Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair
Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair
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DOI：
10.1007/s00423-006-0073-1
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发表时间：
2006-09-01
影响因子：
2.3
通讯作者：
Nair, Jagadeesan
中科院分区：
文献类型：
--
作者：
Bartsch, Helmut;Nair, Jagadeesan
背景和目的由生物、化学和物理因素引起的慢性炎症与人类不同部位的癌症风险增加有关。慢性炎症过程诱导氧化/亚硝化应激和脂质过氧化（LPO），从而产生过量的活性氧（ROS）、活性氮（RNS）和dna反应性醛。除其他外，DNA与这些主要的LPO产物反应会产生错误编码的乙烯和丙基修饰的DNA碱基。研究人员研究了受持续炎症过程影响的器官中lpo衍生的DNA加合物的稳态水平，作为评估炎症性癌症易发疾病进展的潜在先导标志物。结果利用超灵敏和特异的检测方法对人体组织、细胞和尿液进行分析，发现慢性胰腺炎、溃疡性结肠炎和克罗恩病患者的受影响器官中乙烯- dna加合物水平显著升高。酒精相关性肝病患者肝脏DNA损伤从肝炎、脂肪肝到肝硬化逐渐增加。乙型肝炎病毒相关慢性肝炎和肝硬化患者DNA修复后尿液中乙炔脱氧腺苷的排泄量增加了90倍。本文综述了可能控制炎症组织中DNA损伤的可能机制，包括受损或不平衡的DNA修复途径。结论持续的氧化/亚硝应激和过量的LPO是由炎症过程诱导的，并在自我延续的过程中引起靶器官DNA损伤的进行性积累。随着细胞稳态的解除，由此产生的遗传变化在慢性炎症相关的人类疾病发病机制中起着驱动作用。因此，由ROS、RNS和LPO最终产物引起的DNA损伤的稳态水平为风险预测和潜在的靶点和预防措施的生物标志物提供了有希望的分子特征。
Background and aims Chronic inflammation, induced by biological, chemical, and physical factors, was associated with increased risk of human cancer at various sites. Chronic inflammatory processes induce oxidative/nitrosative stress and lipid peroxidation (LPO), thereby generating excess reactive oxygen species (ROS), reactive nitrogen species (RNS), and DNA-reactive aldehydes. Miscoding etheno- and propano-modified DNA bases are generated inter alia by reaction of DNA with these major LPO products. Steady-state levels of LPO-derived (etheno-) DNA adducts in organs affected by persistent inflammatory processes were investigated as potential lead markers for assessing progression of inflammatory cancer-prone diseases.Results Using ultrasensitive and specific detection methods for the analysis of human tissues, cells, and urine, etheno-DNA adduct levels were found to be significantly elevated in the affected organs of subjects with chronic pancreatitis, ulcerative colitis, and Crohn's disease. Patients with alcohol-related liver diseases showed excess hepatic DNA damage progressively increasing from hepatitis, fatty liver, to liver cirrhosis. Ethenodeoxyadenosine excreted after DNA repair in urine of hepatitis B virus-related chronic hepatitis and liver cirrhosis patients was increased up to 90-fold. Putative mechanisms that may control DNA damage in inflamed tissues including impaired or imbalanced DNA repair pathways are reviewed.Conclusion Persistent oxidative/nitrosative stress and excess LPO are induced by inflammatory processes in a self-perpetuating process and cause progressive accumulation of DNA damage in target organs. Together with deregulation of cell homeostasis, the resulting genetic changes act as driving force in chronic inflammation-associated human disease pathogenesis. Thus steady-state levels of DNA damage caused by ROS, RNS, and LPO end products provide promising molecular signatures for risk prediction and potential targets and biomarkers for preventive measures.