April 2009
Volume 50, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2009
Synthetic Triterpenoids Inhibit Human Corneal Myofibroblast Differentiation in vitro
Author Affiliations & Notes
  • A. E. Kuriyan
    School of Medicine and Dentistry,
    University of Rochester, Rochester, New York
  • G. M. Lehmann
    Department of Environmental Medicine,
    University of Rochester, Rochester, New York
  • S. E. Feldon
    University of Rochester Eye Institute,
    University of Rochester, Rochester, New York
  • P. Sime
    Department of Environmental Medicine,
    University of Rochester, Rochester, New York
  • K. R. Huxlin
    University of Rochester Eye Institute,
    University of Rochester, Rochester, New York
  • R. P. Phipps
    Department of Environmental Medicine,
    University of Rochester Eye Institute,
    University of Rochester, Rochester, New York
  • Footnotes
    Commercial Relationships  A.E. Kuriyan, None; G.M. Lehmann, None; S.E. Feldon, None; P. Sime, None; K.R. Huxlin, None; R.P. Phipps, None.
  • Footnotes
    Support  TL1 RR024135 from the NCRR, a component of the NIH and NIH Roadmap for Medical Research, NIH Grant EY11708
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 1944. doi:
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      A. E. Kuriyan, G. M. Lehmann, S. E. Feldon, P. Sime, K. R. Huxlin, R. P. Phipps; Synthetic Triterpenoids Inhibit Human Corneal Myofibroblast Differentiation in vitro . Invest. Ophthalmol. Vis. Sci. 2009;50(13):1944.

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

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Abstract

Purpose: : Corneal scarring is a common consequence of ocular surgeries, infections, and trauma, resulting in corneal opacification. There are few, safe and efficacious treatments for corneal scarring. Transforming growth factor beta-1 (TGFβ1) is a powerful model agent for inducing differentiation of keratocytes to myofibroblasts. Synthetic triterpenoids, such as cyano-3,12-dioxolean-1,9-dien-28-oic acid (CDDO) and its derivatives are electrophilic peroxisome proliferator-activated receptor gamma (PPARγ) agonists that have many interesting properties. Here, we contrasted the ability of CDDO derivatives and traditional PPARγ agonists to inhibit myofibroblast differentiation in human corneal fibroblasts in vitro, providing a potential novel anti-scarring therapy for the prevention and/or treatment of corneal scarring.

Methods: : Alpha smooth muscle actin (SMA) expression is a hallmark of myofibroblast differentiation. Western blotting (WB) and immunofluorescence microscopy (IFM) were used to assess the level of SMA expression in primary human corneal fibroblasts treated with 5ng/ml TGFβ1 and varying doses of the PPARγ ligands, CDDO-ethyl amide (Ea), methyl-2-CDDO (CDDO-Me), and CDDO-imidazolide (Im), 15-Deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2), Prostaglandin A2 (PGA2), rosiglitazone, and CAY10410, after 72 hours in culture.

Results: : CDDO derivatives inhibited TGFβ1-induced myofibroblast differentiation in a dose-dependent fashion in primary human corneal fibroblasts in vitro as demonstrated by WB and IFM. Nanomolar concentrations of CDDO-Ea inhibited TGFβ1-induced myofibroblast differentiation to a greater extent than did micromolar concentrations of the other electrophilic PPARγ agonists, PGA2 and 15d-PGJ2. The non-electrophilic PPARγ agonists, CAY10410 and rosiglitazone, were much less potent inhibitors of SMA expression than were any of the electrophilic PPARγ agonists.

Conclusions: : CDDO derivatives inhibit TGFβ1-induced myofibroblast differentiation more potently than other PPARγ agonists in primary human corneal fibroblasts. The reduced ability of non-electrophilic PPARγ agonists to inhibit SMA expression suggests that the electrophilic carbon of CDDO is important for this particular activity. CDDO derivatives have the potential to fill the current need for more effective therapies to combat corneal scarring in humans.

Keywords: cornea: basic science • inflammation • drug toxicity/drug effects 
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