HYALURONAN-MEDIATED NITRIC OXIDE PRODUCTION BY MACROPHAG

风湿性关节炎（RA）是一种常见的疾病，其导致严重的痛苦、残疾和死亡率增加，并且代表慢性炎性免疫应答的一个实例。RA的特征在于透明质酸（HA）的过度产生和具有促炎特性的低分子量HA寡糖的产生。 一氧化氮（NO）和肿瘤坏死因子α（TNF α）是RA的两种重要炎症介质。 在人类滑膜巨噬细胞中诱导NO产生的机制和NO的下游炎症作用知之甚少，特别是在疾病如RA的背景下。 同样，RA中持续产生TNF α的机制尚未完全确定。 该提案将测试以下假设：低分子量HA寡糖通过细胞表面HA受体CD 44使RA中滑膜巨噬细胞产生的一氧化氮（NO）和TNF α的炎症循环永久化，这导致片段化HA寡糖的进一步产生。 具体目标是：（1）比较不同分子量的HA寡糖诱导人单核细胞和组织巨噬细胞产生NO的能力。 2.）的情况。确定HA寡糖是否诱导RA患者单核细胞和滑膜巨噬细胞产生NO。 3.）第三章测定HA寡糖诱导人巨噬细胞细胞因子产生的能力。 4.）确定单核细胞和滑膜巨噬细胞产生的NO是否诱导HA片段化。这些研究将导致未来的工作，定义参与CD 44信号传导和NO生产的人巨噬细胞的分子事件，也将提供RA患者的治疗试验，靶向抑制NO生产和抑制CD 44-HA相互作用的原理。

Rheumatoid arthritis (RA) is a common disease that causes important suffering, disability and increased mortality, and represents an example of a chronic inflammatory immune response. RA is characterized by the overproduction of hyaluronan (HA) and production of low molecular weight HA oligosaccharides which have proinflammatory properties. Nitric oxide (NO) and TNFalpha are two important inflammatory mediators in RA. The mechanisms that induce NO production in human synovial macrophages and the downstream inflammatory effects of NO are poorly understood, especially in the context of diseases such as RA. Likewise, the mechanisms that perpetuate the continued production of TNFalpha in RA have not been completely characterized. This proposal will test the postulate that low molecular weight HA oligosaccharides perpetuate an inflammatory cycle of nitric oxide (NO) and TNFalpha production by synovial macrophages in RA, via the cell surface HA receptor CD44, that leads to further production of fragmented HA oligosaccharides. The specific aims are to: 1.) Compare the ability of HA oligosaccharides of different molecular weight to induce NO production by human monocytes and tissue macrophages. 2.) Determine whether HA oligosaccharides induce NO production by monocytes and synovial macrophages from patients with RA. 3.) Determine the ability of HA oligosaccharides to induce human macrophage cytokine production. 4.) Determine whether NO production by monocytes and synovial macrophages induces HA fragmentation. These studies will lead to future work that defines the molecular events involved in CD44 signaling and NO production by human macrophages and will also provide the rationale for therapeutic trials in RA patients that target inhibition of NO production and inhibition of CD44-HA interactions.