硫酸葡聚糖钠在肿瘤坏死因子-α缺陷小鼠中诱导的肠道炎症增强。
Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice.
作者信息
Naito Yuji, Takagi Tomohisa, Handa Osamu, Ishikawa Takeshi, Nakagawa Shuji, Yamaguchi Taiji, Yoshida Norimasa, Minami Masato, Kita Masakazu, Imanishi Jiro, Yoshikawa Toshikazu
机构信息
First Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto, Japan.
出版信息
J Gastroenterol Hepatol. 2003 May;18(5):560-9. doi: 10.1046/j.1440-1746.2003.03034.x.
BACKGROUND AND AIMS
Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine thought to be involved in the pathogenesis of inflammatory bowel disease. To further define the role of TNF-alpha in intestinal inflammation, we studied the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of TNF-alpha gene.
METHODS
Acute colitis was induced in female TNF-alpha-/- and TNF-alpha+/+ mice by administering 4.5% DSS orally in drinking water for seven days. The colonic mucosal injury and inflammation was evaluated based on body weight changes, total colon length, luminal hemoglobin, and histological findings. Colonic mRNA expression for inducible nitric oxide synthase (iNOS), TNF-alpha, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured by reverse transcription polymerase chain reaction (RT-PCR), and nuclear factor kappaB (NF-kappaB) activation was evaluated by electrophoretic mobility shift assay.
RESULTS
In each assessment, colonic injury was significantly aggravated in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. The survival rate of TNF-alpha-/- mice on day seven was 40%; in contrast, all TNF-alpha+/+ mice were alive. Histological study also showed an enhanced infiltration of inflammatory cells, especially neutrophils, and mucosal cell disruption in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. On day seven, mRNA levels of IFN-gamma and IL-4 in the colons of TNF-alpha-/- mice were faint or not detected; in contrast, those of TNF-alpha+/+ mice were detected. Although the expression of iNOS mRNA and luminal nitrite levels were similarly increased in both mice on day seven, this induction was delayed in TNF-alpha-/- mice during the early phase. The degree of NF-kappaB binding activity seemed to be similar between the two types of mice on day seven.
CONCLUSION
DSS-induced inflammation is significantly enhanced in TNF-alpha-/- mice compared to TNF-alpha+/+ mice. These data suggest that persistent and marked blockage of TNF-alpha bioactivity may provide a detrimental effect on acute intestinal inflammation.
背景与目的
肿瘤坏死因子-α（TNF-α）是一种强效促炎细胞因子，被认为参与炎症性肠病的发病机制。为进一步明确TNF-α在肠道炎症中的作用，我们研究了给予硫酸葡聚糖钠（DSS）对TNF-α基因靶向缺失小鼠的影响。
方法
通过在饮用水中口服4.5% DSS 7天，诱导雌性TNF-α-/-和TNF-α+/+小鼠发生急性结肠炎。基于体重变化、结肠总长度、肠腔血红蛋白和组织学结果评估结肠黏膜损伤和炎症。通过逆转录聚合酶链反应（RT-PCR）检测结肠中诱导型一氧化氮合酶（iNOS）、TNF-α、干扰素-γ（IFN-γ）和白细胞介素-4（IL-4）的mRNA表达，并通过电泳迁移率变动分析评估核因子κB（NF-κB）的激活情况。
结果
在各项评估中，与接受DSS治疗的TNF-α+/+小鼠相比，接受DSS治疗的TNF-α-/-小鼠的结肠损伤明显加重。TNF-α-/-小鼠在第7天的存活率为40%；相比之下，所有TNF-α+/+小鼠均存活。组织学研究还显示，与接受DSS治疗的TNF-α+/+小鼠相比，接受DSS治疗的TNF-α-/-小鼠的炎症细胞，尤其是中性粒细胞浸润增强，黏膜细胞破坏。在第7天，TNF-α-/-小鼠结肠中IFN-γ和IL-4的mRNA水平微弱或未检测到；相比之下，TNF-α+/+小鼠的则可检测到。尽管在第7天两种小鼠中iNOS mRNA的表达和肠腔亚硝酸盐水平均同样升高，但在早期阶段，TNF-α-/-小鼠的这种诱导延迟。在第7天，两种类型小鼠的NF-κB结合活性程度似乎相似。
结论
与TNF-α+/+小鼠相比，TNF-α-/-小鼠中DSS诱导的炎症明显增强。这些数据表明，持续且显著阻断TNF-α生物活性可能对急性肠道炎症产生有害影响。
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