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L. Bellner, K. A. Patil, M. W. Dunn, N. G. Abraham, M. Laniado Schwartzman; Biliverdin Rescues the HO-2 Null Mouse Phenotype of Unresolved Chronic Inflammation Following Corneal Epithelial Injury. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2378. doi: https://doi.org/.
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The heme oxygenase system (HO-1 and HO-2) represents an intrinsic cytoprotective and anti-inflammatory pathway 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). We have shown that epithelial injury in HO-2 null mice leads to impaired healing and chronic inflammatory complications including ulceration, perforation and neovascularization. We examined whether topically administered biliverdin can counteract the effects of HO deficiency in a corneal epithelial injury model.
Mice were treated with biliverdin [(20 mg/kg in 100 µl ip once daily; and topical (10 µl of 100 µM), or its vehicle (Hank’s balanced salt solution, pH 7.4) one hour prior to injury and bid thereafter]. The corneal epithelium was removed using an Alger Brush in anesthetized mice. Re-epithelialization was assessed at days 2, 4 and 7 by fluorescein staining. Neovascularization was assessed at days 2, 4 and 7 by vital microscopy and quantified by image analysis. Expression of inflammatory cytokines was assessed using the Pierce SearchLight mouse microarray.
Treatment with biliverdin significantly accelerated wound closure when compared with vehicle-treated group (86.39±2.38 vs. 34.92±9.60 % wound closure; p<0.001; n=6-8, 4 days after injury, and 90.95±1.70 vs. 68.95±10.12 %; p<0.05; n=4, 7 days after injury). Biliverdin treatment inhibited neovascularization as evidenced by a significant decrease in the length (mm) of infiltrating vessels (1.60±0.43 vs. 12.11±3.98; p<0.05; n=6-8, 4 days after injury, and 0.84±0.54 vs. 18.81±3.98; p<0.05; n=4, 7 days after injury) and attenuated ulceration and perforation (mm2) (1.42±0.36 vs. 2.38±0.38; p<0.05; n=6-8, 4 days after injury, and 0.88±0.42 vs. 2.55±0.38; p<0.05; n=4, 7 days after injury). This was associated with a 30-50% reduction in the expression of inflammatory cytokines including IL1-α, MIP-2, MCP-1, and KC.
Biliverdin and its metabolite bilirubin has been shown to protect against tissue damage by exerting antioxidant and anti-inflammatory effects, including inhibition of adhesion molecules and leukocyte recruitment, and suppression of cytokine/chemokine expression. The results of this study clearly indicate that biliverdin rescues the aberrant inflammatory phenotype and further underscores the importance of the HO system in the cornea for the execution of an ordered inflammatory and reparative response.
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