Role of Placenta Growth factor in Sickle ACS

胎盘生长因子在镰状 ACS 中的作用

• 批准号: 6897725
• 负责人: PUNAM MALIK
• 金额: $ 85.89万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 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/6897725
• 关键词: angiogenesis factor; biological signal transduction; blood tests; clinical research; cytokine; genetically modified animals; human subject; immunocytochemistry; inflammation; inhibitor /antagonist; laboratory mouse; leukotrienes; lipoxygenase; lung disorder; lung imaging /visualization /scanning; lung injury; lung lavage; medical complication; pathologic process; sickle cell anemia; spirometry; transcription factor; urinalysis; vascular endothelial growth factors

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) 是镰状细胞病 (SCD) 的一种破坏性并发症，是疾病相关死亡的最常见原因。尽管如此，人们对其病理生理学知之甚少，只有在疾病过程顺利进行后才能诊断和治疗。我们实验室的工作对 ACS 的潜在病理生理学提出了新的见解。我们发现，红细胞衍生的血管生成生长因子胎盘生长因子 (PIGF) 可促进 SCD 中的强烈炎症反应：它增加 VEGF、IL-1β、IL-8、MCP-1、TNF α 和组织因子的表达。 TF）通过与 VEGFR1/Flt-1 结合从单核细胞中产生。 SCD 血浆中 PIGF 水平升高，且与疾病严重程度相关。 PIGF 可由缺氧和促红细胞生成素 (Epo) 诱导，这些因素在 SCD 中升高。最近发现 PIGF 可以强烈预测 a) 出现胸痛的患者的死亡或非致命性心肌梗塞，以及 b) 新生儿支气管肺发育不良的发展和严重程度。我们发现 PIGF 启动下游信号事件，导致早期生长反应 1 (Egr-1) 的激活。 Egr-1 的下游靶标包括 VEGF、IL-1beta、MCP-1、TNFα、TF 和 5-脂氧合酶 (5LO)，所有这些都会增加白细胞趋化性和炎症； 5LO 启动产生白三烯 (LT) 的级联反应。我们发现 SCD 患者在基线时有反应性气道疾病的证据； PIGF 增加人肺内皮细胞 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 常常发生在与血红蛋白下降相关的急性事件之后。后者会增加缺氧、红细胞生成素和红细胞生成，所有这些都会增加 PIGF 的产生。我们假设 PIGF 升高，通过其对炎症细胞趋化因子和白三烯的影响，导致 SCD 患者基线炎症和反应性气道疾病增加。急性镰状细胞事件期间 PIGF 水平的进一步升高会加剧炎症和反应性气道疾病，并显着促进导致 ACS 的级联事件。目的1：敲除转基因镰状小鼠的PIGF基因并研究其疾病严重程度和对急性肺损伤的反应。目标 2：确定升高的 PIGF 水平是否可以预测因急性事件住院的 SCD 患者的 ACS，以及 PLGF 水平和 LT 水平是否可以预测 SCD 患者气道反应性和阻塞性肺病的程度。总之，这些目标是一种将基础科学和临床研究相结合的重点方法，以阐明可能导致 ACS 的机制，以便能够对 ACS 高风险患者进行早期干预，并在潜在疾病过程中进行靶向治疗。 VEGFR 拮抗剂正在进行临床试验，白三烯阻滞剂已获得 FDA 批准并用于临床治疗哮喘，并且可能成为 ACS 预防试验的候选药物。