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L. Bellner, F. Seta, N.G. Abraham, M.W. Dunn, K. Gronert, M. Laniado–Schwartzman; Biliverdin and Carbon Monoxide Ameliorate Corneal Inflammation and Neovascularization in Heme Oxygenase (HO)–2 Deficient Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):1624.
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© ARVO (1962-2015); The Authors (2016-present)
HO represents an intrinsic cytoprotective and anti–inflammatory system based on its ability to modulate leukocyte migration and to inhibit expression of inflammatory cytokines and proteins via its products biliverdin/bilirubin and carbon monoxide (CO). Lack of HO activity results in unresolved corneal inflammation and chronic inflammatory complications including ulceration, perforation and neovascularization. We examine whether topically administered biliverdin and/or CO can counteract the effects of HO deficiency in a model of inflammation–associated corneal neovascularization.
A 7.0 silk suture was placed halfway between the limbus and the apex; neovascularization was monitored for one week in wild type (wt) and HO–2 null mice. Eyes of HO–2 null mice were treated topically once a day with a drop of 100 µM biliverdin or 100 µM CORM–3, a CO donor. Neovascularization was assessed by slit–lamp vital microscopy and quantified by image analysis. Leukocyte influx was determined by measuring myeloperoxidase activity.
Corneal sutures produced a consistent inflammatory response and a time–dependent neovascularization. The response in HO–2 null mice was associated with a greater increase compared to wt in the number of neutrophils (267,600±183,200 vs 79,020±31,090; p<0.05) and neovessels (5.39±0.71 vs 1.37±0.45 mm; p<0.05). Topical application of biliverdin or CO–donor to the eyes of HO–2 null mice markedly reduced corneal opacity, leukocyte influx, and neovascularization by 50 – 80% compared to untreated eyes.
HO–2 deficiency resulted in exaggerated inflammatory response and marked neovascularization. Moreover, the demonstration that supplementation of HO products, biliverdin and CO, lessens inflammatory neovascularization strongly supports the notion that the HO system is critical for the regulation of the inflammatory and neovascular response of the cornea and provides evidence that the anti–inflammatory and protective mechanisms of the HO system in the cornea include bilirubin/biliverdin and CO, potent endogenous antioxidant and anti–inflammatory molecules.
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