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Lars Bellner, Michael Covey, Michael W Dunn, Michal Schwartzman; Macrophage Heme Oxygenase 2 is necessary but not sufficient for successful corneal wound healing response. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5499.
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We have shown that in HO-2 null mice epithelial injury leads to massive infiltration of inflammatory cells, chronic inflammation, ulceration, perforation and neovascularization. We examined the effect of systemic depletion of macrophages and allogeneic bone marrow transfer in HO-2 null and wild type mice on corneal wound healing and inflammatory response.
Clodronate liposomes were injected into the peritoneum starting one day prior to injury and every other day thereafter. For bone marrow transfer experiments, mice were lethally irradiated followed by transfer of 10*106 allogeneic bone marrow cells. The corneal epithelium was removed using an Alger Brush on anesthetized mice. Re-epithelialization was assessed by fluorescein staining. Inflammatory response was quantified by histology and MPO activity. Levels of mRNA were measured by RT-PCR.
Macrophage depletion of WT mice delayed corneal re-epithelialization when compared with the control treated group by 15% at day 4 after injury (p<0.05). Corneal wound healing in HO-2 null mice was significantly delayed as compared to WT at day 4 after injury (p<0.05). Surprisingly, macrophage depletion of HO-2 null mice had no additional effect on an already impaired corneal wound healing. Wild type mice receiving bone marrow from HO-2 knockout mice showed no impairment of the wound healing response, whereas the corneal wound healing in HO-2 null mice receiving wild type bone marrow was significantly accelerated as compared to HO-2 null mice receiving isogeneic bone marrow 79.1% vs 58.9% at day 4 after injury.
This study shows that macrophage depletion has a negative impact on wound healing rate in WT, but not in HO-2 null mice. More importantly, corneal wound healing in HO-2 null mice receiving wild type bone marrow is significantly improved, whereas wild type mice receiving bone marrow from HO-2 null mice was not impaired. Together these data strongly suggest that HO-2 is important in macrophages, but crucial in corneal epithelium in the orchestration of an ordered wound healing response upon injury.
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