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性疾病，影响着数以千计的美国人，目前还没有有效的治疗方法。几项研究表明，IPF患者体内抗氧化剂水平降低，抗氧化剂策略似乎在肺纤维化的动物模型中有效。因此，人们提出使用抗氧化剂治疗特发性肺间质纤维化。然而，这一方法被认为有很大的争议，因为氧化应激在IPF发病机制中的作用尚不清楚，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也不清楚。IPF临床研究网络(IPFnet)是由NIH/NHLBI发起的一个多中心网络，旨在进行受控良好的随机临床试验，以测试IPF环境下的新治疗方案。该提案的PI在IPFnet指导委员会任职，并指导位于埃默里的IPFnet中心之一。IPFnet将很快进行一项临床试验，测试糖皮质激素、硫唑嘌呤和抗氧化剂N-乙酰半胱氨酸(NAC)的组合对IPF管理的有效性，这种疗法已经成为治疗IPF的标准护理。这项名为Panther的试验将包括三种治疗药物：1)安慰剂，2)强的松+硫唑嘌呤+NAC，以及3)单独使用NAC。在其他方面，这项试验将确定NAC(联合或单独使用)是否有益。然而，尽管重点放在抗氧化治疗上，但由于资源有限，Panther试验不会确定患有氧化应激的受试者。换句话说，被招募的受试者的氧化还原状态将是未知的，因此，将不会评估新来港儿童对这一过程的影响。这一点很重要，因为抗氧化剂可能在治疗纤维化肺疾病方面有效，但只在氧化还原状态的受试者中有效。如果不对这种可能性进行评估，IPFnet可能会忽视一种可能有效的治疗策略，该策略可能会帮助相当一部分IPF患者。我们假设NAC对IPF的治疗可能是有效的，但仅限于由于内源性抗氧化活性不足而导致氧化还原状态的患者。具体地说，我们假设氧化还原电位的受试者将从抗氧化治疗中受益，氧化电位由一个或多个硫醇二硫键对半胱氨酸和半胱氨酸(Cys/Cyss)和谷胱甘肽和谷胱甘肽二硫键(GSH/GSSG)的氧化确定。为了测试这一点，我们建议：目的1)测量IPFnet Panther试验三个组受试者血浆中Cys/CySS和GSH/GSSG的氧化还原电位，并确定氧化还原电位是否与结果有关。目的2)确定NAC是否能逆转有氧化应激证据的人的硫醇二硫键对氧化。公共卫生相关性：特发性肺纤维化(IPF)是一种进行性和致命性疾病，影响着数以千计的美国人，并且没有有效的药物治疗。该项目将探索氧化应激作为IPF疾病进展和治疗反应的生物标记物的作用。它将与Panther试验一起进行，这是一项由NIH/NHLBI的IPF临床研究网络赞助的3期试验，目的是评估入选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有关。(摘要结束)

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)