NITRIC OXIDE AND RHEUMATOID ARTHRITIS

类风湿性关节炎是一种常见的疾病，它会导致重要的 痛苦、残疾和增加的死亡率。有很大的需求 以获得对疾病机制的新见解。一氧化氮(NO)起着一定作用 炎症性疾病，包括类风湿性关节炎。诱发的因素(S) 人类单个核细胞表达诱导型一氧化氮合酶(NOS2) 而产生NO的原因还没有完全清楚地确定。我们最近 研究表明，干扰素-α(干扰素-α)有效 “激活”单核细胞表达NOS2，产生NO。我们假设 干扰素-α在系统和局部(联合)过度生产 组织)，这有助于。NOS2激活和 类风湿关节炎患者可见炎症反应。丹参的抗炎作用 四环素类药物与其抗微生物作用无关 行为。虽然这些药物抑制基质金属蛋白酶，但它们也 体外抑制NOS2的表达。我们假设2号 抑制作用的部分原因是它们的抗炎作用。 在活体内。类风湿关节炎患者，因为疼痛、夹板和关节 畸形会给他们的关节带来异常的机械应力 软骨。我们证明了机械应力通过以下方式诱导NO产生 那块软骨。我们假设一氧化氮在人的软骨中过度产生 类风湿关节炎患者(与正常受试者或 骨关节炎)对机械应力的反应，以及诱导的 一氧化氮改变类风湿关节炎软骨内环境平衡。 我们的目标是(1)确定干扰素-α在“激活”中的作用。 对人单核巨噬细胞NOS2表达和NO产生的影响 RA；(2)确定是否用多西环素治疗RA患者 减少其外周血单核细胞一氧化氮合酶的表达和一氧化氮的产生； 确定机械应力对软骨一氧化氮合酶的影响 在RA中有表达，无产物产生。 完成我们提议的工作将回答一些重要的问题 关于NO、NOS2、干扰素-α和机械应力及其相互作用 在RA中的关系。这些答案将提供重要的新的 可能导致治疗类风湿关节炎的新方法的信息。

Rheumatoid arthritis is a common disease that causes important suffering, disability, and increased mortality. There is a great need for new insight into disease mechanisms. Nitric oxide (NO) plays a role in inflammatory disorders, including RA. The factor(s) that induces mononuclear cells in humans to express the inducible NO synthase (NOS2) and to produce NO has not fully been clearly identified. Our recent studies have indicated that interferon-alpha (IFN-alpha) potently "activates" monocytes to express NOS2 and produce NO. We hypothesize that IFN-alpha is overproduced systemically and locally (in joint tissues) in RA and that this contributes to the. NOS2 activation and inflammation seen in patients with RA. The anti-inflammatory actions of tetracycline-related drugs are independent of their anti-microbial actions. While these drugs inhibit matrix metalloproteinases, they also inhibit expression of NOS2 in vitro. We hypothesize that the NOS2 inhibitory actions account in part for their anti-inflammatory effects in vivo. Patients with RA, because of pain, splinting, and joint deformities place abnormal mechanical stresses on their articular cartilage. We showed that mechanical stress induces NO production by that cartilage. We hypothesize that NO is overproduced in cartilage of RA patients (as compared to that of normal subjects or subjects with osteoarthritis) in response to mechanical stress, and that the induced NO alters cartilage homeostasis in RA. Our aims are to (1) determine the role of IFN-alpha in the "activation" of human mononuclear phagocytes for NOS2 expression and NO production in RA; (2) determine' whether treatment of RA patients with doxycycline reduces their blood mononuclear cell NOS expression and NO production; and (3) determine the role of mechanical stress on cartilage NOS expression and NO production in RA. Accomplishing our proposed work will answer important questions regarding NO, NOS2, IFN-alpha, and mechanical stress, and their inter- relationships in RA. These answers will provide important new information that may lead to new approaches to the treatment of RA.