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，其中一些可能看起来是矛盾的。例如，在某些情况下，一氧化氮水平升高与细胞生长增强有关，而在其他情况下，高浓度的一氧化氮会降低细胞增殖。一氧化氮是通过三种形式的一氧化氮合酶（NOS）之一的活性合成的：神经元一氧化氮合酶（nNOS或nos1）；诱导型NOS (iNOS或nos2)；内皮细胞NOS （eNOS或NOS 3）。正如其名称所示，iNOS可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。自身免疫性疾病（包括动物和人类的炎症性关节炎）中已经描述了NO的变化。许多上调iNOS的分子也会刺激环氧合酶（COX）家族的活性。这些酶负责从花生四烯酸合成前列腺素（pg）。酶的诱导异构体COX-2也与炎症性关节炎有关。NO可调节COX活性，pg可调节NOS活性。作为COX抑制剂的药物已经被开发出来，包括最初的非甾体抗炎药（NSAIDs），它非特异性地阻断两种形式的COX酶，以及更新的，更特异性的COX-2抑制剂。虽然COX-2抑制剂已显示在某些情况下改变iNOS活性，但它们对炎症性关节炎中iNOS的影响知之甚少。由于诱导COX-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，COX-2抑制剂似乎也可能改变iNOS的活性。本研究将通过研究非特异性和选择性COX抑制剂在不同NOS遗传背景小鼠中的作用来研究NOS和COX在炎症性关节炎中的相互关系，从而揭示iNOS、eNOS和COX在炎症严重程度中的作用。此外，将使用蛋白质组学分析工具探索血清蛋白的变化，以确定关节炎进展和治疗反应的潜在生物标志物，并作为了解COX和NOS相互作用的潜在机制的一部分，这些机制可能解释NO对炎症过程的一些看似矛盾的影响。

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.