Heme Oxygenase-1 Induction Attenuates Corneal Inflammation and Accelerates Wound Healing after Epithelial Injury
Kiran A Patil 1,
Lars Bellner 1,
Giuseppe Cullaro 1,
Katherine Gotlinger 2,
Michael W Dunn 1,
and
M. Laniado Schwartzman 3*
1 Pharmacology, New York Medical College, Valhalla, New York, United States
2 New York Medical College, Valhalla, New York, United States
3 New York Medical College, Department of Pharmacology, Grassland Road, BSB 530, Valhalla, New York, 10595, United States
* To whom correspondence should be addressed. E-mail: michal_schwartzman{at}nymc.edu.
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Abstract |
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Purpose: Heme oxygenase (HO) is considered a fundamental endogenous immunomodulatory, cytoprotective and anti-inflammatory system. 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.
Methods: C57BL6 mice were treated with SnCl2 one day prior to epithelial injury and once daily, thereafter. The corneal epithelium was removed using an Alger Brush in anesthetized mice. Re-epithelialization was measured by fluorescein staining. The inflammatory response was examined by histology and quantified by the myeloperoxidase assay. Inflammatory lipid mediators were detected and quantified by LC-MS-MS-based lipidomic analysis. HO-1 expression was assessed by real-time PCR and HO activity was determined by measuring HO-dependent carbon monoxide (CO) production.
Results: Epithelial injury caused a time-dependent transient increase in HO-1 expression and HO activity which was significantly amplified by treatment with SnCl2 resulting in a 2-3-fold increase in mRNA levels and a similar increase in corneal HO activity. Induction of HO-1 was associated with a significant acceleration of wound healing when compared with a vehicle-treated group and with attenuation of the inflammatory response evidenced by a significant decrease in the number of infiltrating cells and by a significant reduction in the expression and production of pro-inflammatory lipid mediators and cytokines.
Conclusions: We conclude that increased expression of HO-1 provides a mechanism that modulates inflammation and promotes wound closure; pharmacological amplification of this system may constitute a novel strategy to treat corneal inflammation while accelerating wound repair following injury.
Key Words:
anti-inflammatory agents, corneal wound healing, corneal epithelium, arachidonic acid
