Asthma Increases Vaso-occlusion in Sickle Cell Disease

哮喘增加镰状细胞病的血管闭塞

• 批准号: 8139181
• 负责人: Cheryl A Hillery
• 金额: $ 51.27万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-05 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139181
• 关键词: 3-nitrotyrosine; Adhesives; African American; Airway Resistance; Allopurinol; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Apolipoproteins B; Asthma; Attenuated; Binding; Biological Markers; Blood; Blood Vessels; Cells; Cessation of life; Chemotaxis; Child Mortality; Cholesterol; Clinical Data; Collagen; Coupled; Data; Deposition; Disease; Endothelial Cells; Engineering; Enzymes; Erythrocytes; Exhibits; F2-Isoprostanes; Genetic; Goals; Hemoglobin; High Density Lipoproteins; Histology; Human; Hydrolase; Hypoxia; IgE; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Infiltration; Inflammation; Inflammatory; Injury; Intercellular adhesion molecule 1; Iron; Label; Lead; Leukocytes; Lipoproteins; Low Density Lipoprotein oxidation; Low-Density Lipoproteins; Lung; Mediating; Modeling; Morbidity - disease rate; Mus; Ovalbumin; Oxidative Stress; Oxygen; Pathway interactions; Patients; Peroxidases; Pharmacotherapy; Plasma; Platelet Activating Factor; Play; Pneumonia; Predisposition; Property; Pulmonary Hypertension; Pulmonary artery structure; Pulmonary vessels; Quality of life; Reperfusion Injury; Reporting; Role; Serum amyloid A protein; Sickle Cell; Sickle Cell Anemia; Staining method; Stains; Structure of parenchyma of lung; Testing; Vascular Cell Adhesion Molecule-1; Vasodilation; Xanthine Oxidase; airway hyperresponsiveness; airway inflammation; aryldialkylphosphatase; base; clinically relevant; cohort; design; enzyme activity; eosinophil; functional restoration; improved; injured; insight; mimetics; monocyte; mortality; novel; novel therapeutics; oxidation; oxidized lipid; pressure; prevent; public health relevance; pulmonary arterial hypertension; pulmonary function; response; sickling; sphingosine 1-phosphate

DESCRIPTION (provided by applicant): Asthma is a co-morbid condition that increases morbidity and mortality of children who have sickle cell disease (SCD). Recently, we reported that experimental asthma induced by ovalbumin (OVA) sensitization of SCD mice increases pulmonary inflammation and collagen deposition in SCD mice to a much greater extent than in OVA-sensitized control mice. Preliminary Results show that OVA-sensitization also increases airway resistance in SCD mice to a greater degree than in OVA-sensitized controls. Additionally, OVA-sensitization increases proinflammatory high-density lipoprotein (HDL) levels in SCD mice, indicating that HDL from SCD+asthma mice is oxidatively modified to a greater extent than HDL from SCD mice. Further proof that HDL plays an important role in preventing pulmonary inflammation comes from histology and airway response studies in mice lacking apolipoprotein A-I (apoA-I), the major anti- inflammatory apolipoprotein in HDL. Genetic loss of HDL via apoA-I deletion dramatically increases pulmonary inflammation and collagen deposition and increases airway resistance even without OVA sensitization. On the basis of these findings, we hypothesize that the oxidative stress induced by asthma and SCD synergize to increase HDL oxidation, which then impairs HDL function. Further, we hypothesize that the loss of HDL function (either directly or indirectly) increases endothelial cell activation (increased VCAM-1 expression) in pulmonary vessels, which in turn, increases the susceptibility of SCD+asthma mice to pulmonary vaso-occlusion when subjected to hypoxia/reperfusion (H/R) injury. To test these hypotheses we propose 3 aims. Aim 1 will determine if the combination of asthma and SCD increases oxidation of HDL and therefore HDL function and if targeting oxidative stress induced by 1) xanthine oxidase (XO); 2) myeloperoxidase (MPO); 3) cell free hemoglobin (Hb); and, 4) oxidized lipids prevents oxidation of HDL and other lipoproteins in the SCD mice with asthma. Aim 2 will determine if the combination of asthma plus SCD impairs pulmonary artery vasodilatation, increases pulmonary arterial hypertension (PAH) and increases airway hyperresponsiveness. These studies will reveal whether targeting oxidative stress (i.e., XO, MPO, free Hb and oxidized lipids) actually improves HDL function and restores pulmonary and airway function. Aim 3 will determine the extent to which VCAM-1 (and ICAM-1) mediates red cell vascular congestion in SCD+asthma mice; whether targeting oxidative enzyme activity, free Hb or oxidized lipids attenuates pulmonary inflammation and reduces vaso-congestion; and finally, whether treatments with apoA-I can reduce pulmonary inflammation and vaso-congestion. If our hypotheses are correct, restoring HDL function should decrease pulmonary inflammation and attenuate vaso-occlusion in the lungs of SCD+asthma mice. Findings from our studies will reveal new insight into the inflammatory and oxidative mechanisms by which asthma increases airway hyperresponsiveness and PAH in SCD. Novel therapeutic strategies will be used to determine the extent to which asthma increases these four different oxidative pathways to induce pulmonary inflammation, airway hyperresponsiveness and vaso-occlusion in SCD. PUBLIC HEALTH RELEVANCE: Asthma increases morbidity and mortality in individuals afflicted with sickle cell disease. We want to determine why asthma increases inflammation and red cell vascular congestion in lungs of sickle cell mice. We think that the oxidative stress induced by asthma coupled with oxidative stress induced by sickle cell disease team up to oxidize high-density lipoprotein (HDL). Oxidation changes "good cholesterol" into "bad cholesterol," which can no longer clean up blood vessels and airways. Thus, lung tissues bind more white blood cells causing the airways to shrink, which restricts airflow. This decreases blood and oxygen exchange in the lung, which in turn, increases red cell sickling and vaso-occlusion in sickle cell disease. We plan to reduce oxidative stress and decrease HDL oxidation by using a combination of standard and novel drug therapies. If we are correct, then our drug therapies should improve blood vessel function and decrease airway resistance in SCD mice with experimental asthma.

