Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)

肺动脉高压和 SCD 中的缺氧反应 (PUSH)

• 批准号: 8149544
• 负责人: Gregory Kato
• 金额: $ 24.92万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149544
• 关键词: Adolescence; Adult; Candidate Disease Gene; Chronic; Clinical; Erythropoietin; Exercise; Female; Fetal Hemoglobin; Glucosephosphate Dehydrogenase Deficiency; Hematological Disease; Hemoglobin; Hemolysis; Hypoxia; Molecular; Pathologic; Pathway interactions; Pulmonary Hypertension; Recording of previous events; Subgroup; Vascular Endothelial Growth Factors; base; glucose-6-phosphate dehydrogenase A-; hydroxyurea; improved; primary pulmonary hypertension; response; trend

Our published preliminary studies indicate that pulmonary hypertension occurs in nearly one-third of adults with sickle cell disease, that it is associated with increased mortality although pulmonary artery pressures are lower than in patients with primary pulmonary hypertension, and that chronic hemolysis with nitric oxide scavenging may be a part of the pathogenesis. The present proposal is based on three postulates. First, the problem of sickle cell-associated pulmonary hypertension may begin during childhood and adolescence. Second, the pathogenesis of sickle cell-associated pulmonary hypertension may not only include the effects of chronic hemolysis, but also the consequences of chronic hypoxia related to severe anemia and repeated vaso-occlusive episodes. Pulmonary hypertension is a recognized complication of conditions marked by chronic hypoxia, and we have recently found evidence that pulmonary hypertension complicates Chuvash polycythemia, a congenital disorder of oxygen sensing in which the hypoxic response is constitutively up regulated in the absence of hypoxia and in which high hemoglobin concentrations would promote nitric oxide scavenging. Third, the pathophysiology of sickle cell-associated pulmonary hypertension may be elucidated by comparing components of the hypoxic response in patients with sickle cell disease and Chuvash polycythemia according to the presence or absence of pulmonary hypertenson. Both sickle cell disease and Chuvash polycythemia may be characterized by nitric oxide scavenging and upregulated hypoxia inducible factor, leading to stimulation of pulmonary vascular proliferative pathways that eventuate in pulmonary hypertension. Comparing specific responses in both conditions may identify shared pathways that have a central role in sickle cell-related pulmonary hypertenison. New Findings to date: 1. The genetic bases of the highly variable degrees of anaemia and haemolysis in persons with Hb SS are not fully known, but several studies have indicated that G6PD deficiency is not a factor. The G6PD(202A) and G6PD(376G) alleles and alpha-thalassaemia were determined by molecular genetic testing in 261 children and adolescents with Hb SS in a multicentre study. G6PD(202A,376G) (G6PD A-) was defined as hemizygosity for both alleles in males and homozygosity in females. Among the participants 41% were receiving hydroxycarbamide. The prevalence of G6PD(202A,376G) was 13.6% in males and 3.3% in females with an overall prevalence of 8.7%. G6PD(202A,376G) was associated with a 10 g/l decrease in haemoglobin concentration (P = 0.008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P > 0.09). Similar results were found within a sub-group of children who were not receiving hydroxycarbamide. By comparison, single and double alpha-globin deletions were associated with progressively higher haemoglobin concentrations (P = 0.005 for trend), progressively lower values for haemolytic component (P = 0.007), and increased severe pain episodes (P < 0.001). In conclusion, G6PD(202A,376G) may be associated with lower haemoglobin concentration in sickle cell anaemia by a mechanism other than increased haemolysis. 