PURPOSE. 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 the expression of inflammatory
cytokines and
proteins by its products
biliverdin/
bilirubin and
carbon monoxide.
Corneal injury in HO-2 null mice leads to impaired healing and chronic inflammatory complications, including ulceration and neovascularization. The authors examined whether topically administered
biliverdin can counteract the effects of HO deficiency in a corneal epithelial injury model. METHODS. HO-2 null mice were treated with
biliverdin 1 hour before epithelial injury and twice a day thereafter. Reepithelialization and neovascularization were assessed by
fluorescein staining and vital microscopy, respectively, and were quantified by image analysis.
Inflammation was quantified by histology and Gr-1-specific immunofluorescence, and oxidative stress was assessed by DHE fluorescence. RESULTS. Treatment with
biliverdin accelerated
wound closure, inhibited neovascularization and reduced epithelial defects. It also reduced
inflammation, as evidenced by a reduction in the appearance of inflammatory cells and the expression levels of inflammatory and
oxidant proteins, including KC and NOXs. CONCLUSIONS. The results clearly show that
biliverdin, directly or through its metabolism to
bilirubin by
biliverdin reductase-the expression of which is increased after injury-rescues the aberrant inflammatory phenotype, further underscoring the importance of the HO system in the cornea for the execution of an ordered inflammatory and reparative response.