Roles of MIF and iNOS in SLE-associate inflammation

MIF 和 iNOS 在 SLE 相关炎症中的作用

• 批准号: 7099569
• 负责人: MICHAEL J HICKEY
• 金额: $ 23.99万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-10 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099569
• 关键词: Australia; cell adhesion molecules; cell cell interaction; cell migration; disease /disorder model; fluorescence microscopy; genetically modified animals; inflammation; intravital microscopy; laboratory mouse; leukocytes; microcirculation; migration inhibition factor; nitric oxide; nitric oxide synthase; pathologic process; systemic lupus erythematosus; vascular endothelium

DESCRIPTION (provided by applicant): Diverse inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) share the manifestation of organ injury induced by activation of inflammatory pathways. A feature common to inflammatory diseases is the infiltration into tissues of blood-derived leukocytes, a phenomenon that requires specific leukocyte-endothelial cell interactions in the microcirculation. While many molecules important in leukocyte-endothelial interactions have been identified, the specific events operative in the recruitment of leukocytes to target organs remain incompletely understood. A greater understanding of these pathways has the potential to lead to the discovery of novel, specific, yet broad-spectrum therapeutic modalities. For example, it is unclear whether distinct leukocyte-endothelial interactions are operative in rheumatic diseases, or indeed in mediating the distinct organ manifestations in these diseases. Complete characterization of the mechanisms of leukocyte recruitment requires the direct examination of leukocyte-endothelial interactions in vivo. This is possible using the technique of intravital microscopy (IVM), which has now been applied to many tissues including skin, brain, and synovium. Strong preliminary data suggests the involvement of mediators such as nitric oxide (NO) and the cytokine macrophage migration inhibitory factor (MIF) in the modulation of leukocyte-endothelial interactions. The long-term objectives of this project are to expand understanding of the role of these and other mediators in the microcirculation in models of SLE and RA. The specific aims of this project are to: (i) Examine the leukocyte-endothelial interactions in the pathogenesis of murine SLE. Using IVM, we will define the regulatory role of NO in the MRL/fas-lpr model of SLE. (ii) Examine the role of MIF in the regulation of leukocyte-endothelial interactions. WT and MIF-/- mice, as well as mice treated with anti-MIF mAb and recombinant MIF will be studied using IVM of the synovial and muscle microcirculations under conditions of antigen-driven inflammation. (iii) Examine the role of MIF in the modulation of leukocyte-endothelial interactions in the pathogenesis of murine SLE. Using rMIF, anti-MIF mAb, and anti-MIF small molecules, and by generating MRL/Ipr/MIF -/- mice, we will examine the role of MIF in the modulation of leukocyte-endothelial interactions in murine SLE.

描述（由申请人提供）： 系统性红斑狼疮（SLE）和类风湿性关节炎（RA）等多种炎症性疾病都具有炎症通路激活引起的器官损伤的表现。炎症性疾病的一个共同特征是血液来源的白细胞浸润到组织中，这种现象需要微循环中特定的白细胞-内皮细胞相互作用。虽然已经鉴定出许多在白细胞-内皮相互作用中重要的分子，但在将白细胞募集到靶器官中起作用的具体事件仍然不完全清楚。对这些途径的更深入了解有可能导致发现新颖、特异且广谱的治疗方式。例如，尚不清楚不同的白细胞-内皮相互作用是否在风湿性疾病中发挥作用，或者是否确实介导这些疾病中的不同器官表现。白细胞募集机制的完整表征需要直接检查体内白细胞-内皮相互作用。这可以通过活体显微镜（IVM）技术来实现，该技术现已应用于包括皮肤、大脑和滑膜在内的许多组织。强有力的初步数据表明，一氧化氮（NO）和细胞因子巨噬细胞迁移抑制因子（MIF）等介质参与白细胞-内皮相互作用的调节。该项目的长期目标是加深对这些介质和其他介质在 SLE 和 RA 模型微循环中的作用的理解。该项目的具体目标是： (i) 检查小鼠 SLE 发病机制中的白细胞-内皮相互作用。使用 IVM，我们将定义 NO 在 SLE 的 MRL/fas-lpr 模型中的调节作用。 (ii) 检查 MIF 在白细胞-内皮相互作用调节中的作用。将在抗原驱动的炎症条件下使用滑膜和肌肉微循环的 IVM 研究 WT 和 MIF-/- 小鼠以及用抗 MIF mAb 和重组 MIF 治疗的小鼠。 (iii) 检查 MIF 在调节小鼠 SLE 发病机制中白细胞-内皮相互作用中的作用。使用 rMIF、抗 MIF 单克隆抗体和抗 MIF 小分子，并通过生成 MRL/Ipr/MIF -/- 小鼠，我们将研究 MIF 在调节小鼠 SLE 中白细胞-内皮相互作用中的作用。