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K. A. Patil, L. Bellner, M. W. Dunn, K. Gronert, M. Laniado-Schwartzman; Heme Oxygenase-1 Induction Attenuates Corneal Inflammation and Accelerates Wound Healing After Epithelial Injury. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4315.
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Heme oxygenase (HO) is considered a fundamental endogenous cytoprotective and anti-inflammatory system; it is readily upregulated in response to injury and its activity (production of bilirubin, a potent endogenous antioxidant, and carbon monoxide (CO), a major signaling molecule for maintaining cell function) results in less tissue damage with reduction in inflammatory events including leukocyte adhesion and migration, and production of inflammatory cytokines/proteins. This protective function is primarily ascribed to the inducible HO-1. We examined the effect of HO-1 induction on corneal inflammation and wound healing in mice undergoing epithelial injury.
SnCl2 is a potent inducer of HO-1 in numerous tissues including the cornea (Conners et al, IOVS, 1995). Mice (C57BL6, 6-8 wks old) were treated with SnCl2 (100µl of 10mg/ml, ip; plus topical 10 µl of 100µg/ml) or its vehicle (0.1M potassium phosphate buffer, pH 7.4) one day prior to injury and once daily thereafter. The corneal epithelium was removed using Alger Brush in anesthetized mice. Re-epithelialization was assessed by Fluorescein staining using dissecting microscope and image analysis. Inflammatory response was quantified by myeloperoxidase activity. Protein expression was measured by Western blot and HO activity was determined by measuring CO production.
SnCl2 treatment accelerated re-epithelialization when compared with vehicle-treated group by 40%, 30% and 10% at days 1, 2 and 3 after injury, respectively (n=8, p<0.05). Leukocyte migration to the cornea was also decreased in SnCl2-treated group as compared to vehicle-treated group (55%, 42% and 25% at days 1, 2 and 3 after injury, respectively, n=5; p<0.05). Treatment with SnCl2 increased corneal HO-1 expression by 2-3-fold as compared to vehicle-treated cornea. The increased HO-1 expression was associated with a 2-fold increase in corneal HO activity, i.e., CO production, as compared to the vehicle-treated group.
Induction of corneal HO-1 expression and increased corneal HO activity following SnCl2 treatment was associated with attenuated inflammatory response and accelerated epithelialization of the wounded cornea. We postulate that increased production of the anti-inflammatory and cytoprotective CO and biliverdin provides a mechanism that modulates inflammation and promotes wound closure. Hence, HO-1 represents a fundamental protective system in the cornea and pharmacological amplification of this system may constitute a novel strategy to treat corneal injury.
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