Project 2: Scleroderma-Associated Pulmonary Arterial Hypertension: The Role of the Oxidant State

肺动脉高压是一种危及生命的疾病，其特征是 肺血管阻力进行性增加，最终可导致右室 失败和死亡。在系统性硬化症(SSC)中，PAH是发病率和死亡率的主要原因。 此外，SSc-PAH患者的预后比特发性PAH患者差。至 为了改善SSc-PAH的治疗方案，需要更好地了解SSC-PAH的发病机制。 虽然PAH的确切病理生理机制尚不清楚，但由 线粒体动力学改变，现在被认为是导致病理改变的重要因素 多环芳烃的改变。在之前的资助期间，我们证明内质网增加。 (ER)SSC循环免疫细胞的应激和未折叠蛋白反应(UPR) 局限性疾病患者(LcSSc)，其中LcSSc-PAH患者水平更高。我们也 在lcSSc PBMCsM中显示高度碎片化的线粒体，将这些研究扩展到肺 接受移植的SSc-PAH患者，我们观察到UPR标记物在 内皮细胞(EC)和巨噬细胞，氧化增加的证据。考虑到这个复杂的 PAH的本质，一种能够调节几个关键通路的治疗剂将是一种 对PAH的治疗方案有吸引力的补充。作为可能的候选人，我们一直专注于 富马酸二甲酯(DMF)，一种增强细胞内在抗氧化反应的试剂， 最近批准(Tecfidera®)用于治疗多发性硬化症。利用啮齿动物缺氧模型 对于PH，我们发现DMF预防和逆转了血流动力学变化，使肺组织肌化 血管和右室肥厚。DMF还可减轻氧化所致的肺损伤 应激和减少免疫细胞对处理小鼠肺的渗透。要翻译这些结果， 对于人类SSc-PAH，我们建议：1)确定线粒体动力学改变在 LcSScM中免疫细胞的激活决定了新分离的 行右心导管术的伴有和不伴有PAH的LcSSC患者的PAEC DMF对异体远端阻力肺血管功能的影响 自发性硬化性肺高压患者的肺移植。这些互补性的研究将会发展 更好地理解氧化还原状态在SSc-PAH发病机制中的作用 抗氧化剂，如DMF，作为这一实体的潜在治疗方法，并开发合作 波士顿大学和匹兹堡大学医学中心之间的疾病模型，两 长期对SSC和SSC-PAH感兴趣的专家中心。

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by a progressive increase in pulmonary vascular resistance that can eventually lead to right ventricular failure and death. In systemic sclerosis (SSc), PAH is a leading cause of morbidity and mortality. Moreover, patients with SSc-PAH have a poorer prognosis than patients with idiopathic PAH. To improve treatment options for SSc-PAH, a better understanding of SSc-PAH pathogenesis is needed. Although the exact pathophysiology of PAH is unknown, abnormal cellular metabolism caused by altered mitochondrial dynamics, is now considered an important contributor to pathological alterations in PAH. During the prior grant period, we demonstrated increased endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in circulating immune cells (PBMCs) from SSc patients with limited disease (lcSSc), with even higher levels in lcSSc-PAH patients. We also demonstrated highly fragmented mitochondria in lcSSc PBMCsM extending these studies to lungs from SSc-PAH patients undergoing transplantation, we observed highly increased UPR markers in endothelial cells (EC) and macrophages and evidence of increased oxidation. Given the complex nature of PAH, a therapeutic agent capable of modulating several key pathways would be an attractive addition to the treatment regimen of PAH. As a possible candidate, we have focused on dimethyl fumarate (DMF), an agent that augments the intrinsic cellular antioxidant response and was recently approved (Tecfidera®) for treatment of multiple sclerosis. Using the rodent-hypoxia model of PH, we found DMF prevented and reversed hemodynamic changes, muscularization of pulmonary vessels, and right ventricular hypertrophy. DMF also attenuated lung damage caused by oxidative stress and reduced immune cell infiltration into lungs of treated mice. To translate these results to human SSc-PAH, we propose: 1) Determine the role of altered mitochondrial dynamics on activation of immune cells in lcSScM 2) Determine the molecular characteristics of freshly isolated PAEC from lcSSc patients with and without PAH undergoing right heart catheterizationM and 3) Determine the effect of DMF on the function of distal resistance pulmonary arteries from explanted lungs of patients with SSc-PAH undergoing transplantation. These complementary studies will develop better understanding of the role of the redox state in the pathogenesis of SSc-PAH, validate anti-oxidants, such as DMF, as potential treatment for this entity, and develop collaborative disease models between Boston University and the University of Pittsburgh Medical Centers, two expert centers with long-standing interest in SSc and SSc-PAH.