July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Chronic oxidation promotes epithelial-mesenchymal transition in lens epithelial cells via a Wnt/b-catenin dependent and TGFb independent pathway
Author Affiliations & Notes
  • Xingjun Fan
    Pathology, Case Western Reserve Univ, Cleveland, Ohio, United States
  • Zongbo Wei
    Pathology, Case Western Reserve Univ, Cleveland, Ohio, United States
  • Hong Yan
    The Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute , The First Affiliated Hospital of Chongqing Medical University, Chongqing, Chongqing, China
    Ophthalmology, The Fourth Military Medical University, Xian, Shaanxi, China
  • Footnotes
    Commercial Relationships   Xingjun Fan, None; Zongbo Wei, None; Hong Yan, None
  • Footnotes
    Support  NEI Grant EY024553
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1207. doi:https://doi.org/
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      Xingjun Fan, Zongbo Wei, Hong Yan; Chronic oxidation promotes epithelial-mesenchymal transition in lens epithelial cells via a Wnt/b-catenin dependent and TGFb independent pathway. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1207. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : Lens epithelial cell transformation via epithelial-mesenchymal transition (EMT) after cataract surgery is considered a key pathogenic process in the formation of posterior capsule opacification (PCO). The operation results in a permanent chronic oxidative stressed growth environment for residual lens epithelial cells due to a 1000-fold reduction of extracellular glutathione (GSH). We hypothesize that chronic oxidation is playing a key role in the lens epithelial cell transformation.

Methods : EMT protein markers, αSMA, vimentin, fibronectin, and collagen 1, Wnt/b-catenin signaling cascades were determined in both wild-type and glutathione biosynthesis deficiency (Gclc-/- or Gclm-/-) mice lenses, as well as in HLE-B3 cells. The time course of Wnt signaling activation and redox status was also investigated in rabbit after mock cataract surgery for intraocular lens (IOL) implantation. The antioxidants and Wnt inhibitors, i.e., glutathione ethyl ester (GSH-EE), N-acetylcysteine (NAC), and LGK974 were used both in vitro and in vivo.

Results : A dramatic increase of pro-EMT markers, such as type I collagen, αSMA, vimentin, and fibronectin was observed in Gclc-/- and Gclm-/- lenses and buthionine sulfoximine (BSO) treated HLE-B3 cells. Transcriptome, protein expression, and signaling transduction analysis suggest that chronic oxidation-mediated EMT process is via Wnt/β-catenin dependent and TGFβ independent signaling transduction pathway. Equally important, the antioxidants and Wnt inhibitors, i.e., N-acetyl cysteine (10mM) and LGK794 (100nM) could significantly attenuate the EMT signaling stimulated by decreased GSH levels. These findings were further confirmed by mock cataract surgery in both Gclc and Gclm knockout mouse models. To further validate our results, we also carried out the rabbit cataract surgical study with IOL implantation. The preliminary study demonstrated a strong association of intracellular and extracellular ROS formation and Wnt/ β-catenin activation. This study, for the first time we believe, links oxidative stress to lens fibrosis and PCO formation via TGFβ independent EMT-mediated mechanisms.

Conclusions : These results imply that survival signaling pathways are involved in oxidative stress adaptive response and may play a critical role in residual epithelial cells transdifferentiation after cataract surgery

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.


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