Vivekanandan-Giri Anuradha, Byun Jaeman, Pennathur Subramaniam
Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Methods Enzymol. 2011;491:73-89. doi: 10.1016/B978-0-12-385928-0.00005-5.
Oxidative stress plays a central role in the pathogenesis of diverse chronic inflammatory disorders including diabetic complications, cardiovascular disease, aging, neurodegenerative disease, autoimmune disorders, and pulmonary fibrosis. Protein misfolding can lead to chronic endoplasmic reticulum (ER) stress which can exacerbate oxidative stress. This can trigger apoptotic cascades resulting in chronic inflammatory disorders. Despite intense interest in origins and magnitude of oxidative stress, ability to quantify oxidants has been limited because they are short lived. We have developed quantitative mass spectrometry (MS)-based analytical strategies to analyze stable end products of protein oxidation. These molecules provide quantitative and mechanistic assessment of degree of oxidative stress in cell cultures, tissues, and biofluids of animal models of disease and human samples. Our studies support the hypothesis that unique reactive intermediates generated in localized microenvironments of vulnerable tissues promote end-organ damage. The ability to quantify these changes and assess response to therapies will be pivotal in understanding disease mechanisms and monitoring efficacy of therapy.
氧化应激在多种慢性炎症性疾病的发病机制中起核心作用，这些疾病包括糖尿病并发症、心血管疾病、衰老、神经退行性疾病、自身免疫性疾病和肺纤维化。蛋白质错误折叠可导致慢性内质网（ER）应激，进而加剧氧化应激。这可触发凋亡级联反应，导致慢性炎症性疾病。尽管人们对氧化应激的起源和程度极为关注，但由于氧化剂寿命短暂，对其进行量化的能力一直有限。我们已开发出基于定量质谱（MS）的分析策略，以分析蛋白质氧化的稳定终产物。这些分子可对疾病动物模型和人类样本的细胞培养物、组织及生物流体中的氧化应激程度进行定量和机制评估。我们的研究支持这样一种假说，即在易损组织的局部微环境中产生的独特反应性中间体促进终末器官损伤。量化这些变化并评估对治疗反应的能力，对于理解疾病机制和监测治疗效果至关重要。
