Sex-specific Regulation of Acute Inflammation and Resolution

关于雌激素在免疫和免疫调节中的复杂作用， 炎症反应。性别特异性差异和雌激素在眼部炎症性疾病中的作用并不 尽管干眼症主要影响女性，但这一点已经得到很好的理解。雌激素受体， ER <$和ER <$在白细胞和每个眼组织中表达。急性健康炎症取决于 中性粒细胞的早期募集、其严格控制的活化和随后被募集的 巨噬细胞这种基本反应的失调可能代表了触发 炎症和慢性疾病。脂质介质脂氧素A4（LXA 4）已被鉴定为 炎症消退和白细胞功能调节剂。角膜高度表达一种关键酶， LXA 4形成、15-脂氧合酶（15-LOX）及其G蛋白偶联受体ALX。基因破坏 15-LOX/LXA 4回路导致炎症失调，伤口愈合和病理性血管生成 角膜初步研究表明，雌性小鼠一贯表现出延迟上皮伤口， 结束一项在120名角膜溃疡患者中进行的前瞻性临床试验首次记录了 女性患者的上皮伤口愈合速度是男性的两倍。伤口愈合延迟的女性表型 可以通过用局部雌激素处理雄性小鼠和在体外实验中用角膜移植来概括。 上皮细胞更重要的是，ER和ER特异性激动剂差异调节炎症， 上皮伤口愈合和内在15-LOX/LXA 4回路的表达和活性。这些发现 与干眼症模型的脂质组学分析相关，干眼症模型显示角膜15-LOX显著受损 在雌性小鼠中的活性。雌激素对这种内在脂质回路的选择性调节可能提供新的见解 性别特异性眼表炎性疾病的病因或发病机制，将在 三个具体目标：一。表征在15-LOX和LXA 4回路中的性别特异性差异， 角膜中的急性和复发性上皮损伤和炎症。二.阐明雌激素的作用 受体（ER <$和ER <$）调节角膜上皮和白细胞伤口愈合功能， 定义这些细胞中15-LOX和LXA 4回路的受体特异性调节。三.描述ER的作用， ER在小鼠干眼角膜发病机制中的作用，并确定了内源性15-LOX和 LXA 4电路。这项研究的结果将解决关于雌激素作用的关键知识空白， 它的受体在眼睛的急性炎症/修复反应，并将首次定义性别特异性 （雌激素）调节对炎症消退至关重要的内在脂质回路。我们的知识 LXA 4和相关模拟物的结构功能关系、受体和信号转导途径， 在动物模型中已经建立了相对先进和有效性/安全性。因此，本研究的结果 可迅速为临床带来眼表炎性疾病的新治疗选择。 !

There is a great interest and unresolved paradox regarding the complex role of estrogen in immune and inflammatory responses. Sex-specific differences and estrogen's role in ocular inflammatory diseases are not well understood, even though Dry Eye Syndromes primarily affect women. Receptors for estrogens, ER¿ and ER¿, are expressed in leukocytes and in every ocular tissue. Acute healthy inflammation depends on the early recruitment of neutrophils, their tightly controlled activation and subsequent removal by recruited macrophages. Dysregulation of this essential response likely represent the early event that triggers inflammatory and chronic diseases. The lipid mediator lipoxin A4 (LXA4) has been identified as key mediator of inflammatory resolution and regulators of leukocyte function. The cornea highly expresses a key enzyme for LXA4 formation, 15-lipoxygenase (15-LOX), and its G-protein coupled receptor ALX. Genetic disruption of the 15-LOX/LXA4 circuit leads to dysregulated inflammation, wound healing and pathological angiogenesis in the cornea. Preliminary studies demonstrate that female mice consistently exhibit delayed epithelial wound closure. A prospective clinical trial in 120 patients with corneal ulcers, documents for the first time, that epithelial wounds healed twice as slow in female patients. The female phenotype of delayed wound healing can be recapitulated by treating male mice with topical estrogen and in in vitro experiments with corneal epithelial cells. More importantly, ER¿ and ER¿ specific agonists differentially regulated inflammation, epithelial wound healing and the expression and activity of the intrinsic 15-LOX/LXA4 circuit. These findings correlate with lipidomic analysis from a dry eye model that demonstrates striking impairment in corneal 15-LOX activity in female mice. Estrogen's selective regulation of this intrinsic lipid circuit may provide novel insights into the etiology or pathogenesis of sex-specific ocular surface inflammatory diseases, which will be tested in three specific aims: I. Characterize sex-specific differences in the intrinsic 15-LOX and LXA4 circuit during acute and reoccurring epithelial injury and inflammation in the cornea. II. Elucidate the role of the estrogen receptors (ER¿ and ER¿) in the regulation of corneal epithelial and leukocyte wound healing function and define receptor specific regulation of the 15-LOX and LXA4 circuit in these cells. III. Delineate the role ER¿ and ER¿ in the corneal pathogenesis of dry eye in mice and define the protective role of the intrinsic 15-LOX and LXA4 circuit. Result from this study will address critical gaps of knowledge regarding the role of estrogen and its receptors in acute inflammatory/reparative responses in the eye and will define for the first time sex-specific (estrogen) regulation of intrinsic lipid circuits that are critical for inflammatory resolution. Our knowledge of structure function relationships, receptors and signal transduction pathways for LXA4 and related mimetics is relatively advanced and efficacy/safety in animal models have been established. Hence, results from this study could rapidly bring novel treatment options for ocular surface inflammatory diseases to the clinic. !