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Originally published In Press as doi:10.1074/jbc.M410638200 on February 11, 2005

J. Biol. Chem., Vol. 280, Issue 15, 15267-15278, April 15, 2005
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A Role for the Mouse 12/15-Lipoxygenase Pathway in Promoting Epithelial Wound Healing and Host Defense*{boxs}

Karsten Gronert{ddagger}, Neha Maheshwari, Nabeela Khan, Iram R. Hassan, Michael Dunn, and Michal Laniado Schwartzman

From the New York Medical College, Department of Pharmacology, Valhalla, New York 10595

The surface of the eye actively suppresses inflammation while maintaining a remarkable capacity for epithelial wound repair. Our understanding of mechanisms that balance inflammatory/reparative responses to provide effective host defense while preserving tissue function is limited, in particular, in the cornea. Lipoxin A4 (LXA4) and docosahexaenoic acid-derived neuroprotectin D1 (NPD1) are lipid autacoids formed by 12/15-lipoxygenase (LOX) pathways that exhibit anti-inflammatory and neuroprotective properties. Here, we demonstrate that mouse corneas generate endogenous LXA4 and NPD1. 12/15-LOX (Alox15) and LXA4 receptor mRNA expression as well as LXA4 formation were abrogated by epithelial removal and restored during wound healing. Amplification of these pathways by topical treatment with LXA4 or NPD1 (1 µg) increased the rate of re-epithelialization (65–90%, n = 6–10, p < 0.03) and attenuated the sequelae of thermal injury. In contrast, the proinflammatory eicosanoids, LTB4 and 12R-hydroxyeicosatrienoic acid, had no impact on corneal re-epithelialization. Epithelial removal induced a temporally defined influx of neutrophils into the stroma as well as formation of the proinflammatory chemokine KC. Topical treatment with LXA4 and NPD1 significantly increased PMNs in the cornea while abrogating KC formation by 60%. More importantly, Alox15-deficient mice exhibited a defect in both corneal re-epithelialization and neutrophil recruitment that correlated with a 43% reduction in endogenous LXA4 formation. Collectively, these results identify a novel action for the mouse 12/15-LOX (Alox15) and its products, LXA4 and NPD1, in wound healing that is distinct from their well established anti-inflammatory properties.

Received for publication, September 15, 2004 , and in revised form, February 8, 2005.

* This work was supported by National Institutes of Health Grants DK6053 (to K. G.) and EY06513 (to M. L. S.). 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.

{boxs} The on-line version of this article (available at http://www.jbc.org) contains an additional figure.

{ddagger} To whom correspondence should be addressed: Dept. of Pharmacology, NY Medical College, Valhalla, NY 10595. Tel.: 914-594-4625; Fax: 914-594-4273; E-mail: karsten_gronert{at}nymc.edu.


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