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

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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)