2. Plasma concentrations of interleukin-8, interleukin-10 and VEGF were elevated in the patients with sickle cell disease compared to controls (P < or =0.003). By logistic regression, greater values for PDGF-BB (P = 0.009), interleukin-6 (P = 0.019) and the hemolytic component (P = 0.026) were independently associated with increased odds of elevated tricuspid regurgitation velocity while higher VEGF concentrations were associated with decreased odds (P = 0.005) among the patients with sickle cell disease. These findings, which are consistent with reports that PDGF-BB stimulates and VEGF inhibits vascular smooth muscle cell proliferation, did not apply to E/Etdi. Circulating concentrations of angiogenic and pro-Inflammatory markers are altered in sickle cell disease children and adolescents with elevated tricuspid regurgitation velocity, a subgroup that may be at risk for developing worsening pulmonary hypertension. Further studies to understand the molecular changes in these children are indicated. 3. Hydroxyurea and higher hemoglobin F improve the clinical course and survival in sickle cell disease, but their roles in protecting from pulmonary hypertension are not clear. We studied 399 children and adolescents with sickle cell disease at steady state; 38% were being treated with hydroxyurea. Patients on hydroxyurea had higher hemoglobin concentration and lower values for a hemolytic component derived from 4 markers of hemolysis (P < or = .002) but no difference in tricuspid regurgitation velocity compared with those not receiving hydroxyurea; they also had higher hemoglobin F (P < .001) and erythropoietin (P = .012) levels. Hemoglobin F correlated positively with erythropoietin even after adjustment for hemoglobin concentration (P < .001). Greater hemoglobin F and erythropoietin each independently predicted higher regurgitation velocity in addition to the hemolytic component (P < or = .023). In conclusion, increase in hemoglobin F in sickle cell disease may be associated with relatively lower tissue oxygen delivery as reflected in higher erythropoietin concentration. Greater levels of erythropoietin or hemoglobin F were independently associated with higher tricuspid regurgitation velocity after adjustment for degree of hemolysis, suggesting an independent relationship of hypoxia with higher systolic pulmonary artery pressure. The hemolysis-lowering and hemoglobin F-augmenting effects of hydroxyurea may exert countervailing influences on pulmonary blood pressure in sickle cell disease. 4. Low steady state haemoglobin oxygen saturation in patients with sickle cell anaemia has been associated with the degree of anaemia and haemolysis. How much pulmonary dysfunction contributes to low saturation is not clear. In a prospective study of children and adolescents with sickle cell disease aged 3-20 years at steady state and matched controls, 52% of 391 patients versus 24% of 63 controls had steady state oxygen saturation <99% (P < 0.0001), 9% of patients versus no controls had saturation <95% (P = 0.008) and 