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)：哮喘是一种并存的疾病，会增加患有镰状细胞病(SCD)的儿童的发病率和死亡率。最近，我们报道了SCD小鼠卵白蛋白(OVA)致敏所致的实验性哮喘增加了SCD小鼠的肺部炎症和胶原沉积，其程度比OVA致敏的对照组小鼠要大得多。初步结果表明，与OVA致敏对照组相比，OVA致敏也增加了SCD小鼠的呼吸道阻力。此外，OVA致敏增加了SCD小鼠的促炎高密度脂蛋白(HDL)水平，这表明SCD+哮喘小鼠的高密度脂蛋白比SCD小鼠的高密度脂蛋白受到更大程度的氧化修饰。组织学和对缺乏载脂蛋白A-I(载脂蛋白A-I)的小鼠的呼吸道反应研究进一步证明，高密度脂蛋白在预防肺部炎症中发挥重要作用。载脂蛋白A-I是高密度脂蛋白中主要的抗炎载脂蛋白。由于apoA-I缺失导致的高密度脂蛋白基因缺失显著增加了肺部炎症和胶原沉积，并增加了呼吸道阻力，即使没有卵清蛋白致敏。在这些发现的基础上，我们假设哮喘和SCD诱导的氧化应激协同增加高密度脂蛋白的氧化，从而损害高密度脂蛋白的功能。此外，我们假设，高密度脂蛋白功能的丧失(直接或间接)增加了肺血管内皮细胞的激活(VCAM-1表达增加)，这反过来又增加了SCD+哮喘小鼠在受到缺氧/再灌注(H/R)损伤时对肺血管闭塞的易感性。为了检验这些假设，我们提出了三个目标。目的1确定哮喘和SCD的结合是否增加了高密度脂蛋白的氧化，从而增加了高密度脂蛋白的功能，以及是否针对1)黄嘌呤氧化酶(XO)，2)髓过氧化物酶(MPO)，3)细胞游离血红蛋白(Hb)，以及4)氧化的脂类阻止高密度脂蛋白和其他脂蛋白的氧化。目的2将确定哮喘合并SCD是否损害了肺血管扩张，增加了肺动脉高压(PAH)，并增加了呼吸道高反应性。这些研究将揭示靶向氧化应激(即XO、MPO、游离Hb和氧化脂质)是否真的改善了高密度脂蛋白功能，恢复了肺和呼吸道功能。目的3将确定VCAM-1(和ICAM-1)在多大程度上介导SCD+哮喘小鼠的红细胞血管充血；靶向氧化酶活性、游离Hb或氧化脂质是否减轻肺部炎症和减少血管充血；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，恢复高密度脂蛋白功能应该会减少SCD+哮喘小鼠的肺部炎症和肺血管闭塞。我们的研究结果将揭示哮喘增加SCD的气道高反应性和PAH的炎症和氧化机制。新的治疗策略将被用来确定哮喘在多大程度上增加了这四种不同的氧化途径，从而在SCD中诱导肺部炎症、呼吸道高反应性和血管闭塞。 公共卫生相关性：在患有镰状细胞疾病的个体中，哮喘会增加发病率和死亡率。我们想要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共同作用，氧化高密度脂蛋白。氧化作用将“好胆固醇”转变为“坏胆固醇”，而坏胆固醇不再能净化血管和呼吸道。因此，肺组织结合了更多的白细胞，导致呼吸道收缩，从而限制了气流。这会减少肺内的血液和氧气交换，进而增加镰状细胞病中的红细胞镰状和血管闭塞。我们计划通过结合使用标准和新的药物疗法来减少氧化应激和减少高密度脂蛋白的氧化。如果我们是正确的，那么我们的药物疗法应该会改善患有实验性哮喘的SCD小鼠的血管功能，降低呼吸道阻力。