HYALURONAN MEDIATED NITRIC OXIDE PRODUCTION BY MACROPHAG

类风湿性关节炎（RA）是一种常见疾病，可导致严重痛苦、残疾和死亡率增加，是慢性炎症免疫反应的一个例子。RA的特征是透明质酸（HA）的过量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tnf α是RA中两种重要的炎症介质。人类滑膜巨噬细胞诱导NO生成的机制以及NO的下游炎症作用尚不清楚，特别是在诸如RA等疾病的背景下。同样，RA中持续产生TNFalpha的机制尚未完全确定。本研究将验证低分子量HA寡糖通过细胞表面HA受体CD44导致RA滑膜巨噬细胞产生一氧化氮（NO）和tnf α的炎症循环，从而进一步产生碎片化HA寡糖的假设。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)。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)。测定HA低聚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NO是否诱导血凝素分裂。这些研究将导致未来的工作，以确定CD44信号传导和人类巨噬细胞产生NO的分子事件，并将为RA患者的治疗试验提供理论基础，以抑制NO的产生和抑制CD44- ha的相互作用。

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.