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M. L. Schwartzman, L. Bellner, K. Patil, L. Martinelli, M. W. Dunn, K. Gronert, N. G. Abraham; The Heme Oxygenase (ho) System: An Endogenous Anti-Inflammatory and Protective Circuit for a Self-Resolving Inflammatory-Reparative Process in the Cornea. Invest. Ophthalmol. Vis. Sci. 2008;49(13):444. doi: https://doi.org/.
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In recent years, the heme oxygenase (HO-1 and HO-2) system has emerged as a fundamental endogenous cytoprotective (anti-oxidative) and anti-inflammatory system in many tissues. It is readily upregulated in response to injury and its activity (heme degradation to bilirubin and carbon monoxide,CO) results in lessening tissue damage with significant reductions in inflammatory events including leukocyte adhesion and migration, and production of inflammatory cytokines. The role of the HO system in the cornea is unexplored. We embarked on studies to systematically characterize the HO system in the cornea and evaluate its function in response to injury.
HO-2 null (HO-2-/-), C57BL/129/Sv (wt) and C57BL/6J mice were used. The corneal epithelium was removed using an Alger Brush. Re-epithelialization was monitored by fluorescein staining and quantified by image analysis. Inflammatory neovascularization was induced by placing an 8.0 silk suture at the corneal apex. Hemangiogenesis and lymphangiogenesis were determined by immunofluorescence using anti-CD31 and anti-LYVE-1 antibodies, respectively. Inflammation was assessed by histology and by measuring myeloperoxidase activity, cytokines and inflammatory lipid mediators.
We showed that 1) HO-2 is highly expressed in normal, wounded and repairing corneas; 2) injury rapidly and markedly induced HO-1 mRNA and increased HO activity; 3) induction of HO-1 attenuated inflammation while accelerating wound healing; 4) HO deficiency (HO-2-/-) led to an aberrant inflammatory/reparative response to epithelial injury including increased inflammatory cells and the associated chemokines KC, MIP-2 and MCP-1, impaired re-epithelialization, ulceration, perforation and persistent corneal neovascularization; 5) In the suture-induced neovascularization model, the inflammatory response and the rates of hemeangiogensis and lymphangiogenesis were greater in HO-2-/- mice; and 6) treatment with biliverdin and CO donor rescued the HO-2 null mouse phenotype of unresolved chronic inflammation.
The results strongly implicate a critical role for both HO-1 and HO-2 in the regulation of the inflammatory and reparative response in the cornea and suggest that the HO system acts through its catalytic products, biliverdin/bilirubin or CO, to modulate leukocyte migration and inhibit key proinflammatory circuits, thereby, promoting resolution and repair.
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