Fenyk-Melody J E, Garrison A E, Brunnert S R, Weidner J R, Shen F, Shelton B A, Mudgett J S
Merck Research Laboratories, Rahway, NJ 07065, USA.
J Immunol. 1998 Mar 15;160(6):2940-6.
Nitric oxide is believed to be a prominent mediator of inflammation based in part on the correlative expression of the inducible nitric oxide synthase (iNOS) gene in various pathologies. The resulting high output of the highly reactive molecule nitric oxide is then believed to play an important role in the evolving inflammatory response. Studies have shown that iNOS and nitric oxide are present in the tissues of patients with multiple sclerosis (MS). In rodent models of MS, experimental autoimmune encephalomyelitis (EAE), it has been shown that nonspecific NOS inhibitors partially ameliorate the disease. To determine the importance of iNOS in this model of MS, we induced EAE in mice containing a disrupted iNOS (NOS2) gene. Surprisingly, by day 24, the NOS2 knockout mice had a greater incidence of EAE than wild-type control mice (75 vs 12%), and had a higher average severity score (2.42 vs 0.44). These differences appear to result largely from the failure of the disease to remit in NOS2 KO mice. Wild-type mice have a profound ability to reverse EAE (82%) compared with the knockout mice (19%). This result implies that iNOS may in some instances play a protective role in autoimmune-mediated tissue destruction.
一氧化氮被认为是炎症的主要介质，部分原因是诱导型一氧化氮合酶（iNOS）基因在各种病理状态下的相关表达。随后，人们认为由此产生的高活性分子一氧化氮的高产量在不断演变的炎症反应中起重要作用。研究表明，iNOS和一氧化氮存在于多发性硬化症（MS）患者的组织中。在MS的啮齿动物模型实验性自身免疫性脑脊髓炎（EAE）中，已表明非特异性NOS抑制剂可部分改善该疾病。为了确定iNOS在这种MS模型中的重要性，我们在含有iNOS（NOS2）基因破坏的小鼠中诱导EAE。令人惊讶的是，到第24天时，NOS2基因敲除小鼠的EAE发病率高于野生型对照小鼠（75%对12%），并且平均严重程度评分更高（2.42对0.44）。这些差异似乎主要是由于NOS2基因敲除小鼠的疾病未能缓解所致。与基因敲除小鼠（19%）相比，野生型小鼠具有显著的逆转EAE的能力（82%）。这一结果表明，iNOS在某些情况下可能在自身免疫介导的组织破坏中起保护作用。
