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: 8463546
• 负责人: KARSTEN GRONERT
• 金额: $ 35.73万
• 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/8463546
• 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; Sjogren' s Syndrome; Structure-Activity Relationship; 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免疫系统中的复杂作用，存在着极大的兴趣和未解决的悖论。 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重要 众所周知，尽管干眼综合症主要影响女性。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、其严格控制的激活以及随后募集的中性粒细胞的去除 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。脂质介质脂氧素 A4 (LXA4) 已被确定为关键介质 炎症消退和白细胞功能调节剂。角膜高度表达一种关键酶 LXA4 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/LXA4 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始终表现出延迟性上皮伤口 关闭。一项针对 120 名角膜溃疡患者的前瞻性临床试验首次证明 女性患者的上皮伤口愈合速度要慢两倍。伤口愈合延迟的女性表型 可以通过用局部雌激素治疗雄性小鼠以及用角膜进行体外实验来概括 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， 上皮伤口愈合以及内在 15-LOX/LXA4 回路的表达和活性。这些发现 与干眼模型的脂质组学分析相关，表明角膜 15-LOX 存在显着损伤 雌性小鼠的活动。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 研究性别特异性眼表炎症性疾病的病因或发病机制，将在 三个具体目标： I. 表征内在 15-LOX 和 LXA4 回路中的性别特异性差异 急性和反复发生的角膜上皮损伤和炎症。二.阐明雌激素的作用 受体（ER¿ 和 ER¿）在调节角膜上皮和白细胞伤口愈合功能中的作用 定义这些细胞中 15-LOX 和 LXA4 回路的受体特异性调节。三．描述 ER¿ 的角色和 ER¿ 在小鼠干眼症角膜发病机制中的作用，并定义了内在 15-LOX 和 LXA4电路。这项研究的结果将弥补有关雌激素和雌性激素作用的关键知识空白。 它的受体在眼睛的急性炎症/修复反应中，并将首次定义性别特异性 （雌激素）对内在脂质回路的调节对于炎症消退至关重要。我们的知识 LXA4 及相关模拟物的结构功能关系、受体和信号转导途径 相对先进且在动物模型中的有效性/安全性已经建立。因此，本研究的结果 可以迅速为临床带来眼表炎症性疾病的新治疗选择。 ！