Impaired integrity of DNA after recovery from inflammation causes persistent dysfunction of colonic smooth muscle.
Impaired integrity of DNA after recovery from inflammation causes persistent dysfunction of colonic smooth muscle.
复制标题
DOI：
10.1053/j.gastro.2011.06.074
复制
发表时间：
2011-10
期刊：
影响因子：
29.4
通讯作者：
Sarna SK
中科院分区：
文献类型：
--
作者：
Choi K;Chen J;Mitra S;Sarna SK
处于缓解期的炎症性肠病患者和肠道感染后发生炎症性肠病综合征的患者在没有明显炎症的情况下继续出现腹泻或便秘症状，表明动力功能障碍。我们研究了炎症过程中的氧化应激是否会损害Cacna 1c启动子的完整性，Cacna 1c编码Cav1.2b钙通道的成孔α1C亚基。我们使用长延伸PCR（LX-PCR）来评估大鼠远端结肠组织中DNA的完整性;使用三硝基苯磺酸（TNBS）来诱导炎症。TNBS诱导炎症后1 ~ 7天，H2 O2在肌层中增加。氧化应激显著损害了Cacna 1c启动子的两个特定片段的DNA完整性：−506至−260和− 2，193至− 1，542。损伤在第3天达到峰值，并在诱导炎症后第7天部分恢复; Cacna 1c产物的表达遵循类似的时间过程。氧化应激抑制抗氧化蛋白的重要调节因子Nrf 2的表达。腹腔注射莱菔硫烷显著逆转了炎症第7天Nrf 2的抑制、Cacna 1c启动子的氧化损伤和Cacna 1c的抑制。在诱导炎症后56天，炎症完全消退;然而，DNA完整性受损、Nrf 2和Cacna 1c表达以及平滑肌对乙酰胆碱的反应性在此时间点仍受到抑制。炎症过程中的氧化应激损害了Cacna 1c启动子的完整性;炎症消退后，损伤部分持续存在。Cacna 1c的转录减少在没有炎症的情况下导致平滑肌功能障碍。
Patients with inflammatory bowel disease who are in remission and those that developed inflammatory bowel syndrome after enteric infection continue to have symptoms of diarrhea or constipation in the absence of overt inflammation, indicating motility dysfunction. We investigated whether oxidative stress during inflammation impairs integrity of the promoter of Cacna1c, which encodes the pore-forming α1C subunit of Cav1.2b calcium channels. We used long-extension PCR (LX-PCR) to evaluate DNA integrity in tissues from distal colons of rats; trinitrobenzene sulfonic acid (TNBS) was used to induce inflammation. H2O2 increased in the muscularis externa 1 to 7 days after inflammation was induced with TNBS. The oxidative stress significantly impaired DNA integrity in 2 specific segments of the Cacna1c promoter: −506 to −260 and −2,193 to −1,542. The impairment peaked at day 3 and recovered partially by day 7 after induction of inflammation; expression of the products of Cacna1c followed a similar time course. Oxidative stress suppressed the expression of Nrf2, an important regulator of anti-oxidant proteins. Intra-peritoneal administration of sulforaphane significantly reversed the suppression of Nrf2, oxidative damage in the promoter of Cacna1c, and suppression of Cacna1c on day 7 of inflammation. The inflammation subsided completely by 56 days after inflammation was induced; however, impairment of DNA integrity, expression of Nrf2 and Cacna1c, and smooth muscle reactivity to acetylcholine remained suppressed at this timepoint. Oxidative stress during inflammation impairs the integrity of the promoter of Cacna1c; impairment persists partially after inflammation has subsided. Reduced transcription of Cacna1c contributes to smooth muscle dysfunction in the absence of inflammation.
登录
查看更多内容
影响因子：
10.5
作者：
Itoh, K;Wakabayashi, N;Yamamoto, M
通讯作者：
Yamamoto, M
影响因子：
24.5
作者：
Gwee, KA;Leong, YL;Read, NW
通讯作者：
Read, NW
DOI：
10.1016/s0006-291x(02)00894-x
发表时间：
2002-08-16
影响因子：
3.1
作者：
Dai, BS;Saada, N;Palade, P
通讯作者：
Palade, P
影响因子：
5.3
作者：
Cullinan, SB;Gordan, JD;Diehl, JA
通讯作者：
Diehl, JA
影响因子：
4.8
作者：
Ayala-Torres, S;Chen, YM;Van Houten, B
通讯作者：
Van Houten, B