Oxidant Stress: Is it a biomarker of disease progression and response to therapy

描述（由申请人提供）： 特发性肺纤维化（IPF）是一种进行性和致命的疾病，影响成千上万的美国人，没有有效的治疗方法。几项研究已证明IPF患者的抗氧化剂水平降低，抗氧化剂策略在肺纤维化动物模型中似乎有效。因此，已经提出使用抗氧化剂治疗IPF。然而，这种方法被认为是高度有争议的，因为氧化应激在IPF发病机制中的作用尚未明确，目前尚不清楚目前可用的抗氧化策略是否能够恢复IPF患者的正常氧化还原电位。IPF临床研究网络（IPFNET）是一个由NIH/NHLBI申办的多中心网络，旨在开展对照良好的随机临床试验，以测试IPF背景下的新治疗方案。该提案的PI在IPFNET指导委员会任职，并指导埃默里的一个IPFNET中心。IPFNET将很快参与一项临床试验，测试可以说已成为IPF管理标准治疗的有效性：糖皮质激素，硫唑嘌呤和抗氧化剂N-乙酰半胱氨酸（NAC）的组合。这项试验，黑豹试验，将包括三个治疗组：1）安慰剂，2）泼尼松+硫唑嘌呤+ NAC，3）NAC单独。除此之外，这项试验将确定NAC（联合或单独）是否有益。然而，尽管关注抗氧化治疗，但由于资源有限，Panther试验不会识别出氧化应激受试者。换句话说，招募的受试者的氧化还原状态将是未知的，因此，将不会评价NAC对该过程的影响。这是重要的，因为抗氧化剂可能在纤维化肺病的管理中有效，但仅在具有氧化的氧化还原状态的受试者亚组中有效。如果不对这种可能性进行评估，IPFNET就有可能忽视一种可能帮助大部分IPF患者的潜在有效治疗策略。我们假设NAC可能对IPF的治疗有效，但仅适用于内源性抗氧化活性缺乏导致氧化还原状态的患者。具体而言，我们假设具有氧化的氧化还原电位的受试者将从抗氧化治疗中获益，所述氧化的氧化还原电位通过巯基二硫化物对半胱氨酸和胱氨酸（Cys/CySS）以及谷胱甘肽和谷胱甘肽二硫化物（GSH/GSSG）中的一种或多种的氧化来确定。为了测试这一点，我们建议：目的1）测量从招募到IPFNET Panther试验的三个分支的受试者中获得的血浆中的Cys/CySS和GSH/GSSG氧化还原电位，并确定氧化还原电位是否与结果相关。目的2）确定NAC是否可以逆转具有氧化应激证据的那些中硫醇二硫键对的氧化。公共卫生相关性：特发性肺纤维化（IPF）是一种进行性和致命的疾病，影响成千上万的美国人，没有有效的药物治疗。本项目将探讨氧化应激作为IPF疾病进展和治疗反应的生物标志物的作用。该研究将与PANTHER TRIAL（一项由NIH/NHLBI的IPF临床研究网络申办的III期试验）联合进行，目的是评价招募患者血浆中的氧化还原电位，并确定该参数是否与疾病进展和治疗反应相关。(End摘要）

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans for which no effective treatments are available. Several studies have demonstrated decreased levels of anti- oxidants in patients with IPF, and anti-oxidant strategies seem effective in animal models of lung fibrosis. Consequently, the use of anti-oxidants for the treatment of IPF has been proposed. However, this approach is considered highly controversial because the role of oxidant stress in the pathogenesis of IPF is not clearly established, and it is unclear whether currently available anti-oxidant strategies are capable of restoring normal redox potential in IPF patients. The IPF Clinical Research Network (IPFNET) is a multicenter network sponsored by the NIH/NHLBI and created to engage in well-controlled randomized clinical trials that test new therapeutic regimens in the setting of IPF. The PI of this proposal serves on the IPFNET Steering Committee and directs one of the IPFNET centers at Emory. The IPFNET will soon engage in a clinical trial that tests the effectiveness of what has arguably become the standard of care in the management of IPF: the combination of glucocorticoids, azathioprine, and the anti-oxidant N-acetylcysteine (NAC). This trial, the Panther Trial, will include three treatment arms: 1) placebo, 2) prednisone + azathioprine + NAC, and 3) NAC alone. Among other things, this trial, will determine if NAC (in combination or alone) is beneficial. However, despite the focus on anti-oxidant therapy, the Panther Trial will not identify subjects with oxidant stress due to limited resources. In other words, the redox state of the recruited subjects will not be known and, therefore, the impact of NAC on this process will not be evaluated. This is important because it is possible that anti-oxidants might be effective in the management of fibrotic lung disorders, but only in the subgroup of subjects with an oxidized redox state. If this possibility is not evaluated, the IPFNET runs the risk of overlooking a potentially effective therapeutic strategy that might help a significant portion of IPF patients. We hypothesize that NAC may be effective in the treatment of IPF, but only in patients with an oxidized redox state caused by deficiencies in endogenous anti-oxidant activity. Specifically, we hypothesize that subjects with an oxidized redox potential, as determined by oxidation of one or more of the thiol disulfide couples cysteine and cystine (Cys/CySS) and glutathione and glutathione disulfide (GSH/GSSG), will be the ones to benefit from anti-oxidant therapy. To test this, we propose to: Aim 1) Measure the Cys/CySS and GSH/GSSG redox potential in plasma obtained from subjects recruited to the three arms of the IPFNET Panther Trial, and determine if the redox potential relates to outcome. Aim 2) Determine if NAC can reverse oxidation of the thiol disulfide couples in those with evidence of oxidant stress. PUBLIC HEALTH RELEVANCE: Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal disease that affects thousands of Americans and has no effective medical treatment. This project will explore the role of oxidant stress as a biomarker of disease progression and response to therapy in IPF. It will be conducted in conjunction with the PANTHER TRIAL, a phase 3 trial sponsored by the IPF Clinical Research Network of the NIH/NHLBI, with the purpose of evaluating redox potential in the plasma of recruited patients and determine if this parameter correlates with progression of disease and response to therapy. (End of Abstract)