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Exacerbated corneal inflammation and neovascularization in the HO-2 null mice is ameliorated by biliverdin.

Abstract
Heme oxygenase (HO-1 and HO-2) represents an intrinsic cytoprotective and anti-inflammatory system based on its ability to modulate leukocyte migration and to inhibit expression of inflammatory cytokines and proteins. HO-2 deletion leads to unresolved corneal inflammation and chronic inflammatory complications including ulceration, perforation and neovascularization. We examined the consequences of HO-2 deletion on hemangiogenesis and lymphangiogenesis in the model of suture-induced inflammatory neovascularization. An 8.0 silk suture was placed at the corneal apex of wild type and HO-2 null mice. Neovascularization was assessed by vital microscopy and quantified by image analysis. Hemangiogenesis and lymphangiogenesis were determined by immunofluorescence staining using anti-CD31 and anti-LYVE-1 antibodies, respectively. Inflammation was quantified by histology and myeloperoxidase activity. The levels of HO-1 expression and inflammatory cytokines were determined by real time PCR and ELISA, respectively. Corneal sutures produced a consistent inflammatory response and a time-dependent neovascularization. The response in HO-2 null mice was associated with a greater increase compared to the wild type in the number of leukocytes (827,600+/-129,000 vs. 294,500+/-57,510; p<0.05), neovessels measured by vital microscopy (21.91+/-1.05 vs. 12.77+/-1.55 mm; p<0.001) 4 days after suture placement. Hemangiogenesis but not lymphangiogenesis was more pronounced in HO-2 null mice compared to wild type mice. Induction of HO-1 in sutured corneas was greatly attenuated in HO-2 null corneas and treatment with biliverdin diminished the exaggerated inflammatory and neovascular response in HO-2 null mice. The demonstration that the inflammatory responses, including expression of proinflammatory proteins, inflammatory cell influx and hemangiogenesis are exaggerated in HO-2 knockout mice strongly supports the notion that the HO system is critical for controlling the inflammatory and neovascular response in the cornea. Hence, pharmacological amplification of this system may constitute a novel therapeutic strategy for the treatment of corneal disorders associated with excessive inflammation and neovascularization.
AuthorsLars Bellner, Marco Vitto, Kiran A Patil, Michael W Dunn, Raymond Regan, Michal Laniado-Schwartzman
JournalExperimental eye research (Exp Eye Res) Vol. 87 Issue 3 Pg. 268-78 (Sep 2008) ISSN: 1096-0007 [Electronic] England
PMID18602389 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Peroxidase
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • heme oxygenase-2
  • Biliverdine
Topics
  • Animals
  • Biliverdine (therapeutic use)
  • Cornea (enzymology)
  • Corneal Neovascularization (enzymology, pathology, prevention & control)
  • Disease Progression
  • Drug Evaluation, Preclinical
  • Female
  • Heme Oxygenase (Decyclizing) (deficiency, metabolism, physiology)
  • Heme Oxygenase-1 (metabolism)
  • Keratitis (enzymology, pathology, prevention & control)
  • Male
  • Mice
  • Mice, Knockout
  • Peroxidase (metabolism)

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