( MAPK) in transforming growth factor ( TGF)-beta 2-dependent enhancement of the fibrogenic reaction in a human retinal pigment epithelial cell line, ARPE-19, and also evaluated the therapeutic efficacy of inhibiting p38MAPK by adenoviral gene transfer of dominant-negative ( DN) p38MAPK in a mouse model of PVR. Exogenous TGF-beta 2 activates p38MAPK in ARPE-19 cells. It also suppresses cell proliferation, but this was unaffected by addition of the p38MAPK inhibitor, SB202190. SB202190 interfered with TGF-beta 2-dependent cell migration and production of collagen type I and fibronectin, but had no effect on basal levels of these activities. While SB202190 did not affect phosphorylation of the C-terminus of Smads2/3, it did suppress the transcriptional activity of Smads3/4 as indicated by a reporter gene, CAGA12-Luc. Gene transfer of DN-p38MAPK attenuated the post-retinal detachment fibrotic reaction of the retinal pigment epithelium in vivo in mice, supporting its effectiveness in preventing/treating PVR.