Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment
Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment
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DOI：
10.1002/ijc.22943
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发表时间：
2007-11-01
影响因子：
6.4
通讯作者：
Kensler, Thomas W.
中科院分区：
文献类型：
--
作者：
Osburn, William O.;Karim, Baktiar;Kensler, Thomas W.
慢性炎症与患癌症的风险增加有关。转录因子NF-E2相关因子2（Nrf 2）控制许多抗氧化酶的表达，这些酶已被证明可以减轻急性炎症。本研究探讨了Nrf 2基因型在调节炎症促进的结直肠肿瘤发生中的作用。向Nrf 2野生型（WT）和Nrf 2缺陷型（NO）小鼠施用单剂量的氧化偶氮甲烷，随后施用1周剂量的含有或不含1%葡聚糖硫酸钠（DSS）的饮用水。在停止DSS治疗后3周对异常隐窝病灶进行计数。DSS治疗显著增加了NO小鼠中异常隐窝病灶的数量，但WT小鼠没有。在两种基因型中分析DSS治疗过程中的炎症程度。结肠切片的组织学分析揭示，当与WT小鼠相比时，从DSS治疗的第6天开始，NO小鼠具有显著增加的炎症和粘膜损伤。尽管在DSS治疗开始时，WT和NO小鼠的结肠中的炎症和氧化损伤生物标志物的水平相似，但在NO小鼠中，但在DSS治疗的第6天，观察到结肠促炎细胞因子mRNA转录水平、髓过氧化物酶活性和3-硝基酪氨酸免疫反应性增加，而WT小鼠则没有。此外，DSS治疗导致NO小鼠脂质过氧化增加和乌头酸酶活性丧失，但WT小鼠没有，反映NO小鼠结肠氧化损伤增加。综上所述，这些结果清楚地说明了Nrf 2在调节适应性反应中的作用，该适应性反应可防止早期炎症介导的肿瘤发生。(c)2007 Wiley-Liss，Inc.
Chronic inflammation has been associated with increased risk of developing cancer. The transcription factor NF-E2-related factor 2 (Nrf2) controls the expression of numerous antioxidative enzymes that have been shown to attenuate acute inflammation. The present study investigated the role of Nrf2 genotype in modulating inflammation-promoted colorectal tumorigenesis. Nrf2 wild-type (WT) and Nrf2-deficient (NO) mice were administered a single dose of azoxymethane followed by a 1-week dose of drinking water with or without 1 % dextran sulfate sodium (DSS). Aberrant crypt foci were counted 3 weeks after the cessation of DSS treatment. DSS treatment significantly increased numbers of aberrant crypt foci in NO mice, but not WT mice. The extent of inflammation over the course of DSS treatment was analyzed in both genotypes. Histological analysis of colon sections revealed that NO mice had markedly increased inflammation and mucosal damage when compared to WT mice beginning on Day 6 of DSS treatment. Although similar levels of inflammatory and oxidative damage biomarkers were evident in colons from WT and NO mice at the start of DSS treatment, increased colonic proinflammatory cytokine mRNA transcript levels, myeloperoxidase activity and 3-nitrotyrosine immunoreactivity were observed on Day 6 of DSS treatment in NO mice, but not WT mice. Additionally, DSS treatment resulted in increased lipid peroxidation and loss of aconitase activity in NO mice, but not WT mice, reflecting increased oxidative damage in colons from NO mice. Taken together, these results clearly illustrate the role of Nrf2 in regulating an adaptive response that protects against early-phase inflammation-mediated tumorigenesis. (c) 2007 Wiley-Liss, Inc.