Inflammation in Sickle Disease

镰状病的炎症

• 批准号: 6721321
• 负责人: Gregory M Vercellotti
• 金额: $ 34.39万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721321
• 关键词: CD antigens; antiinflammatory agents; blood cell count; blood vessel occlusion; cytomegalovirus; disease /disorder model; gene targeting; genetically modified animals; hemoglobin Ss; hypoxia; inflammation; interleukin 1; laboratory mouse; leukocyte adhesion molecules; lipopolysaccharides; monoclonal antibody; nuclear factor kappa beta; oxygen transport; pathologic process; sickle cell anemia; thalassemia; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION: (Investigator's abstract) Sickle cell anemia patients suffer end organ damage due to vaso-occlusion. Over the past two decades investigations of red blood cell/vessel wall interactions have led to a revised paradigm for the understanding of vaso-occlusive phenomena in sickle cell disease. Clinical conditions associated with inflammation such as infections, surgery and others exacerbate crises in sickle cell anemia patients. Preliminary data demonstrate that patients with sickle cell disease have markers of inflammation including elevated C-reactive protein levels and activated monocytes. In vitro these monocytes activate human endothelial cell NF-kB and adhesion molecule expression. Transgenic mouse models of human sickle cell disease also have markers of inflammation, including elevated white blood cell counts and activated monocytes. This proposal posits that an inflammatory phenotype augments tissue injury through worsened vasoocclusion. Thus, inflammation augments vaso-occlusion while anti-inflammatory agents may minimize vaso-occlusion. The project will examine these hypotheses in transgenic mouse models of human sickle cell disease: (1) Anti-inflammatory agents decrease vascular inflammation and improve blood flow. (2) Pro-inflammatory agents such as murine cytomegalovirus, lipopolysaccharide and hypoxia/reoxygenation, increase vascular inflammation and worsen vaso-occlusion. (3) TNF-alpha, IL-1 beta and CD18 transgenic knockout mice that express human betaS hemoglobin have decreased vascular inflammation and improved blood flow parameters. These studies will provide information for understanding the role of the inflammatory response and its relationship to vaso-occlusion in sickle cell disease and serve as an important foundation for developing new and novel therapies to prevent organ dysfunction.

描述：（研究者的摘要）镰状细胞贫血患者遭受终结 由于血管封闭而造成的器官损坏。在过去的二十年中 红细胞/容器壁相互作用导致了修订的范式 了解镰状细胞疾病中的血管熟悉现象。临床 与炎症相关的疾病，例如感染，手术等 镰状细胞贫血患者的危机加剧。初步数据证明了 患有镰状细胞疾病的患者有炎症标志 C反应性蛋白水平升高和活化的单核细胞。在体外这些 单核细胞激活人内皮细胞NF-KB和粘附分子 表达。人镰状细胞疾病的转基因小鼠模型也有 炎症的标记，包括升高的白细胞计数和 活化的单核细胞。该提议认为炎症表型 通过恶化的血管牙合增加组织损伤。因此，炎症 增强血管咬合而抗炎剂可能最小化 血管封闭。该项目将在转基因小鼠中检查这些假设 人类镰状细胞疾病的模型：（1）抗炎药降低 血管炎症并改善血流。 （2）促炎剂此类 作为鼠的巨细胞病毒，脂多糖和缺氧/重氧， 增加血管炎症并恶化血管咬合。 （3）TNF-Alpha，IL-1 β和CD18表达人β血红蛋白的转基因敲除小鼠具有 减少血管炎症和改善的血流参数。这些 研究将提供信息以了解炎症的作用 反应及其与镰状细胞疾病中的血管咬合的关系 作为开发新疗法的重要基础 防止器官功能障碍。