NITRIC OXIDE AND RHEUMATOID ARTHRITIS

风湿性关节炎是一种常见的疾病， 痛苦、残疾和死亡率上升。非常需要 对疾病机制的新见解。一氧化氮（NO）在 炎症性疾病，包括RA。诱发因素 人单核细胞表达诱导型NO合酶（NOS 2） 而产生NO还没有完全明确。我们最近 研究表明，干扰素-α（IFN-α） “激活”单核细胞表达NOS 2并产生NO。 IFN-α是全身性和局部（联合）过度产生的， 在RA中，这有助于。NOS 2激活和 RA患者中常见的炎症。的抗炎作用 四环素相关药物不依赖于它们的抗微生物 行动虽然这些药物抑制基质金属蛋白酶， 抑制体外NOS 2表达。我们假设NOS 2 抑制作用部分地解释了它们抗炎作用 in vivo. RA患者，由于疼痛、夹板和关节 畸形会在关节上施加异常的机械应力， 软骨我们发现，机械应力诱导NO的产生， 那个软骨我们假设NO在软骨中过量产生， RA患者（与正常受试者或 骨关节炎）对机械应力的反应， 一氧化氮改变类风湿关节炎的软骨稳态。 我们的目的是（1）确定IFN-α在“激活” 人单核吞噬细胞的NOS 2表达和NO产生 RA;（2）确定是否用强力霉素治疗RA患者 减少血液单核细胞NOS表达和NO产生; （3）确定机械应力对软骨NOS的作用 表达和NO产生。 完成我们提出的工作将回答重要的问题 关于NO，NOS 2，IFN-α和机械应力，以及它们之间的相互作用， 在RA的关系这些答案将提供重要的新的 这些信息可能导致治疗RA的新方法。

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.