Pulmonary Hypertension in SCD

描述(由申请人提供)： 肺部并发症，如肺动脉高压(PHTN)，已成为发病率和死亡率的主要来源。杜克-北卡罗来纳大学综合镰状细胞中心提供了一个庞大的、具有良好特征的患者群体，用来研究SCD中pHTN的许多方面。我们提出的工作的长期目标是(1)增加我们对pHTN在SCD中的自然历史以及导致其发展的病理生理机制的了解；(2)确定可以改善这一毁灭性并发症过程的特定治疗干预措施。为此，我们将实现以下三个具体目标。目的1：研究该病的自然病史和病程，寻找SCD的疾病标志物和与pHTN相关的疾病修饰基因。我们将对另外200名SCD患者进行pHTN筛查，并将在不少于2年、最长4年的随访期内对100名轻度、重度pHTN和SCD患者进行研究。研究将侧重于临床特征(项目1)，以及疾病标记和遗传多态(项目2)。目的：观察波生坦和输液两种治疗方法对pHTN等肺功能和心血管功能参数的影响，以及SCD活性的生物标志物。我们将在60名轻度pHTN患者中进行波生坦(方案3)与安慰剂的随机试验。此外，我们还将研究输血对中重度pHTN的影响(项目4)。目的3：我们将研究涉及NO、超氧化物和红细胞生物学的基本病理生理机制(项目5)，因为它们影响人和动物的肺循环。这些目标的实现将有助于更深入地了解pHTN在SCD中的发展和自然历史，有助于识别pHTN的高危患者，阐明pHTN的发病机制，并为这种危及生命的综合征的有效治疗提供指导。(描述结束)

DESCRIPTION (provided by applicant): Pulmonary complications such as pulmonary hypertension (pHTN) have become a major source of both morbidity and mortality. The Duke-UNC Comprehensive Sickle Cell Center offers a large and well characterized patient population with which to study many aspects of pHTN in SCD. The long-term goals of our proposed work are (1) to increase our understanding of both the natural history of pHTN in SCD, as well as the pathophysiologic mechanisms leading to its development; and (2) to identify specific therapeutic interventions that can ameliorate the course of this devastating complication. To these ends, we will accomplish the following three Specific Aims. AIM 1: We will study the natural history and course of disease progression, as well as identify disease markers of SCD and disease-modifying genes associated with pHTN. We will screen 200 additional patients with SCD for pHTN and we will study >100 patients with mild severe pHTN and SCD during follow up periods of no less than two years and up to 4 years. Studies will focus on clinical characteristics (Project 1), as well as disease markers and genetic polymorphisms (Project 2). AIM 2: We will determine the effects of two therapeutic maneuvers-bosentan and transfusion-on pHTN and other parameters of pulmonary and cardiovascular function, as well as biomarkers of SCD activity. We will conduct a randomized trial of bosentan (Project 3) vs. placebo in 60 patients with mild pHTN. In addition, we will study the effects of transfusion on moderate-severe pHTN (Project 4). AIM 3: We will investigate basic pathophysiologic mechanisms involving NO, superoxide and red cell biology (Project 5), as they affect the pulmonary circulation in humans and animals. Achievement of these aims will provide a more in-depth understanding of the development and natural history of pHTN in SCD, help identify those patients at greatest risk for pHTN, elucidate pathogenetic mechanisms in pHTN, and provide guidance toward effective treatment of this life-threatening syndrome. (End of Description)