Interferon‐gamma (IFN‐γ)‐ and tumour necrosis factor (TNF)‐induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)‐induced colitis in mice
Interferon‐gamma (IFN‐γ)‐ and tumour necrosis factor (TNF)‐induced nitric oxide as toxic effector molecule in chronic dextran sulphate sodium (DSS)‐induced colitis in mice
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DOI：
10.1046/j.1365-2249.1999.00878.x
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发表时间：
1999-05
影响因子：
4.6
通讯作者：
F. Obermeier;G. Kojouharoff;W. Hans;J. Schölmerich;V. Gross;W. Falk
中科院分区：
文献类型：
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作者：
F. Obermeier;G. Kojouharoff;W. Hans;J. Schölmerich;V. Gross;W. Falk
诱导型一氧化氮合酶活性引起的过量一氧化氮形成已被认为是实验性结肠炎和炎症性肠病发病机制中的毒性效应分子。因此，研究是否抑制这种合酶或细胞因子TNF和IFN‐γ（一氧化氮合酶的诱导剂）对小鼠慢性结肠炎有影响。反复饲喂DSS诱导小鼠慢性结肠炎。细胞因子被MoAbs中和，一氧化氮合酶被氨基胍抑制。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 cm （P = 0.002）。与对照组相比，TNF和IFN‐γ的中和作用导致结肠长度增加（0.7 cm, P = 0.07和0.8 cm, P = 0.03），组织学评分提高（19%,P = 0.045和25%，P = 0.013），一氧化氮活性降低（31%,P = 0.07和54%，P = 0.004）。联合抗细胞因子治疗具有叠加效应。TNF和IFN‐γ参与慢性DSS诱导的结肠炎的持续，诱导过度的一氧化氮活性可能是它们共同的效应机制。
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‐γ, 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‐γ 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‐γ are involved in perpetuation of chronic DSS‐induced colitis, and induction of excessive nitric oxide activity could be their common effector mechanism.