Sex-specific Regulation of Acute Inflammation and Resolution

关于雌激素在免疫和免疫系统中的复杂作用，人们有很大的兴趣和尚未解决的悖论。 炎症反应。性别差异和雌激素在眼部炎症性疾病中的作用 众所周知，尽管干眼症主要影响女性。雌激素受体， ER？和ER？在白细胞和所有眼组织中均有表达。急性健康炎症依赖于 中性粒细胞的早期招募，其严格控制的激活和随后被招募的 巨噬细胞。这一基本反应的失调很可能是触发 炎症性和慢性病。脂质介质脂氧素A4(LXA4)已被确定为 炎症消解和白细胞功能的调节。角膜高度表达一种关键的酶， LXA4的形成、15-脂氧合酶(15-LOX)及其G蛋白偶联受体ALX。人类基因的破坏 15-LOX/LXA4通路导致炎症、创面愈合和病理性血管生成失调 眼角膜。初步研究表明，雌性小鼠持续表现出延迟的上皮损伤。 结案了。一项对120名角膜溃疡患者的前瞻性临床试验，首次有文献表明， 在女性患者中，上皮伤口愈合的速度是女性的两倍。伤口延迟愈合的女性表型 可以通过用局部雌激素治疗雄性小鼠和在体外角膜实验中重现 上皮细胞。更重要的是，ER和ER特异性激动剂对炎症有不同的调节作用， 上皮创面愈合和15-LOX/LXA4内源性通路的表达和活性。这些发现 与干眼模型中显示角膜15-LOX显著损害的脂组分析相关 雌性小鼠的活动。雌激素对这一内在脂质循环的选择性调节可能提供新的见解 性别特异性眼表炎症性疾病的病因或发病机制，这将在 三个特定的目标：I.表征15-LOX和LXA4内在回路中的性别差异 急性和反复发生的角膜上皮损伤和炎症。II.阐明雌激素的作用 受体(ER？和ER？)在调节角膜上皮和白细胞创伤愈合功能中的作用 确定这些细胞中15-LOX和LXA4回路的受体特异性调节。三、界定急诊室和 ER？在小鼠干眼的角膜发病机制中的作用并确定内源性15-LOX和 LXA4电路。这项研究的结果将解决关于雌激素和 其受体在眼睛的急性炎症/修复反应中的作用，并将首次确定性别特异性 (雌激素)对内源性脂环的调节，这对炎症的消退至关重要。我们所了解的 LXA4及其相关模拟物的结构功能关系、受体和信号转导途径 已经建立了相对先进和有效/安全的动物模型。因此，这项研究的结果 可以迅速为临床带来治疗眼表炎症性疾病的新选择。 好了！

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. !