8% of patients versus no controls had exercise-induced reduction in saturation > or =3%. Decreasing haemoglobin concentration (P < or = 0.001) and increasing haemolysis (P < or = 0.003) but not pulmonary function tests were independent predictors of both lower steady-state saturation and exercise-induced reduction in saturation. Neither history of stroke nor history of acute chest syndrome was significantly associated with lower steady-state oxygen saturation or exercise-induced reduction in saturation. Tricuspid regurgitation velocity was higher in patients with lower steady state haemoglobin oxygen saturation (P = 0.003) and with greater decline in oxygen saturation during the six-minute walk (P = 0.022). In conclusion, lower haemoglobin oxygen saturation is independently associated with increasing degrees of anaemia and haemolysis but not pulmonary function abnormalities among children and adolescents with sickle cell disease.

我们发表的初步研究表明，肺部高血压发生在近三分之一的患有镰状细胞疾病的成年人中，尽管肺动脉压力低于原发性肺动脉高压症患者，但它与死亡率的增加有关，而慢性溶血进行了清除量的慢性溶血，可能是发病机理的一部分。 本提案基于三个假设。首先，镰状细胞相关的肺动脉高压的问题可能会在儿童期和青春期开始。其次，镰状细胞相关的肺动脉高压的发病机理不仅包括慢性溶血的作用，还包括与严重贫血和重复进行的血管co症相关的慢性缺氧的后果。肺动脉高压是由慢性缺氧标记的疾病的公认并发症，我们最近发现证据表明，肺动脉高血压使Chuvash多性性炎症复杂化，Chuvash多性炎症是一种氧气感应的过敏性疾病，其中低氧反应在缺乏低氧和缺乏高血压的情况下受到高度调节，并在其上可以促进血红蛋白浓度高的氧化氧化剂。第三，可以通过比较镰状细胞疾病患者的低氧反应和Chuvash多性疾病的患者根据肺催眠术的存在或不存在Chuvash多性疾病的患者，可以阐明与镰状细胞相关性高血压的病理生理学。镰状细胞疾病和Chuvash多细性疾病的特征是一氧化氮清除和上调的缺氧诱导因子，导致刺激肺血管增生途径，这些肺血管增生途径在肺动脉高压中发生。在两种情况下比较特定的反应都可以识别在与镰状细胞相关的肺催眠期中具有核心作用的共同途径。 迄今为止的新发现： 1。贫血高度可变程度的遗传基础和HB SS患者的血液解析尚不完全清楚，但是一些研究表明G6PD缺乏症并不是一个因素。在一项多中心研究中，通过261名患有HB SS的儿童和青少年在分子基因测试中确定了G6PD（202a）和G6PD（376G）等位基因和α-甲状腺肿。 G6PD（202A，376G）（G6PD A-）被定义为男性等位基因的半合理性和女性纯合性。在参与者中，有41％的人接受了羟基甲酰胺。男性的G6PD（202a，376G）的患病率为13.6％，女性为3.3％，总体患病率为8.7％。 G6PD(202A,376G) was associated with a 10 g/l decrease in haemoglobin concentration (P = 0.008) but not with increased haemolysis as measured by lactate dehydrogenase, bilirubin, aspartate-aminotransferase, reticulocyte count or a haemolytic component derived from these markers (P > 0.09).在未接受羟基甲酰胺的儿童子组中发现了类似的结果。相比之下，单α-珠蛋白缺失与逐渐更高的血红蛋白浓度（趋势p = 0.005）相关，溶血成分的值逐渐降低（p = 0.007）和增加的剧烈疼痛发作（p <0.001）。总之，G6PD（202a，376g）可能通过促进溶血量以外的机制在镰状细胞贫血中较低的血红蛋白浓度有关。 与对照组相比，镰状细胞疾病患者的白细胞介素-8，白介素10和VEGF的血浆浓度升高（P <OR = 0.003）。通过逻辑回归，PDGF-BB（p = 0.009），白介素-6（P = 0.019）和溶血成分（P = 0.026）的较高值独立于三肌刺激速度升高的几率，而VEGF较高的VEGF浓度升高，而较高的VEGF浓度与降低的患者（P = 0.005）相关（P = 0.005）。这些发现与PDGF-BB刺激和VEGF抑制血管平滑肌细胞增殖的报道是一致的，不适用于E/ETDI。 镰状细胞疾病儿童和青少年的循环浓度改变了三尖瓣反流速度的升高，这是一个可能有可能导致肺动脉高压恶化的危险的亚组。进一步的研究以了解这些儿童的分子变化。 3。羟基脲和较高的血红蛋白F改善了镰状细胞病的临床过程和存活，但是它们在保护肺动脉高压症中的作用尚不清楚。我们研究了399名处于稳态疾病的儿童和青少年。 38％的人正在用羟基脲治疗。羟基脲的患者的血红蛋白浓度较高，溶血成分的值较高，该溶血成分衍生自4个标记溶血标记（P <OR = .002），但与未接受羟基脲的患者相比，三尖次刺激性反流速度没有差异；他们还具有较高的血红蛋白F（P <.001）和促红细胞生成素（P = .012）水平。血红蛋白F即使在调整了血红蛋白浓度后，血红蛋白F与促红细胞生成素的正相关（P <.001）。较大的血红蛋白F和促红细胞生成素每个独立地预测了溶血成分以外的较高的反流速度（p <or = .023）。总之，镰状细胞疾病中血红蛋白F的增加可能与较高的红细胞生成素浓度反映的组织氧相对较低有关。调整溶血程度后，较高水平的红细胞生成素或血红蛋白F与较高的三尖瓣反流速度独立相关，这表明缺氧与收缩期肺动脉压力较高的独立关系。羟基脲的降血和血红蛋白F-效果可能对镰状细胞疾病中的肺血压产生反补偿影响。 4。镰状细胞贫血患者的低稳态血红蛋白氧饱和度与贫血和溶血的程度有关。尚不清楚多少肺功能障碍导致低饱和度。在对稳态和匹配对照的3-20岁儿童和青少年的前瞻性研究中，391例患者中有52％，而在63个对照中的24％的患者中有52％的稳态氧饱和度<99％（p <0.0001）（p <0.0001），9％的患者与任何对照组的饱和度<95％（p = 0.008）和8％的对照组为3％，并且= 3％或8％的患者= 3％。降低血红蛋白浓度（P <OR = 0.001）和增加的血液解（P <OR = 0.003），但肺功能测试不是独立的稳态饱和度和运动诱导的饱和度减少的独立预测指标。中风病史和急性胸部综合征的病史均未与较低的稳态氧饱和度或运动诱导的饱和度减少显着相关。稳态血红蛋白氧饱和度较低的患者（p = 0.003），六分钟步行期间的氧饱和度较高（P = 0.022），稳态血红蛋白氧饱和度（P = 0.003）的患者较高（P = 0.022）。总之，较低的血红蛋白氧饱和度与贫血和血液溶液的增加独立相关，但镰状细胞疾病的儿童和青少年的肺功能异常与肺功能异常相关。