title: Knockdown of heme oxygenase-2 impairs corneal epithelial cell wound healing.
abstract: Heme oxygenase (HO) represents an intrinsic cytoprotective system based on its anti-oxidative and anti-inflammatory properties mediated via its products biliverdin/bilirubin and carbon monoxide (CO). We showed that deletion of HO-2 results in impaired corneal wound healing with associated chronic inflammatory complications. This study was undertaken to examine the role of HO activity and the contribution of HO-1 and HO-2 to corneal wound healing in an in vitro epithelial scratch injury model. A scratch wound model was established using human corneal epithelial (HCE) cells. These cells expressed both HO-1 and HO-2 proteins. Injury elicited a rapid and transient increase in HO-1 and HO activity; HO-2 expression was unchanged. Treatment with biliverdin or CORM-A1, a CO donor, accelerated wound closure by 10% at 24 h. Inhibition of HO activity impaired wound closure by more than 50%. However, addition of biliverdin or CORM-A1 reversed the effect of HO inhibition on wound healing. Moreover, knockdown of HO-2 expression, but not HO-1, significantly impaired wound healing. These results indicate that HO activity is required for corneal epithelial cell migration. Inhibition of HO activity impairs wound healing while amplification of its activity restores and accelerates healing. Importantly, HO-2, which is highly expressed in the corneal epithelium, appears to be critical for the wound healing process in the cornea. The mechanisms by which it contributes to cell migration in response to injury may reside in the cytoprotective properties of CO and biliverdin.
authors.affiliation: Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: Adna
authors.initials: A
authors.lastname: Halilovic
authors.forename: Kiran A
authors.initials: KA
authors.lastname: Patil
authors.forename: Lars
authors.initials: L
authors.lastname: Bellner
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Marrazzo
authors.forename: Kirkland
authors.initials: K
authors.lastname: Castellano
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cullaro
authors.forename: Michael W
authors.initials: MW
authors.lastname: Dunn
authors.forename: Michal Laniado
authors.initials: ML
authors.lastname: Schwartzman
mesh_terms: D001664:Biliverdine / Q000378:metabolism; D001880:Boranes / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism; D002254:Carbonates / Q000494:pharmacology; D002465:Cell Movement; D002478:Cells, Cultured; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D019573:Epithelium, Corneal / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000172:deficiency* / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics; D006801:Humans; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D014945:Wound Healing / Q000187:drug effects
chemical_list: D001880:Boranes; D002254:Carbonates; C503854:sodium boranocarbonate; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D001664:Biliverdine