Abstract
Abstract: :
Purpose:Heme oxygenases (HO–1 and HO–2) constitute an intrinsic cytoprotective and anti–inflammatory system in cells and tissues. This cytoprotection is attributed to the ability of HO to inhibit expression of inflammatory cytokines and proteins as well as to its products bilirubin (a powerful antioxidant) and CO (a vasodilator and anti–apoptotic factor). Coexisting with the HO system in the corneal epithelium is the cytochrome P450 (CYP) dependent pathway that converts arachidonic acid into two potent inflammatory mediators that constitute a critical part of the ocular surface inflammatory response. Induction of HO activity substantially attenuates the ocular surface inflammatory response and the associated corneal changes while enhancing cell survival by decreasing CYP activity. The present study was set to examine whether a deficiency in the ability to express this system impairs corneal recovery following injury. Methods:We used HO–2 knockout mice. Injury was performed by removing the epithelium from corneas using an Algerbrush. Wound healing, re–epithelialization, opacity and neo–vascularization were assessed by slit lamp vital microscopy. Corneas were collected at different time after injury (1–14 days) and inflammatory markers quantified by ELISA, mass spectrometry, and RT–PCR. Results:This injury produced a consistent and predictable inflammatory response including injection, neutrophil infiltration and neovascularization and a time dependent re–epithelization with full wound closure by 4 days. The results clearly indicate that HO–2 deficiency results in an aberrant inflammatory response including delayed wound closure, ulceration, persistent neovascularization and perforation. This response was associated with inability to upregulate HO–1, increased expression of inflammatory genes including CYP, COX–2 and IL–12, and increased production of inflammatory mediators such as PGE2 and the angiogenic CYP–derived eicosanoid, 12–HETrE. Conclusions:These results demonstrate that the HO–2 knockout mice experience an exaggerated uncontrolled chronic inflammation and suggest a novel role for HO–2 in providing cytoprotection, a role previously assigned primarily to the HO inducible form, HO–1. Better understanding of the complex heme–heme oxygenase system may result in novel tools to combat diverse conditions, such as inflammation.
Keywords: inflammation • wound healing • eicosanoids