The role of factor Xa and PAR2 in inflammation and pulmonary hypertension in sick

Xa因子和PAR2在患者炎症和肺动脉高压中的作用

• 批准号: 8837910
• 负责人: Erica M Sparkenbaugh
• 金额: $ 2.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837910
• 关键词: Animal Model; Anticoagulant therapy; Attenuated; Biological Markers; Blood Vessels; Bone Marrow Transplantation; Cells; Child; Clinical; Clinical Data; Coagulation Process; Communities; Complex; Complication; Data; Deep Vein Thrombosis; Development; Disease; Endothelial Cells; Etiology; Factor VIIa; Factor Xa; Functional disorder; Generations; Genes; Globin; Health; Hematological Disease; Hemoglobin; Hemolysis; Hemolytic Anemia; Hypoxia; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Ischemia; Link; Long-Term Effects; Longevity; Lung; Lung Inflammation; Mediating; Medical; Mus; Mutation; Neutrophil Activation; Neutrophil Infiltration; Nucleotides; Organ; Oxidative Stress; PAR-1 Receptor; PAR-2 Receptor; Pathogenesis; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Play; Proteinase-Activated Receptors; Pulmonary Embolism; Pulmonary Hypertension; Reperfusion Therapy; Rodent Model; Role; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Signal Transduction; Smooth Muscle Myocytes; Stroke; Testing; Thrombin; Thromboplastin; Thrombosis; Tissues; Vascular remodeling; cytokine; hydroxyurea; inhibitor/antagonist; insight; mouse model; neutrophil; prevent; therapeutic target; treatment strategy; vascular inflammation; vasoconstriction

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a hematological disorder caused by a single nucleotide mutation in the ¿-globin gene of hemoglobin (Hb). Under hypoxic conditions, sickle Hb tetramers polymerize which results in sickling of red blood cells, leading to hemolytic anemia and vaso-occlusion. This leads to a complex vascular pathophysiology associated with oxidative stress, ischemia/reperfusion, endothelial cell activation, inflammation and activation of coagulation1. We have recently demonstrated that tissue factor (TF), the primary initiator of the extrinsic coagulation pathway, contributes to coagulation activation, endothelial cell activation and inflammation in the two mouse models of SCD2. TF and the downstream coagulation proteases factor VIIa (FVIIa), FXa, and thrombin, can contribute to the inflammatory response by activating protease activated receptors (PARs). Thrombin and other proteases activate PAR-1, whereas TF:FVIIa and FXa activate PAR-2. In addition to systemic inflammation and neutrophil activation, PAR-2 signaling is associated with pulmonary hypertension (PH), a common clinical complication in SCD patients. PH in SCD has been linked to pulmonary vasoconstriction, mediated by hemolysis and NO depletion3. An alternative hypothesis that thrombosis may contribute to the development of PH has recently been proposed4-6. Interestingly, FXa7, PAR-28,9 and IL-610,11 have been linked to that pathogenesis of PH in rodent models. Therefore, I will test the hypothesis that FXa mediates both thrombosis and PAR-2 dependent inflammation, which contribute to PH in SCD. My proposal is divided into two aims. In Aim 1, I will assess the effects of PAR-2 deficiency or pharmacologic inhibition of PAR-2 on the development of PH in sickle cell mice. In Aim 2 I will use the clinically approved FXa inhibitor rivaroxaban to determine the effect of long-term FXa inhibition on coagulation, inflammation and PH in sickle cell mice. These results will be compared to those obtained from mice treated with the thrombin inhibitor dabigatran. These studies will increase our understanding of the etiology of PH in SCD, and provide insight into therapeutic targets that could be used to reduce inflammation, coagulation, and PH in patients.

描述(申请人提供)：镰状细胞病(SCD)是一种血液学疾病，由血红蛋白(Hb)的珠蛋白基因的单核苷酸突变引起。在低氧条件下，镰刀状Hb四聚体聚合，导致红细胞呈镰状，导致 溶血性贫血和血管闭塞。这导致了与氧化应激、缺血/再灌注、内皮细胞激活、炎症和凝血激活相关的复杂的血管病理生理1。我们最近已经证明，组织因子(TF)是外源性凝血途径的主要启动者，在两种SCD2小鼠模型中参与凝血激活、内皮细胞激活和炎症。Tf及其下游凝血酶因子VIIa(FVIIa)、FXA和凝血酶可通过激活蛋白酶激活受体(PARs)参与炎症反应。凝血酶和其他蛋白酶激活PAR-1，而Tf：FVIIa和FXA激活PAR-2。除了全身炎症和中性粒细胞激活外，PAR-2信号与肺动脉高压(PH)有关，PH是SCD患者常见的临床并发症。SCD中的pH与肺血管收缩有关，这种收缩是由溶血和NO消耗介导的。最近提出了另一种假说，即血栓形成可能有助于PH的发展。有趣是，FXa7、PAR-28、9和IL-610、11与啮齿动物模型中的PH的发病机制有关。因此，我将验证FXA同时介导血栓形成和PAR-2依赖性炎症的假设，后者有助于SCD的PH。我的建议分为两个目标。在目标1中，我将评估PAR-2缺乏或PAR-2的药物抑制对镰状细胞小鼠PH发生的影响。在目标2中，我将使用临床批准的FXA抑制剂利伐沙班来确定长期抑制FXA对镰状细胞小鼠凝血、炎症和PH的影响。这些结果将与用凝血酶抑制剂达比加兰治疗的小鼠的结果进行比较。这些研究将增加我们对SCD中PH的病因的理解，并为可用于减少患者炎症、凝血和PH的治疗靶点提供洞察力。