ROLE OF THE SELECTIONS IN THE DEVELOPMENT OF VASCULITIS

在狼疮红斑狼疮、韦格纳肉芽肿和血管紊乱等疾病中，导致血管炎发展的炎症事件知之甚少。白细胞和内皮细胞上黏附分子的表达被认为是这些疾病和其他疾病中血管病变的开始和发展的关键。选择素家族的黏附蛋白(P-、E-和L-选择素)介导白细胞滚动，这是炎症反应期间白细胞从血管系统向组织迁移的第一步。抑制或丢失一种或多种选择素已被证明在急性和慢性炎症反应中可以减少白细胞募集和随后的组织损伤。然而，如果有的话，选择素在血管炎发病机制中的确切作用仍有待确定。MRL/MPJ-Fas/LPR小鼠是一种以免疫复合体为基础的血管炎和肾小球肾炎为特征的全身性自身免疫性疾病，是研究血管性疾病的良好模型系统。我们现在已经建立了P-和/或E-选择素突变的MRL/MPJ-Fas/LPR小鼠，以便在该模型中分析这些黏附分子在血管炎发展中的体内作用。其具体目的是：(I)确定P-选择素和E-选择素在MRL/MPJ-Fas/LPR小鼠中的时间和血管特异性表达模式，以及(Ii)确定P-选择素和E-选择素零突变的MRL/MPJ-Fas/LPR小鼠是否是该模型中血管炎发生和发展的重要决定因素，并可能将这些黏附蛋白确定为药物干预治疗血管疾病的可能分子靶点。

The inflammatory events which lead to the development of vasculitis in diseases such as lupus erythematosis, Wegener's granulomatosis, and vasculitic disorders are poorly understood. The expression of adhesion molecules on leukocytes and endothelial cells is thought to be critical for both the initiation and progression of vasculitic lesions in these and other diseases. The selectin family of adhesion proteins (P-, E-, and L-selectin) mediate leukocyte rolling, the initial step in leukocyte emigration from the vasculature into tissue during an inflammatory response. Inhibition or loss of one or more of the selectins has been shown to reduce leukocyte Recruitment and subsequent tissue damage during both acute and chronic inflammatory responses. However, it remains to be determined the exact roles, if any, of the selectins in the pathogenesis of vasculitis. MRL/MpJ- Fas/lpr mice develop a systemic autoimmune disease characterized by immune complex-based vasculitis and glomerulonephritis and these mice serve as an excellent mode system for studies of vasculitic diseases. We have now generated MRL/MpJ-Fas/lpr mice with mutations in P- and/or E-selectin in order to analyze the in vivo role of these adhesion molecules in the development of vasculitis in this model. The specific aims are to: (i) Determine the temporal and vascular specific expression patterns of P- and E-selectin in MRL/MpJ-Fas/lpr mice, and (ii) Determine whether MRL/MpJ-Fas/lpr mice with null mutations in P-selectin, E-selectin, or both P-and E-selectin expression is an important determinant in the initiation and progression of vasculitis in this model and may identify these adhesion proteins as possible molecular targets for pharmacologic intervention in the treatment of vasculitic diseases.