Exhaled NO and Oxidative Stress in Systemic Sclerosis Pulmonary Hypertension

项目总结/摘要 本研究申请建议在计划完成临床试验后立即进行辅助研究， 最近资助的多学科临床导向研究专业中心的组成部分 （SCCOR）在我们机构的肺动脉高压中，其重点是肺动脉 高血压伴系统性硬化症（PAH-SSc）。本研究旨在开发和验证 呼出气一氧化氮（NO）和尿异前列腺素作为PAH-SSc的临床相关生物标志物。过度 氧化应激和随后的NO损伤可能是PAH发展的关键事件， 当前PAH治疗可靶向的SSc。我们假设这些标记物将：1）预测 随后对PAH治疗反应和2）作为替代治疗终点， 相关成果。在母临床试验中，将入组未经治疗的PAH-SSc患者（N=75） 在一项为期16周的波生坦、西地那非或两者联合的随机研究中。这些试剂 目前最广泛使用的治疗这种情况。详细的临床、功能和 血流动力学评估将作为母试验的一部分进行。本辅助研究将获得 基线时呼出的NO和尿F2-异前列烷（氧化应激的标志物）测量值， 在治疗后。在我们的第一个目标中，基线测量将与从SSc患者中获得的测量进行比较 无肺部疾病和健康对照受试者。后两组将从另外两个国家招募 母研究是我们SCCOR计划的组成部分。在目标2中，基线生物标志物测量 将与对治疗的反应相关。此外，在4周、8周和16周后，这些指数的变化 将与16周后疾病严重程度的临床测量的变化相关。的 这项研究的长期目标是确定PAH-SSc中可靠的生物标志物， 了解这种毁灭性疾病的药物治疗的作用机制。验证 这些测量结果最终可以允许对个体患者进行定制治疗或识别那些 不太可能从早期某种治疗中获益的患者，因此可以在临床治疗前进行改变。 发生恶化。随后的研究可以确定这些简单、容易获得、非侵入性的 测试证明是有用的，在确定无症状的SSc患者在高风险， 临床表现PAH的发展，允许预防性治疗的潜在应用。通过 提供机械的见解，这项研究也可以作为测试新的 治疗类，如抗氧化剂和/或NO供体。

Project Summary/Abstract This research application proposes to conduct an ancillary study to a clinical trial planned soon as a component of the recently funded, multi-disciplinary Specialized Center of Clinically Oriented Research (SCCOR) in Pulmonary Hypertension at our institution, which has as its focus, Pulmonary Arterial Hypertension Associated with Systemic Sclerosis (PAH-SSc). This study seeks to develop and validate exhaled nitric oxide (NO) and urine isoprostanes as clinically relevant biomarkers in PAH-SSc. Excessive oxidative stress with consequent impairment in NO, may be critical events in the development of PAH- SSc that can be targeted by current PAH therapies. We hypothesize that these markers will: 1) predict the subsequent response to PAH therapy and 2) serve as surrogate therapeutic end-points to clinically relevant outcomes. In the parent clinical trial, treatment na¿ve PAH-SSc patients (N=75) will be enrolled in a randomized study of bosentan, sildenafil or the combination of both for 16-weeks. These agents are currently the most widely employed therapies for this condition. Detailed clinical, functional and hemodynamic assessments will be conducted as part of the parent trial. This ancillary study will obtain exhaled NO and urine F2-isoprostane (a marker of oxidative stress) measurements at baseline and after therapy. In our first aim, baseline measures will be compared with those obtained from SSc patients without lung disease and healthy control subjects. The latter goups will be recruited from two other parent studies that are components of our SCCOR program. In aim 2, baseline biomarker measurements will be correlated with response to therapy. In addition, changes in these indices after 4, 8 and 16 weeks of therapy will be correlated with changes in clinical measures of disease severity after 16 weeks. The long-term objectives of this research are to identify reliable biomarkers in PAH-SSc and advance our understanding of the mechanism(s) of action of medical therapy for this devastating disease. Validation of these measurements may ultimately allow tailoring of therapy to individual patients or identify those who are unlikely to benefit from a certain therapy early, so that a change can be made before clinical deterioration occurs. Subsequent studies could determine if these simple, readily obtained, non-invasive tests prove to be useful in identifying asymptomatic patients with SSc at high-risk for subsequent development of clinically manifest PAH, allowing the potential application of preventative therapies. By providing mechanistic insights, this research may also serve as a basis for the testing of novel therapeutic classes, such as anti-oxidants and/or NO donors.