ErbBs in Lens Cell Fibrosis and Secondary Cataract.
ErbBs in Lens Cell Fibrosis and Secondary Cataract.
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晶状体细胞纤维化和继发性白内障中的ERBB。
DOI：
10.1167/iovs.64.10.6
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发表时间：
2023-07-03
影响因子：
4.4
通讯作者：
中科院分区：
文献类型：
--
作者：
转化生长因子β诱导的晶状体上皮细胞向肌成纤维细胞的转化与白内障手术中最常见的视力障碍--后囊混浊有关。尽管ErbB受体酪氨酸激酶家族的抑制剂在模型系统中被证明可以阻断一些与PCO相关的过程，但我们对晶状体中的ErbB信号的了解非常有限。在此，我们研究了β及其配体在原代培养的鸡晶状体上皮细胞中的表达，以及转化生长因子ERB对ERB功能的影响。免疫荧光显微镜和Western blotting分析基础状态和纤维化状态下的DCDMLs。小分子ErbB激酶阻滞剂，包括人类治疗性拉帕替尼，选择性地抑制转化生长因子β诱导的DCDMLs的肌动蛋白转化。晶状体细胞在细胞膜上组成性表达ErbB1(EGFR)、ErbB2和ErbB4蛋白，并释放到ErbB激活的介质中。与转化生长因子β共同培养的DCDMLs增加了可溶性的生物活性ErbB配体，并显著改变了ErbB，减少了总和细胞表面ErbB_2和Erb_4，增加了Erb_1的表达和同源二聚体的形成。同样，当晶状体细胞暴露于促纤维化底物纤维连接蛋白时，转化生长因子β依赖的相对erbB表达的变化也被诱导。一次1小时的拉帕替尼治疗可抑制6天后评估的DCDMLs的EMyT。短期暴露于较低剂量的拉帕替尼也能够引起持久的反应，当与一种机械上不同的多激酶抑制剂的次优水平相结合时。我们的发现支持ErbB1作为纤维化PCO的治疗靶点，它可以被用来在药物上保护数百万白内障患者的视力。
TGFβ-induced epithelial-to-myofibroblast transition (EMyT) of lens cells has been linked to the most common vision-disrupting complication of cataract surgery—namely, posterior capsule opacification (PCO; secondary cataract). Although inhibitors of the ErbB family of receptor tyrosine kinases have been shown to block some PCO-associated processes in model systems, our knowledge of ErbB signaling in the lens is very limited. Here, we investigate the expression of ErbBs and their ligands in primary cultures of chick lens epithelial cells (dissociated cell-derived monolayer cultures [DCDMLs]) and how TGFβ affects ErbB function. DCDMLs were analyzed by immunofluorescence microscopy and Western blotting under basal and profibrotic conditions. Small-molecule ErbB kinase blockers, including the human therapeutic lapatinib, selectively inhibit TGFβ-induced EMyT of DCDMLs. Lens cells constitutively express ErbB1 (EGFR), ErbB2, and ErbB4 protein on the plasma membrane and release into the medium ErbB-activating ligand. Culturing DCDMLs with TGFβ increases soluble bioactive ErbB ligand and markedly alters ErbBs, reducing total and cell surface ErbB2 and ErbB4 while increasing ErbB1 expression and homodimer formation. Similar, TGFβ-dependent changes in relative ErbB expression are induced when lens cells are exposed to the profibrotic substrate fibronectin. A single, 1-hour treatment with lapatinib inhibits EMyT in DCDMLs assessed 6 days later. Short-term exposure to lower doses of lapatinib is also capable of eliciting a durable response when combined with suboptimal levels of a mechanistically distinct multikinase inhibitor. Our findings support ErbB1 as a therapeutic target for fibrotic PCO, which could be leveraged to pharmaceutically preserve the vision of millions of patients with cataracts.
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影响因子：
16
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
影响因子：
11.4
作者：
GrausPorta, D;Beerli, RR;Hynes, NE
通讯作者：
Hynes, NE
影响因子：
5.3
作者：
Bhuyan, DK;Reddy, PG;Bhuyan, KC
通讯作者：
Bhuyan, KC
影响因子：
8
作者：
Gulliford, TJ;Huang, GC;Epstein, RJ
通讯作者：
Epstein, RJ
影响因子：
50.3
作者：
Chan WW;Wise SC;Kaufman MD;Ahn YM;Ensinger CL;Haack T;Hood MM;Jones J;Lord JW;Lu WP;Miller D;Patt WC;Smith BD;Petillo PA;Rutkoski TJ;Telikepalli H;Vogeti L;Yao T;Chun L;Clark R;Evangelista P;Gavrilescu LC;Lazarides K;Zaleskas VM;Stewart LJ;Van Etten RA;Flynn DL
通讯作者：
Flynn DL