Nitric oxide and cyclooxygenase in arthritis

描述（由申请人提供）：一氧化氮（NO）参与许多细胞功能，其中一些似乎是矛盾的。例如，在某些情况下，升高的NO水平与增强的细胞生长相关，而在其他情况下，高浓度的NO降低细胞增殖。NO通过三种形式的一氧化氮合酶（NOS）之一的活性合成：神经元NOS（nNOS或NOS 1）;诱导型NOS（iNOS或NOS 2）;和内皮型NOS（eNOS或NOS 3）。正如其名称所暗示的，iNOS由多种外部刺激诱导，包括细胞因子、免疫复合物、脂多糖和其他促炎分子。已经描述了在自身免疫性疾病中NO的变化，包括动物和人类的炎性关节炎。许多上调iNOS的分子也刺激环氧合酶（考克斯）家族酶的活性。 这些酶负责从花生四烯酸合成洋地黄素（PGs）。酶的诱导型同种型考克斯-2也与炎性关节炎有关。NO可调节考克斯活性，PGs可调节NOS活性。作为考克斯抑制剂的药物已经被开发出来，包括最初的非甾体抗炎药（NSAID），非特异性地阻断两种形式的考克斯酶，以及更新的、更特异的考克斯-2抑制剂。虽然考克斯-2抑制剂已被证明在某些情况下改变iNOS活性，但对它们在炎性关节炎中对iNOS的影响知之甚少。由于诱导考克斯-2和iNOS的刺激的相似性以及这些分子之间的其他相互作用，考克斯-2抑制剂似乎也可能改变iNOS活性。本提案将通过研究非特异性和选择性考克斯抑制剂在不同NOS遗传背景小鼠中的作用，来研究炎症性关节炎中NOS和考克斯之间的一些相互关系，从而允许解剖iNOS、eNOS和考克斯在炎症严重程度中的作用。此外，血清蛋白质的变化将被探索使用蛋白质组学分析的工具，以允许识别关节炎进展和治疗反应的潜在生物标志物，并作为努力的一部分，以了解潜在的机制，参与考克斯和NOS的相互作用，可能占一些看似矛盾的影响NO的炎症过程。

DESCRIPTION (provided by applicant): Nitric oxide (NO) is involved in many cellular functions, some of which may appear to be paradoxical. For example, in some settings elevated NO levels are associated with enhanced cell growth, while in others high concentrations of NO reduce cellular proliferation. NO is synthesized via the activity of one of three forms of nitric oxide synthase (NOS): neuronal NOS (nNOS or NOS 1); inducible NOS (iNOS or NOS 2); and endothelial NOS (eNOS or NOS 3). As implied by its name, iNOS is induced by a variety of external stimuli, including cytokines, immune complexes, lipopolysaccharides, and other pro-inflammatory molecules. Changes in NO have been described in autoimmune disorders, including inflammatory arthritis in animals and in humans. Many of the molecules that upregulate iNOS also stimulate the activity of the cyclooxygenase (COX) family of enzymes. These enzymes are responsible for the synthesis of prostaglandins (PGs) from arachidonic acid. The inducible isoform of the enzyme, COX-2, also has been implicated in inflammatory arthritis. NO can modulate COX activity, and PGs can modulate NOS activity in this and other conditions. Drugs that act as COX inhibitors have been developed, including the original nonsteroidal anti-inflammatory drugs (NSAIDs) that nonspecifically block both forms of the COX enzymes, and the newer, more specific COX-2 inhibitors. While COX-2 inhibitors have been shown to alter iNOS activity in some settings, little is known about their effects on iNOS in inflammatory arthritis. Because of the similarities in the stimuli that induce COX-2 and iNOS and because of the other interactions between these molecules, it seems likely that COX-2 inhibitors might alter iNOS activity as well. This proposal will examine some of the interrelationships between NOS and COX in inflammatory arthritis by studying the effects of nonspecific and selective COX inhibitors in mice with different NOS genetic backgrounds, thus permitting the dissection of the roles of iNOS, eNOS, and COX in the severity of inflammation. Additionally, changes in serum proteins will be explored using the tools of proteomic analysis to permit the identification of potential biomarkers for arthritis progression and therapeutic response and as part of an effort to understand the underlying mechanisms-involved in COX and NOS interactions that may account for some of the seemingly paradoxical effects of NO on the inflammatory process.