Protective Lipid Circuits in Corneal Injury and Disease

描述：角膜过度炎症或无序的伤口修复严重损害视力或导致失明，影响全球数百万人。我们对控制自然分解的内源性机制的了解有限，特别是在眼睛中；破坏促炎循环或促进上皮愈合的途径仍有待确定。我们已经发现了一种新型的抗炎类脂类化合物，它是由omega-3脂肪酸产生的，可以抑制主要的炎症迹象。它们的分子作用机制和形成途径与已知的抗炎脂质介体脂氧素(Lx)是相同的。这些脂环存在于角膜中，更重要的是，LXA4或17S-solvins的治疗应用抑制了炎症并促进了小鼠角膜的伤口愈合。因此，我们假设角膜损伤诱导抗炎脂质介质的形成，即脂氧素和DHA衍生的17S-解决素，这些保护性脂质回路的饮食或治疗放大促进伤口愈合并限制角膜损伤的后遗症。 为了确定脂质类化合物在限制角膜损伤中的作用，我们将使用脂质分析、分子生物学和体内遗传操作的方法来解决三个特定目标：i)确定抗炎脂质介质，即脂氧素和DHA衍生的17S-solvins，作为炎症修复反应的一部分形成；ii)确定omega-3饮食中扩增17S-solvin途径或直接局部应用LXA4或17S-solvins是否加速角膜炎症的溶解和伤口愈合；iii)证明LXA4受体的表达或17S-solvins和lipoxins的生物合成途径是限制角膜损伤的决定因素。这一建议的结果将确定限制角膜炎症和促进上皮伤口愈合的内源性机制，因此，可能对保持角膜透明度至关重要。此外，它们可能为治疗角膜损伤提供一种新的替代方法，即放大内源性保护性脂质回路。

DESCRIPTION: Excessive inflammation or disordered wound repair in the cornea significantly impairs vision or ends in blindness, affecting millions of people worldwide. Our understanding of endogenous mechanisms that govern the natural resolution is limited, especially in the eye; pathways that disrupt pro-inflammatory circuits or promote epithelial healing remain to be identified. We have uncovered a novel class of anti-inflammatory lipid autacoids (resolvins) that are generated from omega-3 fatty acids and inhibit cardinal signs of inflammation. Their molecular mechanisms of action and routes of formation are shared with the well-documented anti-inflammatory lipid mediators, lipoxins (LX). These lipid circuits are present in the cornea and, more significantly, therapeutic applications of LXA4 or 17S-resolvins inhibit inflammation and promote wound healing in mouse corneas. Hence, we hypothesize that corneal injury induces formation of anti-inflammatory lipid mediators, namely, lipoxins and DHA-derived 17S-resolvins, and that dietary or therapeutic amplification of these protective lipid circuits promotes wound healing and limits the sequelae of corneal injury. To establish a role for lipid autacoids in limiting corneal injury, we will employ an approach of lipid analysis, molecular biology and in vivo genetic manipulation to address three specific AIMS: I) establish that anti-inflammatory lipid mediators, namely lipoxins and DHA-derived 17S-resolvins, are formed as part of the inflammatory reparative response; II) determine if omega-3 dietary amplification of the 17S-resolvin pathway or direct topical application of LXA4 or 17S-resolvin accelerates inflammatory resolution and wound healing in the cornea; III) demonstrate that expression of the LXA4 receptor or biosynthetic pathways for the formation of 17S-resolvins and lipoxins is a determinant for limiting corneal damage. Results of this proposal will identify endogenous mechanisms that limit corneal inflammation and promote epithelial wound healing and, therefore, may be critical to preserving corneal transparency. Moreover, they may provide a novel alternative approach to treating corneal injury, namely, the amplification of endogenous protective lipid circuits.