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F. Seta, L. Bellner, M.W. Dunn, N.G. Abraham, K. Gronert, M.L. Schwartzman; Heme Oxygenase–2 (HO–2) Is a Critical Component of the Acute Inflammatory and Reparative Response of the Cornea to Injury . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4914.
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Heme oxygenase (HO–1 and HO–2) is considered an endogenous cytoprotective and anti–inflammatory system; it is readily upregulated in response to injury and its activity (production of bilirubin and carbon monoxide) results in less tissue damage with reduction in inflammatory events including leukocyte adhesion and migration, and production of inflammatory cytokines/proteins. We demonstrated that HO induction attenuated inflammation and neovascularization in a rabbit model of corneal injury. We now examine whether a deficiency in the ability to fully express the HO system impairs corneal recovery following injury.
Injury was performed by removing the epithelium from corneas of wild type (WT) and HO–2 null mice (HO–2–/–). Wound healing and neovascularization were assessed by slit lamp microscopy coupled with image analysis. Inflammatory response was quantified by myeloperoxidase (MPO) activity, histology and immunohistochemistry of CD68 positive cells. Inflammatory chemokines and lipid mediators were measured by ELISA and GC/MS. HO–1, HO–2 and CYP4B1 expression levels were determined by real time PCR and immunoblotting.
Corneal epithelial removal produced a consistent inflammatory response and a time–dependent re–epithelization with wound closure by 5 days in WT. HO–2–/– mice showed an aberrant inflammatory response including impaired wound closure (58.3±5.2% vs 98.7±12% at day 7 after injury), ulceration, and persistent (14 days after injury) neovascularization (32.81±17.34 vs 0.24±0.42 mm; p<0.05). This response was associated with inability to upregulate HO–1, decreased HO activity, increased expression of inflammatory genes (CYP4B1); and increased production of the inflammatory eicosanoid, 12–HETrE (0.38±0.06 vs 0.07±0.01 ng/cornea, p<0.05). Leukocyte influx and macrophage presence in the corneal stroma 2–4–times greater in HO–2–/– as compared to WT and this increase correlated with an higher and sustained (up to 14 days) production of the inflammatory chemokines, KC, MIP–2 and MCP–1.
A deficiency in HO activity, as in the HO–2 null mice, deranges the inflammatory response with respect to cell infiltration, expression of inflammatory genes and production of proinflammatory lipid mediators and impairs wound healing allowing an acute inflammation to become chronic. Moreover, the HO system may constitute an endogenous anti–inflammatory and protective circuit critical for a self–resolving inflammatory–reparative process in the cornea.
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