Heme Oxygenase-1 Induction Attenuates Corneal Inflammation and Accelerates Wound Healing After Epithelial Injury

Overview

Journal Invest Ophthalmol Vis Sci

Specialty Ophthalmology

Date 2008 Apr 29

PMID 18441305

Citations 34

Authors

Kiran Patil

Lars Bellner

Giuseppe Cullaro

Katherine H Gotlinger

Michael W Dunn

Michal Laniado Schwartzman

Affiliations

Soon will be listed here.

Abstract

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. The authors examined the effect of HO-1 induction on corneal inflammation and wound healing in mice undergoing epithelial injury.

Methods: C57BL6 mice were treated with SnCl(2) the day before epithelial injury and once daily thereafter. The corneal epithelium was removed with the use of a corneal rust ring remover in anesthetized mice. Reepithelialization was measured by fluorescein staining. The inflammatory response was examined by histology and was 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 production.

Results: Epithelial injury caused a time-dependent transient increase in HO-1 expression and HO activity that was significantly amplified by treatment with SnCl(2), resulting in a twofold to threefold 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 proinflammatory lipid mediators and cytokines.

Conclusions: Increased expression of HO-1 provides a mechanism that modulates inflammation and promotes wound closure; pharmacologic amplification of this system may constitute a novel strategy to treat corneal inflammation while accelerating wound repair after injury.

Citing Articles

Drug-Repurposing Strategy for Dimethyl Fumarate.

Giunta S, DAmico A, Maugeri G, Bucolo C, Romano G, Rossi S Pharmaceuticals (Basel). 2023; 16(7).

PMID: 37513886 PMC: 10386358. DOI: 10.3390/ph16070974.

Lipoxin A4 alleviates inflammation in stimulated human corneal epithelial cells by Nrf2/HO-1 signaling pathway.

Peng X, Zhu X, Luan J, Lin J, Zhang Y, Wang Q Mol Vis. 2023; 28:441-450.

PMID: 36601409 PMC: 9767844.

Gallic Acid Ameliorates Aspergillus Fumigatus Keratitis Through Reducing Fungal Load and Suppressing the Inflammatory Response.

Luan S, Peng X, Lin J, Zhang Y, Zhan L, Yin J Invest Ophthalmol Vis Sci. 2022; 63(12):12.

PMID: 36350620 PMC: 9652715. DOI: 10.1167/iovs.63.12.12.

Attenuation of High Glucose-Induced Damage in RPE Cells through p38 MAPK Signaling Pathway Inhibition.

Maugeri G, Bucolo C, Drago F, Rossi S, Di Rosa M, Imbesi R Front Pharmacol. 2021; 12:684680.

PMID: 34025440 PMC: 8138305. DOI: 10.3389/fphar.2021.684680.

Proteomics Reveals the Potential Protective Mechanism of Hydrogen Sulfide on Retinal Ganglion Cells in an Ischemia/Reperfusion Injury Animal Model.

Liu H, Perumal N, Manicam C, Mercieca K, Prokosch V Pharmaceuticals (Basel). 2020; 13(9).

PMID: 32867129 PMC: 7557839. DOI: 10.3390/ph13090213.

References

Wagener F, Da Silva J, Farley T, de Witte T, Kappas A, Abraham N . Differential effects of heme oxygenase isoforms on heme mediation of endothelial intracellular adhesion molecule 1 expression. J Pharmacol Exp Ther. 1999; 291(1):416-23. View

Yamada M, Kawai M, Kawai Y, Mashima Y . The effect of selective cyclooxygenase-2 inhibitor on corneal angiogenesis in the rat. Curr Eye Res. 1999; 19(4):300-4. DOI: 10.1076/ceyr.19.4.300.5301. View

Brouard S, Otterbein L, Anrather J, Tobiasch E, Bach F, Choi A . Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med. 2000; 192(7):1015-26. PMC: 2193315. DOI: 10.1084/jem.192.7.1015. View

Abraham N, Kushida T, McClung J, Weiss M, Quan S, Lafaro R . Heme oxygenase-1 attenuates glucose-mediated cell growth arrest and apoptosis in human microvessel endothelial cells. Circ Res. 2003; 93(6):507-14. DOI: 10.1161/01.RES.0000091828.36599.34. View

