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J. Biol. Chem., Vol. 283, Issue 19, 13418-13427, May 9, 2008

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Intestinal Trefoil Factor/TFF3 Promotes Re-epithelialization of Corneal Wounds^*

Friedrich P. Paulsen¹, Chee-Wai Woon, Deike Varoga^¶, Anne Jansen^¶, Fabian Garreis, Kristin Jäger, Marita Amm^||, Daniel K. Podolsky^**, Philipp Steven, Nicholas P. Barker, and Saadettin Sel^||

From the Department of Anatomy and Cell Biology and ^||Department of Ophthalmology, Martin Luther University Halle-Wittenberg, D-06097 Halle, Germany, ^¶Institute of Anatomy, Christian Albrecht University, 24098 Kiel, Germany, The GI Co. Inc., Framingham, Massachusetts 01701, ^**Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, and Department of Ophthalmology, University of Lübeck, 23538 Lübeck, Germany

Disorders of wound healing characterized by impaired or delayed re-epithelialization are a serious medical problem. These conditions affect many tissues, are painful, and are difficult to treat. In this study using cornea as a model, we demonstrate the importance of trefoil factor 3 (TFF3, also known as intestinal trefoil factor) in re-epithelialization of wounds. In two different models of corneal wound healing, alkali- and laser-induced corneal wounding, we analyzed the wound healing process in in vivo as well as in combined in vivo/in vitro model in wild type (Tff3^+/+) and Tff3-deficient (Tff3^-/-) mice. Furthermore, we topically applied different concentrations of recombinant human TFF3 (rTFF3) peptide on the wounded cornea to determine the efficacy of rTFF3 on corneal wound healing. We found that Tff3 peptide is not expressed in intact corneal epithelium, but its expression is extensively up-regulated after epithelial injury. Re-epithelialization of corneal wounds in Tff3^-/- mice is significantly prolonged in comparison to Tff3^+/+ mice. In addition, exogenous application of rTFF3 to the alkali-induced corneal wounds accelerates significantly in in vivo and in combined in vivo/in vitro model wound healing in Tff3^+/+ and Tff3^-/- mice. These findings reveal a pivotal role for Tff3 in corneal wound healing mechanism and have broad implications for developing novel therapeutic strategies for treating nonhealing wounds.

Received for publication, January 9, 2008 , and in revised form, February 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK46906 (to D. K. P.). This work was also supported by the GI Co. Inc.; Deutsche Forschungsgemeinschaft Grants PA 738/6-1 and PA 738/9-1 (to F. P.); Bundesministerium für Bildung und Forschung, Wilhelm Roux Program, Halle, Germany, Program Grants FKZ 14/24 and 14/25; and by a Sicca Research Promotion by the Association of German Ophthalmologits (to A. J. and F. P.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Martin Luther University Halle-Wittenberg, Dept. of Anatomy and Cell Biology, Grosse Steinstrasse 52, D-06097 Halle, Germany. Tel.: 49-345-5571707; Fax: 49-345-5571700; E-mail: friedrich.paulsen{at}medizin.uni-halle.de.

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