Obermeier F, Kojouharoff G, Hans W, Schölmerich J, Gross V, Falk W
Department Of Internal Medicine I, University of Regensburg, Regensburg, Germany.
Clin Exp Immunol. 1999 May;116(2):238-45. doi: 10.1046/j.1365-2249.1999.00878.x.
Excess nitric oxide formation caused by the activity of the inducible nitric oxide synthase has been implicated as a toxic effector molecule in the pathogenesis of experimental colitis and inflammatory bowel disease. It was therefore investigated whether inhibition of this synthase or the cytokines TNF and IFN-gamma, inducers of nitric oxide synthase, had effects on chronic colitis in mice. Chronic colitis was induced in mice by repeated feeding of DSS. Cytokines were neutralized by treatment with MoAbs and nitric oxide synthase was inhibited by aminoguanidine. The degree of colonic inflammation was assessed by a histological score and colon length. Aminoguanidine treatment reduced nitric oxide activity by 60% (P = 0. 0004), the histological score by 31% (P = 0.005) and increased colon length by 1.4 cm (P = 0.002). Neutralization of TNF and IFN-gamma resulted in increased colon length (0.7 cm, P = 0.07 and 0.8 cm, P = 0.03), improved histological score (19%, P = 0.045 and 25%, P = 0. 013), and reduced nitric oxide activity (31%, P = 0.07 and 54%, P = 0.004) compared with controls. The combination of anti-cytokine treatments had additive effects. TNF and IFN-gamma are involved in perpetuation of chronic DSS-induced colitis, and induction of excessive nitric oxide activity could be their common effector mechanism.
诱导型一氧化氮合酶的活性导致过量一氧化氮生成，这被认为是实验性结肠炎和炎症性肠病发病机制中的一种毒性效应分子。因此，研究了抑制该合酶或一氧化氮合酶的诱导剂细胞因子TNF和IFN-γ是否对小鼠慢性结肠炎有影响。通过反复喂食葡聚糖硫酸钠（DSS）诱导小鼠发生慢性结肠炎。用单克隆抗体（MoAbs）处理中和细胞因子，用氨基胍抑制一氧化氮合酶。通过组织学评分和结肠长度评估结肠炎症程度。氨基胍处理使一氧化氮活性降低60%（P = 0.0004），组织学评分降低31%（P = 0.005），结肠长度增加1.4厘米（P = 0.002）。与对照组相比，中和TNF和IFN-γ导致结肠长度增加（分别为0.7厘米，P = 0.07和0.8厘米，P = 0.03），组织学评分改善（分别为19%，P = 0.045和25%，P = 0.013），一氧化氮活性降低（分别为31%，P = 0.07和54%，P = 0.004）。抗细胞因子治疗的联合应用具有相加效应。TNF和IFN-γ参与慢性DSS诱导的结肠炎的持续存在，过量一氧化氮活性的诱导可能是它们共同的效应机制。
