Knockdown of Heme Oxygenase-2 Impairs Corneal Epithelial Cell Wound Healing

被引:38
作者
Halilovic, Adna [1 ]
Patil, Kiran A. [1 ]
Bellner, Lars [1 ]
Marrazzo, Giuseppina [1 ]
Castellano, Kirkland [1 ]
Cullaro, Giuseppe [1 ]
Dunn, Michael W. [1 ]
Schwartzman, Michal Laniado [1 ]
机构
[1] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA
关键词
CARBON-MONOXIDE; BILIVERDIN REDUCTASE; SIGNALING PATHWAY; GROWTH-FACTORS; INFLAMMATION; INJURY; HO-2; ACTIVATION; BILIRUBIN; MOLECULE;
D O I
10.1002/jcp.22502
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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. J. Cell. Physiol. 226: 1732-1740, 2011. (C) 2010 Wiley-Liss, Inc.
引用
收藏
页码:1732 / 1740
页数:9
相关论文
共 49 条
[21]   Distinct protective mechanisms of HO-1 and HO-2 against hydroperoxide-induced cytotoxicity [J].
Kim, YS ;
Zhuang, H ;
Koehler, RC ;
Doré, S .
FREE RADICAL BIOLOGY AND MEDICINE, 2005, 38 (01) :85-92
[22]   Catalytically inactive heme oxygenase-2 mutant is cytoprotective [J].
Kim, YS ;
Doré, S .
FREE RADICAL BIOLOGY AND MEDICINE, 2005, 39 (04) :558-564
[23]   Two waves of neutrophil emigration in response to corneal epithelial abrasion: Distinct adhesion molecule requirements [J].
Li, Zhijie ;
Burns, Alan R. ;
Smith, C. Wayne .
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2006, 47 (05) :1947-1955
[24]   Corneal epithelial wound healing [J].
Lu, L ;
Reinach, PS ;
Kao, WWY .
EXPERIMENTAL BIOLOGY AND MEDICINE, 2001, 226 (07) :653-664
[25]   Heme oxygenase-2 is a hemoprotein and binds heme through heme regulatory motifs that are not involved in heme catalysis [J].
McCoubrey, WK ;
Huang, TJ ;
Maines, MD .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (19) :12568-12574
[26]   Suppression of inflammatory cytokine production by carbon monoxide involves the JNK pathway and AP-1 [J].
Morse, D ;
Pischke, SE ;
Zhou, ZH ;
Davis, RJ ;
Flavell, RA ;
Loop, T ;
Otterbein, SL ;
Otterbein, LE ;
Choi, AMK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (39) :36993-36998
[27]   Heme oxygenase-1, a critical arbitrator of cell death pathways in lung injury and disease [J].
Morse, Danielle ;
Lin, Ling ;
Choi, Augustine M. K. ;
Ryter, Stefan W. .
FREE RADICAL BIOLOGY AND MEDICINE, 2009, 47 (01) :1-12
[28]   CORM-A1: a new pharmacologically active carbon monoxide-releasing molecule [J].
Motterlini, R ;
Sawle, P ;
Bains, S ;
Hammad, J ;
Alberto, R ;
Foresti, R ;
Green, CJ .
FASEB JOURNAL, 2004, 18 (14) :284-+
[29]   Biliverdin protects the functional integrity of a transplanted syngeneic small bowel [J].
Nakao, A ;
Otterbein, LE ;
Overhaus, M ;
Sarady, JK ;
Tsung, A ;
Kimizuka, K ;
Nalesnik, MA ;
Kaizu, T ;
Uchiyama, T ;
Liu, F ;
Murase, N ;
Bauer, AJ ;
Bach, FH .
GASTROENTEROLOGY, 2004, 127 (02) :595-606
[30]   Therapeutic applications of bilirubin and biliverdin in transplantation [J].
Oellinger, Robert ;
Wang, Hongjun ;
Yamashita, Kenichiro ;
Wegiel, Barbara ;
Thomas, Michael ;
Margreiter, Raimund ;
Bach, Fritz H. .
ANTIOXIDANTS & REDOX SIGNALING, 2007, 9 (12) :2175-2185