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K. Gronert, I. Hassan, B. Biteman, E. Walker, M. Dunn; A Critical Role for Lipid Mediators in Balancing the Inflammatory Response of the Cornea . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4368.
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© ARVO (1962-2015); The Authors (2016-present)
We recently identified a constitutive protective lipid circuit in the cornea that limits the sequelae of injury. Therapeutic amplification of this circuit with Lipoxin A4 (LXA4) and docosahexaenoic acid (DHA)–derived neuroprotectin D1 (NPD1) promotes epithelial wound healing while genetic deletion of a key biosynthetic pathway (15–LOX) impairs re–epithelialization. We set out to delineate the role and mechanism of action of this lipid circuit in acute and exasperated corneal inflammation.
Epithelial wound healing and corneal inflammation were assessed in 15–LOX deficient mice and congenic C57BL/6J mice. Partial or full epithelial injuries were generated by an Algerbrush and epithelial defects and wound healing quantitated by digital image analyses. Mouse corneas, isolated macrophages and human corneal epithelial cells were treated topically with LPS (Pseudomonas aeruginosa), saline, LXA4 and/or DHA–derived mediators. RNA expression of 15–LOX (Alox15, ALOX15 and ALOX15B), LXA4 receptor and heme–oxygenases (HO–1, HO–2) was determined by fluorescence based kinetic PCR analysis. LXA4 and NPD1 formation was analyzed by HPLC, GC/MS and ELISA and cytokine/chemokine formation by a custom ELISA Proteome array. Myleoperoxidase activity was selected as a quantitative marker for PMN content of mouse corneas.
Epithelial removal induced a temporally defined influx of PMN and formation of the chemokine IL–8 and MCP–1. Genetic deletion of 15–LOX was associated with delayed wound healing and decreased PMN infiltration in the acute and self–resolving inflammatory/reparative response of the mouse cornea. In contrast, amplification of acute inflammation by chronic LPS treatment significantly increased PMN recruitment (2–3 fold), which was exasperated by genetic deletion of 15–LOX. The 15–LOX products LXA4 and DHA–derived lipid signals proved to be potent inducers of the intrinsic cytoprotective HO–1 system and inhibitors of chemokine formation. LPS amplification of acute inflammation was associated with impaired wound healing and topical treatment with anti–inflammatory lipid mediators restored normal wound healing and abrogated PMN recruitment.
Collectively, these results suggest that 15–LOX products have distinct epithelial and leukocyte bioactions in the cornea that directly depend on the degree of the inflammatory response. Furthermore, these findings indicate an intrinsic role for a protective lipid circuit in balancing the inflammatory/reparative response of the cornea.
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