描述（由申请人提供）：哮喘是一种合并症，可增加镰状细胞病（SCD）儿童的发病率和死亡率。最近，我们报道了由卵清蛋白（OVA）致敏的SCD小鼠诱导的实验性哮喘在SCD小鼠中比在OVA致敏的对照小鼠中更大程度地增加肺部炎症和胶原沉积。初步结果表明，OVA致敏也增加了SCD小鼠的气道阻力在更大程度上比OVA致敏的控制。此外，OVA致敏增加SCD小鼠的促炎性高密度脂蛋白（HDL）水平，表明SCD+哮喘小鼠的HDL比SCD小鼠的HDL氧化修饰程度更大。HDL在预防肺部炎症中起重要作用的进一步证据来自缺乏载脂蛋白A-I（apoA-I）（HDL中的主要抗炎载脂蛋白）的小鼠的组织学和气道反应研究。通过apoA-I缺失导致的HDL基因丢失显著增加了肺部炎症和胶原沉积，并增加了气道阻力，即使没有OVA致敏。基于这些发现，我们推测哮喘和SCD诱导的氧化应激协同作用增加HDL氧化，从而损害HDL功能。此外，我们假设HDL功能的丧失（直接或间接）增加了肺血管中内皮细胞的活化（VCAM-1表达增加），这反过来又增加了SCD+哮喘小鼠在缺氧/再灌注时对肺血管闭塞的易感性（H/R）损伤。为了验证这些假设，我们提出了三个目标。目的1将确定哮喘和SCD的组合是否增加HDL的氧化并因此增加HDL功能，以及靶向由1）黄嘌呤氧化酶（XO）; 2）髓过氧化物酶（MPO）; 3）无细胞血红蛋白（Hb）;和4）氧化脂质诱导的氧化应激是否防止患有哮喘的SCD小鼠中HDL和其他脂蛋白的氧化。目的2将确定哮喘合并SCD是否会损害肺动脉血管舒张，增加肺动脉高压（PAH）和增加气道高反应性。这些研究将揭示是否靶向氧化应激（即，XO、MPO、游离Hb和氧化脂质）实际上改善HDL功能并恢复肺和气道功能。目的3将确定VCAM-1（和ICAM-1）在SCD+哮喘小鼠中介导红细胞血管充血的程度;靶向氧化酶活性、游离Hb或氧化脂质是否减弱肺部炎症并减少血管充血;最后，apoA-I治疗是否可以减少肺部炎症和血管充血。如果我们的假设是正确的，恢复HDL功能应该减少肺部炎症，并减弱SCD+哮喘小鼠肺部血管闭塞。我们的研究结果将揭示哮喘增加SCD患者气道高反应性和PAH的炎症和氧化机制的新见解。新的治疗策略将用于确定哮喘增加这四种不同氧化途径诱导SCD中的肺部炎症、气道高反应性和血管闭塞的程度。 公共卫生相关性： 哮喘会增加镰状细胞病患者的发病率和死亡率。我们想确定为什么哮喘会增加镰状细胞小鼠肺部的炎症和红细胞血管充血。我们认为哮喘引起的氧化应激与镰状细胞病引起的氧化应激联合起来氧化高密度脂蛋白（HDL）。氧化将“好胆固醇”变成“坏胆固醇”，不再能清理血管和气道。因此，肺组织结合更多的白色血细胞，导致气道收缩，这限制了气流。这减少了肺部的血液和氧气交换，这反过来又增加了镰状细胞病中的红细胞镰状化和血管闭塞。我们计划通过使用标准和新型药物疗法的组合来减少氧化应激和降低HDL氧化。如果我们是正确的，那么我们的药物治疗应该改善患有实验性哮喘的SCD小鼠的血管功能并降低气道阻力。