June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Effects of the heat shock protein inhibitor, 17AAG, on corneal stromal haze using an in vivo rabbit phototherapeutic keratectomy model
Author Affiliations & Notes
  • Sydney Garrison Edwards
    Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, United States
  • Philip Kass
    Department of Population Health & Reproduction, School of Veterinary Medicine, University of California, Davis, Davis, California, United States
  • Maryam Ali
    Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, United States
  • Ariana Marangakis
    Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, United States
  • Vijay Krishna Raghunathan
    Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, United States
  • Christopher J Murphy
    Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, United States
    Department of Ophthalmology and Vision Science, School of Medicine, University of California, Davis, CA, Davis, California, United States
  • Sara M Thomasy
    Department of Surgical and Radiological Sciences, University of California, Davis, Davis, California, United States
  • Footnotes
    Commercial Relationships   Sydney Edwards, None; Philip Kass, None; Maryam Ali, None; Ariana Marangakis, None; Vijay Raghunathan, None; Christopher Murphy, None; Sara Thomasy, None
  • Footnotes
    Support  ACVO-Vision for Animals Foundation VAF2015-01, National Institutes of Health K08 EY021142, R01 EY019970, R01 EY016134, and P30 EY12576, Center for Companion Animal Health, School of Veterinary Medicine, UC-Davis.
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3908. doi:
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    • Get Citation

      Sydney Garrison Edwards, Philip Kass, Maryam Ali, Ariana Marangakis, Vijay Krishna Raghunathan, Christopher J Murphy, Sara M Thomasy; Effects of the heat shock protein inhibitor, 17AAG, on corneal stromal haze using an in vivo rabbit phototherapeutic keratectomy model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):3908.

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

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Abstract

Purpose : Corneal scarring remains a leading cause of blindness worldwide. 17-N-allylamino-17-demethoxygeldanamycin (17AAG), an anti-fibrotic heat shock protein 90 (HSP90) inhibitor decreases scar formation in tissues such as the liver and lung, and also stimulates reversion of myofibroblasts to keratocytes in vitro, even in the presence of transforming growth factor-b1 (TGF-b1). We hypothesized that 17AAG would reduce formation of corneal haze in an in vivo rabbit phototherapeutic keratectomy (PTK) model.

Methods : In vivo: 18 New Zealand White Rabbits received an axial 6 mm diameter, 100 mm depth PTK in the right eye (OD), and either 100 mM 17AAG at 6x (n=6), 3x daily (n=6) or topical placebo (vehicle control; 6x; n=6) for 28 days. Stromal haze scoring, slit lamp biomicroscopy, and Fourier-domain optical coherence tomography (FD-OCT) were performed at multiple time points. A mixed-effects ANOVA model was used for statistical analysis. In vitro: Primary rabbit corneal stromal cells were cultured on polyacrylamide gels of differing stiffness (5 or 25 kPa) or tissue culture plastic (TCP, >1 GPa), in the presence or absence of 10 ng/ml TGF-b1, and treated with 17AAG (500 nM) or vehicle control (DMSO), for 72 h. RNA was isolated and qPCR was performed for a-smooth muscle actin (a SMA) expression.

Results : In vivo: Topical 17AAG 6x, but not 3x had a greater corneal stromal haze score (p=0.02) and stromal haze thickness as measured by FD-OCT (p=0.03) versus placebo. In vitro: Treatment with 17AAG resulted in greater (P<0.05) a SMA expression in cells cultured on gels of lesser stiffnesses (5kPa) compared with 25kPa and TCP, in the presence of TGF-b1.

Conclusions : In vivo, 17AAG at high concentration (100 mM) and frequency (6x), when initiated at the time of wounding increases stromal haze in an in vivo rabbit PTK model In vitro, 17AAG increases a SMA expression in cells cultured on soft substrates. Since it is known that stromal stiffness increases during stromal wound healing the effect of 17AAG treatment when initiated later in the wound healing process remains unknown.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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