Role of Placenta Growth factor in Sickle ACS

胎盘生长因子在镰状 ACS 中的作用

基本信息

批准号：
7245880
负责人：
PUNAM MALIK
金额：
$ 82.52万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-06-15 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7245880
关键词：
Acute Acute Lung Injury Admission activity Angiogenesis Inhibitors Arachidonate 5-Lipoxygenase Asthma Basic Science Binding Blood Bronchoconstrictor Agents Bronchopulmonary Dysplasia CCL2 gene Cessation of life Chemotaxis Chest Pain Clinical Clinical Trials Coagulants Complication Development Diagnosis Diagnostic radiologic examination Disease Drops Dysplasia Early Intervention Elevation Endothelial Cells Endotoxins Erythroid Cells Erythropoiesis Erythropoietin Event Exercise stress test Functional disorder Genes Growth Growth Factor Hemoglobin Hemolysis Histology Human Hypoxia IL8 gene Immunohistochemistry Incidence Inflammation Inflammatory Inflammatory Response Interleukin-10 Irrigation Knock-out Knockout Mice Laboratories Leukocyte Chemotaxis Leukocytosis Leukotriene Antagonists Leukotriene B4 Leukotrienes Lung Lung diseases Measures Mus Myocardial Infarction Newborn Infant Obstructive Lung Diseases Patients Peak Expiratory Flow Rate Personal Satisfaction Pharmaceutical Preparations Placental Growth Factor Plasma Prevention Process Production Proteins Pulmonary function tests Pulse Oximetry RALGDS gene Research Personnel Rest Reticulocyte count Risk Role Severities Severity of illness Sickle Cell Sickle Cell Anemia Signal Transduction Smooth Muscle Spirometry Testing Thromboplastin Transgenic Mice Transgenic Organisms Tumor Necrosis Factor-alpha United States Food and Drug Administration Urine Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors White Blood Cell Count procedure Work Zileuton acute chest syndrome cysteinyl-leukotriene human TNF protein inhibitor/antagonist insight macrophage monocyte montelukast mortality neutrophil novel programs pulmonary function ral Guanine Nucleotide Exchange Factor response sickling transcription factor

项目摘要

DESCRIPTION (provided by applicant): Acute chest syndrome (ACS), a devastating complication of sickle cell disease (SCD), is the most common cause of disease-related mortality. Nonetheless, little is known about its pathophysiology, it is diagnosed and treated only after the disease process is well underway. Work from our laboratory suggests a novel insight into the underlying pathophysiology of ACS. We show that an erythroid-cell derived angiogenic growth factor, placental growth factor (PIGF) promotes a strong inflammatory response in SCD: it increases expression of VEGF, IL-1beta, IL-8, MCP-1, TNF alpha and tissue factor (TF) from monocytes via binding to VEGFR1/Flt-1. PIGF levels are increased in SCD plasma and correlate with disease severity. PIGF is inducible by hypoxia and erythropoietin (Epo), factors elevated in SCD. PIGF was recently found to strongly predict a) death or nonfatal myocardial infarction in patients presenting with chest pain and b) development and severity of bronchopulmonary dysplasia in newborns. We show that PIGF initiates downstream signaling events resulting in activation of early growth response-1 (Egr-1). Downstream targets of Egr-1 include VEGF, IL-1beta, MCP-1, TNFalpha, TF and 5-lipoxygenase (5LO), all of which increase leukocyte chemotaxis and inflammation; 5LO initiates the cascade that produces leukotrienes (LT). We show that SCD patients have evidence of reactive airway disease at baseline; PIGF increases expression of 5LO and 5LO activator protein from human pulmonary endothelial cells; and that PIGF-/- mice have a reduced inflammatory response to acute lung injury. ACS often follows an acute event, associated with a drop in hemoglobin. The latter would increase hypoxia, Epo and erythropoiesis, all of which increase PIGF production. We hypothesize that elevated PIGF, via its effect on inflammatory cytochemokines and leukotrienes results in increased inflammation and reactive airway disease at baseline in patients with SCD. Further elevations in PIGF levels during acute sickle events amplify the inflammation and reactive airway disease and contribute significantly to the cascade of events that result in ACS. Aim1: Knock out the PIGF gene in transgenic sickle mice and study their disease severity and response to acute lung injury. Aim 2: Determine whether elevated PIGF levels will predict ACS in SCD patients hospitalized for an acute event and that PLGF levels and LT levels will predict the magnitude of airway reactivity and obstructive lung disease in patients with SCD. Together, these aims are a focused approach combining basic science and clinical investigation to elucidate a mechanism that likely contributes to ACS, in order to enable early intervention in patients at high risk for ACS and target therapy at the underlying disease process. VEGFR-antagonists are in clinical trials and leukotriene blockers are FDA approved and in clinical use for asthma and could be candidates for an ACS prevention trial.

描述（由申请人提供）：急性胸部综合征（ACS）是镰状细胞疾病（SCD）的毁灭性并发症，是与疾病相关死亡率的最常见原因。尽管如此，对其病理生理学知之甚少，只有在疾病过程中进行诊断和治疗。我们实验室的工作提出了对ACS潜在的病理生理学的新颖洞察力。我们表明，红细胞衍生的血管生成生长因子，胎盘生长因子（PIGF）促进了SCD中的强烈炎症反应：它增加了VEGF，IL-1Beta，IL-8，IL-8，MCP-1，TNF alpha和Tankue alpha和Tissue因子的表达（ TF）通过与VEGFR1/FLT-1结合的单核细胞。 SCD血浆中的PIGF水平升高并与疾病严重程度相关。 SCD中升高的因素可通过缺氧和红细胞生成素（EPO）诱导。最近发现PIGF强烈预测a）患有胸痛和b）新生儿支气管肺发育不良的发育和严重程度的患者的死亡或非致命性心肌梗死。我们表明，PIGF启动下游信号传导事件，导致早期生长响应1（EGR-1）激活。 EGR-1的下游靶标包括VEGF，IL-1BETA，MCP-1，TNFALPHA，TF和5-脂氧酶（5LO），所有这些都会增加白细胞趋化性和炎症； 5lo启动产生白细胞（LT）的级联。我们表明，SCD患者在基线时有反应性气道疾病的证据。 PIGF增加了人类肺部内皮细胞中5LO和5LO激活蛋白的表达。 pigf - / - 小鼠对急性肺损伤的炎症反应降低。 ACS通常遵循与血红蛋白下降有关的急性事件。后者会增加缺氧，EPO和红细胞生成，所有这些都会增加pigf的产生。我们假设较高的PIGF通过对SCD患者的炎症细胞化学动物和白细胞的影响导致基线时的炎症和反应性气道疾病增加。急性镰刀事件期间，pigf水平的进一步升高会扩大炎症和反应性气道疾病，并对导致ACS的一系列事件产生重大贡献。 AIM1：在转基因镰刀小鼠中删除PIGF基因，并研究其疾病的严重程度和对急性肺损伤的反应。 AIM 2：确定升高的PIGF水平是否会预测急性事件住院的SCD患者的ACS，并且PLGF水平和LT水平将预测SCD患者气道反应性和阻塞性肺部疾病的大小。总之，这些目标是一种集中的方法，结合了基础科学和临床研究，以阐明一种可能有助于ACS的机制，以便在基本疾病过程中对ACS高风险和靶向治疗的患者进行早期干预。 VEGFR-Antagonists正在临床试验中，白三烯阻滞剂已获得FDA批准，并且在哮喘中使用了临床用途，并且可能是ACS预防试验的候选者。