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: 8230358
• 负责人: KARSTEN GRONERT
• 金额: $ 37.68万
• 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/8230358
• 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

DESCRIPTION (provided by applicant): 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, ER1 and ER2, 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, ER1 and ER2 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 (ER1 and ER2) 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 ER1 and ER2 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. PUBLIC HEALTH RELEVANCE: 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. Due to the advanced pharmacology and clearly defined targets of endogenous protective lipid mediators, results from this study could rapidly bring novel treatment options for ocular surface inflammatory diseases to the clinic.

描述（由申请人提供）：关于雌激素在免疫和炎症反应中的复杂作用，存在极大的兴趣和未解决的矛盾。尽管干眼综合征主要影响女性，但性别特异性差异和雌激素在眼部炎症性疾病中的作用尚不清楚。雌激素受体ER 1和ER 2在白细胞和每种眼组织中表达。急性健康炎症取决于中性粒细胞的早期募集，它们的严格控制的激活和随后被募集的巨噬细胞清除。这种基本反应的失调可能代表触发炎症和慢性疾病的早期事件。脂质介质脂氧素A4（LXA 4）已被鉴定为炎症消退的关键介质和白细胞功能的调节剂。角膜高度表达LXA 4形成的关键酶15-脂氧合酶（15-LOX）及其G蛋白偶联受体ALX。15-LOX/LXA 4回路的遗传破坏导致角膜中失调的炎症、伤口愈合和病理性血管生成。初步研究表明，雌性小鼠始终表现出延迟的上皮伤口闭合。一项在120名角膜溃疡患者中进行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是男性的两倍。通过局部雌激素治疗雄性小鼠和角膜上皮细胞的体外实验，可以重现延迟伤口愈合的雌性表型。更重要的是，ER 1和ER 2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。这些发现与干眼模型的脂质组学分析相关，干眼模型显示雌性小鼠角膜15-LOX活性显著受损。雌激素对这种内在脂质回路的选择性调节可能为性别特异性眼表炎性疾病的病因或发病机制提供新的见解，这将在三个特定的目标进行测试：I。表征角膜中急性和复发性上皮损伤和炎症期间内在15-LOX和LXA 4回路的性别特异性差异。二.阐明雌激素受体（ER 1和ER 2）在调节角膜上皮和白细胞伤口愈合功能中的作用，并确定这些细胞中15-LOX和LXA 4回路的受体特异性调节。三.阐明ER 1和ER 2在小鼠干眼角膜发病机制中的作用，并确定内源性15-LOX和LXA 4回路的保护作用。这项研究的结果将解决关于雌激素及其受体在眼睛急性炎症/修复反应中的作用的关键知识空白，并将首次定义对炎症消退至关重要的内在脂质回路的性别特异性（雌激素）调节。我们对LXA 4和相关模拟物的结构功能关系、受体和信号转导途径的了解相对先进，并且已经建立了动物模型中的有效性/安全性。因此，这项研究的结果可以迅速为临床带来眼表炎性疾病的新治疗选择。 公共卫生关系：这项研究将解决关于雌激素及其受体在眼睛急性炎症/修复反应中的作用的关键知识空白，并将首次定义对炎症消退至关重要的内在脂质回路的性别特异性（雌激素）调节。由于先进的药理学和明确定义的内源性保护性脂质介质的靶点，本研究的结果可以迅速为临床带来眼表炎性疾病的新治疗选择。