New Study Pinpoints Biochemical Mechanism Underlying Fibrosis Following Glaucoma Surgery

Findings suggest VEGF inhibition via TGF-β1 may be beneficial, reports The American Journal of Pathology

Philadelphia, PA, May 17, 2013

The most common cause of failure after glaucoma surgery is scarring at the surgical site, so researchers are actively looking for ways to minimize or prevent scar formation. Previous work had suggested that vascular endothelial growth factor (VEGF) activates fibrosis, whereas VEGF inhibition results in reduced scar formation and better surgical results. In a series of studies using a rabbit model of glaucoma surgery, investigators have determined that VEGF probably exerts its effects through induction of transforming growth factor (TGF)-β1, which may open up a new target for therapies to improve glaucoma surgical outcomes. This study is published in the June 2013 issue of The American Journal of Pathology.

“The cytokine TGF-β1 is a key mediator of wound healing and is critically involved in postoperative scarring,” says Chan Kee Park, MD, PhD, Department of Ophthalmology and Visual Science of Seoul St. Mary’s Hospital and the College of Medicine of the Catholic University of Korea. “Our present study shows that VEGF induces TGF-β1 production, and inhibiting VEGF reduces TFG-β1 levels … and decreases subconjunctival fibrosis after trabeculectomy.” Trabeculectomy is the surgical process by which a filtering bleb is made under the conjunctival and subconjunctival space for the aqueous humor to be driven from the anterior eye chamber, lowering the pressure within the eye.

In this study of 32 white rabbits, some underwent trabeculectomy and others remained unoperated as controls. Immediately after surgery, some rabbits received intraocular injections of 0.2 ml of VEGF at doses ranging from 1 to 50 ng/mL, while others were injected with the VEGF inhibitor bevacizumab in the subconjunctival space.

One of the questions addressed by the researchers was whether VEGF triggers the transformation of fibroblasts to myofibroblasts in the subconjunctiva, since myofibroblasts play a significant role in fibrosis. Using immunohistochemical staining, the researchers found that trabeculectomy activated myoblast transformation as measured by levels of Smad-positive and Snail-positive cells in the conjunctiva and subconjunctiva. This effect increased after VEGF stimulation. Similarly, Western blot analysis of proteins showed increased levels of Smad, phosphorylated Smad, and Snail after surgery, which was intensified by VEGF and inhibited by bevacizumab.

“Our findings suggest that VEGF has potential effects on the TGF-1β/Smad/Snail pathway involved in myoblast transformation. Our study gives an experimental basis for the use of anti-VEGF agents in glaucoma surgery,” says Dr. Park.

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Notes for Editors
"VEGF Induces TGF-β1 Expression and Myofibroblast Transformation after Glaucoma Surgery," by Hae-Young Lopilly Park, MD, Jie Hyun Kim, PhD, Chan Kee Park, MD, PhD (DOI: http://dx.doi.org/10.1016/j.ajpath.2013.02.009). It appears in The American Journal of Pathology, Volume 182, Issue 6 (June 2013) published by Elsevier.

Full text of the article is available to credentialed journalists upon request; contact David Sampson at +1 215 239 3171 or ajpmedia@elsevier.com. Journalists may contact Dr. Hae-Young Lopilly Park directly at lopilly@catholic.ac.kr.



About The American Journal of Pathology
The American Journal of Pathology, (http://ajp.amjpathol.org), official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology. The leading global forum for reporting quality original research on cellular and molecular mechanisms of disease, The American Journal of Pathology is the most highly cited journal in Pathology – over 38,000 cites in 2011 – with an Impact Factor of 4.890 according to 2011 Journal Citation Reports® Thomson Reuters. About Elsevier

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