Kuwano T, Nakao S, Yamamoto H, Tsuneyoshi M, Yamamoto T, Kuwano M . Cyclooxygenase 2 is a key enzyme for inflammatory cytokine-induced angiogenesis. FASEB J. 2004; 18(2):300-10. DOI: 10.1096/fj.03-0473com. View

Seta F, Bellner L, Rezzani R, Regan R, Dunn M, Abraham N . Heme oxygenase-2 is a critical determinant for execution of an acute inflammatory and reparative response. Am J Pathol. 2006; 169(5):1612-23. PMC: 1780218. DOI: 10.2353/ajpath.2006.060555. View

Pfaffl M . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45. PMC: 55695. DOI: 10.1093/nar/29.9.e45. View

Abraham N, Conners M, Dunn M, Levere R, Kappas A . Heme oxygenase induction with attenuation of experimentally induced corneal inflammation. Biochem Pharmacol. 1997; 53(8):1069-75. DOI: 10.1016/s0006-2952(97)00080-4. View

Liu N, Wang X, McCoubrey W, Maines M . Developmentally regulated expression of two transcripts for heme oxygenase-2 with a first exon unique to rat testis: control by corticosterone of the oxygenase protein expression. Gene. 1999; 241(1):175-83. DOI: 10.1016/s0378-1119(99)00439-4. View

10.

Kappas A, Maines M . Tin: a potent inducer of heme oxygenase in kidney. Science. 1976; 192(4234):60-2. DOI: 10.1126/science.1257757. View

11.

Ormerod L, Garsd A, Abelson M, Kenyon K . Effects of altering the eicosanoid precursor pool on neovascularization and inflammation in the alkali-burned rabbit cornea. Am J Pathol. 1990; 137(5):1243-52. PMC: 1877677. View

12.

Xue M, Thakur A, Willcox M, Zhu H, Lloyd A, Wakefield D . Role and regulation of CXC-chemokines in acute experimental keratitis. Exp Eye Res. 2003; 76(2):221-31. DOI: 10.1016/s0014-4835(02)00270-1. View

13.

Hanselmann C, Mauch C, Werner S . Haem oxygenase-1: a novel player in cutaneous wound repair and psoriasis?. Biochem J. 2001; 353(Pt 3):459-66. PMC: 1221590. DOI: 10.1042/0264-6021:3530459. View

14.

Bonazzi A, Mastyugin V, Mieyal P, Dunn M . Regulation of cyclooxygenase-2 by hypoxia and peroxisome proliferators in the corneal epithelium. J Biol Chem. 2000; 275(4):2837-44. DOI: 10.1074/jbc.275.4.2837. View

15.

Minamino T, Christou H, HSIEH C, Liu Y, Dhawan V, Abraham N . Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci U S A. 2001; 98(15):8798-803. PMC: 37515. DOI: 10.1073/pnas.161272598. View

16.

Kampfer H, Kolb N, Manderscheid M, Wetzler C, Pfeilschifter J, Frank S . Macrophage-derived heme-oxygenase-1: expression, regulation, and possible functions in skin repair. Mol Med. 2001; 7(7):488-98. PMC: 1950056. View

17.

Wagener F, van Beurden H, Von den Hoff J, Adema G, Figdor C . The heme-heme oxygenase system: a molecular switch in wound healing. Blood. 2003; 102(2):521-8. DOI: 10.1182/blood-2002-07-2248. View

18.

Ohta K, Kikuchi T, Arai S, Yoshida N, Sato A, Yoshimura N . Protective role of heme oxygenase-1 against endotoxin-induced uveitis in rats. Exp Eye Res. 2003; 77(6):665-73. DOI: 10.1016/j.exer.2003.08.014. View

19.

Bazan H, Birkle D, Beuerman R, Bazan N . Inflammation-induced stimulation of the synthesis of prostaglandins and lipoxygenase-reaction products in rabbit cornea. Curr Eye Res. 1985; 4(3):175-9. DOI: 10.3109/02713688509000847. View

20.

Hume E, Sack R, Stapleton F, Willcox M . Induction of cytokines from polymorphonuclear leukocytes and epithelial cells by ocular isolates of Serratia marcescens. Ocul Immunol Inflamm. 2004; 12(4):287-95. DOI: 10.1080/092739490500318. View