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

肺动脉高压（PAH）是一种危及生命的疾病，其特征是 肺血管阻力进行性增加，最终可导致右心室 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。到 为了改善SSc-PAH的治疗选择，需要更好地理解SSc-PAH的发病机制。 虽然PAH的确切病理生理学尚不清楚，但由PAH引起的异常细胞代谢可能是PAH的主要原因。 改变线粒体动力学，现在被认为是病理性的重要贡献者。 PAH的变化。在之前的研究期间，我们发现在细胞内的内质网增加， (ER)来自SSc的循环免疫细胞（PBMC）中的应激和未折叠蛋白应答（UPR） 局限性疾病（lcSSc）患者，lcSSc-PAH患者的水平甚至更高。我们也 在lcSSc PBMC中证实了高度片段化的线粒体，将这些研究扩展到肺， 在接受移植的SSc-PAH患者中，我们观察到UPR标志物高度增加， 内皮细胞（EC）和巨噬细胞和氧化增加的证据。鉴于复杂的 由于PAH的性质，能够调节几种关键途径的治疗剂将是一种 PAH治疗方案的有吸引力的补充。作为可能的候选人，我们专注于 富马酸二甲酯（DMF），一种增强内在细胞抗氧化反应的药物， 最近批准（Tecfidera®）用于治疗多发性硬化。利用啮齿动物缺氧模型 结果表明，DMF可预防和逆转PH的血流动力学改变， 血管和右心室肥大。DMF还可减轻氧化性肺损伤， 应激和减少的免疫细胞浸润到经治疗的小鼠的肺中。把这些结果 对于人类SSc-PAH，我们提出：1）确定线粒体动力学改变对 2）确定新鲜分离的LcSScM的分子特征 接受右心导管插入术的伴和不伴PAH的lcSSc患者的PAEC M和3） 二甲基甲酰胺对肺动脉远端阻力功能的影响 接受移植的SSc-PAH患者的肺部。这些补充研究将发展 更好地理解氧化还原状态在SSc-PAH发病机制中的作用，验证 抗氧化剂，如DMF，作为这种实体的潜在治疗，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， 长期关注SSc和SSc-PAH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.