Sex-specific Regulation of Acute Inflammation and Resolution

急性炎症和消退的性别特异性调节

• 批准号: 8658092
• 负责人: KARSTEN GRONERT
• 金额: $ 36.79万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658092
• 关键词: Accounting; Acute; Address; Affect; Agonist; Animal Model; Arachidonate 15-Lipoxygenase; Autacoids; Autoimmune Diseases; B-Lymphocytes; Cells; Chronic; Chronic Disease; Clinic; Clinical; Clinical Trials; Complex; Cornea; Corneal Ulcer; Cutaneous; Data Analyses; Disease; Dry Eye Syndromes; Employee Strikes; Enzymes; Epithelial; Epithelial Cells; Estrogen Receptors; Estrogens; Etiology; Event; Excision; Exhibits; Eye; Female; G-Protein-Coupled Receptors; Gene Targeting; Genetic; Human; Immune System Diseases; Immune response; Immune system; Impaired wound healing; Impairment; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knowledge; LOX gene; Lead; Leukocytes; Link; Lipids; Lymphocyte; Mediating; Mediator of activation protein; Menopause; Modeling; Mus; Neutrophil Infiltration; Nuclear Receptors; Opportunistic Infections; Pathogenesis; Pathologic Neovascularization; Pathway interactions; Patients; Pharmacology; Phenotype; Population; Pregnancy; Receptor Signaling; Recruitment Activity; Regulation; Resolution; Retina; Role; Safety; Signal Transduction Pathway; Structure-Activity Relationship; Syndrome; Testing; Time; Tissues; Woman; Wound Healing; corneal epithelium; experience; eye dryness; insight; interest; lipid mediator; lipoxin A4; macrophage; male; mimetics; mouse model; novel; ocular surface; prospective; prostatitis; receptor; research study; response; sex; wound

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. !

关于雌激素在免疫和 炎症反应。性别特定的差异和雌激素在眼部炎症性疾病中的作用不是 即使干眼综合症主要影响女性，也很了解。雌激素的受体， Erâ和Er�在白细胞和每个眼组织中表达。急性健康炎症取决于 早期招募中性粒细胞，其严格控制的激活以及随后被招募的去除 巨噬细胞。这种基本反应的失调可能代表了触发的早期事件 炎症和慢性疾病。脂质介质Lipoxin A4（LXA4）已被确定为 白细胞功能的炎症分辨率和调节剂。角膜高度表达一个关键酶 LXA4形成，15-脂氧合酶（15-lox）及其G蛋白偶联受体ALX。遗传破坏 15-LOX/LXA4电路导致注射失调，伤口愈合和病理血管生成 角膜。初步研究表明，雌性小鼠始终暴露于延迟上皮伤口 关闭。对120例角膜溃疡患者进行的前瞻性临床试验，第一次文件， 女性患者的上皮伤口恢复了两倍。延迟伤口愈合的女性表型 可以通过用局部雌激素和角膜的体外实验来概括雄性小鼠 上皮细胞。更重要的是，Er�和特定的激动剂对注射的调节不同， 上皮伤口愈合以及固有的15-LOX/LXA4电路的表达和活性。这些发现 与干眼模型的脂质分析分析相关，该模型证明了角膜15-LOX的罢工障碍 雌性小鼠的活性。雌激素对这种内在脂质电路的选择性调节可能会提供新颖的见解 进入性别特异性眼表炎性疾病的病因或发病机理，将在 三个具体目的：I。在内在的15-LOX和LXA4电路中表征性别特异性差异 急性和重复发生的上皮损伤和角膜的炎症。 ii。阐明雌激素的作用 在角膜上皮和白细胞伤口愈合功能和 定义这些细胞中15-LOX和LXA4电路的受体特异性调节。 iii。描述了角色和 在小鼠干眼的角膜发病机理中，定义了内在的15-lox和 LXA4电路。这项研究的结果将解决有关雌激素和 它的急性炎症/修复反应中的接收器将首次定义性别特定的 （雌激素）调节对炎症分辨率至关重要的内在脂质电路。我们的知识 LXA4和相关模拟物的结构功能关系，接收器和信号传输途径为 已经建立了相关的先进和有效性/安全性。因此，这项研究的结果 可以迅速将眼部表面炎症性疾病的新型治疗选择带到诊所。 呢