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: 8007265
• 负责人: Cheryl A Hillery
• 金额: $ 64.68万
• 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/8007265
• 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; Normal Range; 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，可提高患有镰状细胞病（SCD）的儿童的发病率和死亡率。最近，我们报道说，SCD小鼠的卵蛋白（OVA）敏化引起的实验性哮喘会增加SCD小鼠的肺部炎症和胶原蛋白沉积的程度，其程度要大得多。初步结果表明，与OVA敏感的对照相比，OVA敏化还会增加SCD小鼠的气道阻力。此外，OVA敏化增加了SCD小鼠中促炎的高密度脂蛋白（HDL）水平，表明来自SCD+哮喘小鼠的HDL在氧化的程度上比SCD小鼠的HDL更大程度地修饰。进一步的证据表明，HDL在预防肺部炎症中起重要作用，来自缺乏载脂蛋白A-I（APOA-I）的小鼠的组织学和气道反应研究，这是HDL中主要的抗炎性垃圾蛋白质。通过APOA-I缺失的HDL遗传丧失会大大增加肺部炎症和胶原蛋白沉积，即使没有OVA敏感性，也会增加气道阻力。根据这些发现，我们假设由哮喘和SCD诱导的氧化应激协同增加了HDL氧化，从而损害了HDL功能。此外，我们假设HDL功能（直接或间接）的丧失会增加肺部血管中内皮细胞的激活（VCAM-1表达增加），而肺部血管中的肺血管中SCD+哮喘小鼠对肺部血管酸的易感性增加，当受到肺动脉血管酸性的敏感性，遭受炎症/REPOXIA/RECERFUSIO（H/R）损伤。为了检验这些假设，我们提出了3个目标。 AIM 1将确定哮喘和SCD的组合是否增加了HDL的氧化，因此是否会增加HDL功能，以及是否靶向由1）黄嘌呤氧化酶（XO）诱导的氧化应激； 2）脊髓过氧化物酶（MPO）； 3）无细胞无细胞血红蛋白（HB）； 4）氧化脂质可防止哮喘中SCD小鼠中HDL和其他脂蛋白的氧化。 AIM 2将确定哮喘加SCD的组合是否会损害肺动脉血管扩张，增加肺动脉高压（PAH）并增加气道高反应性。这些研究将揭示靶向氧化应激（即XO，MPO，游离HB和氧化脂质）是否实际上可以改善HDL功能并恢复肺和气道功能。 AIM 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；无论是靶向氧化酶活性，游离HB还是氧化脂质都会减轻肺部炎症并减少血管结构；最后，使用APOA-1的治疗是否可以减少肺部炎症和血管结构。如果我们的假设是正确的，那么恢复HDL功能应减少肺部炎症并减轻SCD+哮喘小鼠肺中的血管肠结unip。我们研究的发现将揭示有关哮喘增加气道高反应性和SCD中PAH的炎症和氧化机制的新见解。新型的治疗策略将用于确定哮喘在多大程度上增加这四种不同的氧化途径，以诱导SCD中的肺部炎症，气道高反应性和血管结合。 公共卫生相关性：哮喘会增加患有镰状细胞疾病的人的发病率和死亡率。我们要确定为什么哮喘会增加镰状细胞小鼠肺中的炎症和红细胞血管充血。我们认为，哮喘诱导的氧化应激与镰状细胞疾病诱导的氧化应激团队合作，氧化为氧化高密度脂蛋白（HDL）。氧化将“好胆固醇”变成“不良胆固醇”，这无法再清理血管和气道。因此，肺组织结合了更多的白细胞，导致气道收缩，从而限制了气流。这降低了肺中的血液和氧气交换，进而增加了镰状细胞疾病中的红细胞和血管结合。我们计划通过使用标准药物和新型药物疗法的组合来减少氧化应激并降低HDL氧化。如果我们是正确的，那么我们的药物疗法应改善血管功能，并通过实验性哮喘在SCD小鼠中降低气道耐药性。