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（由应用提供）：镰状细胞疾病（SCD）是由血红蛋白（HB）中单个核苷酸突变引起的血液学疾病。在低氧条件下，镰状HB四聚体聚合会导致红细胞病，导致 溶血性贫血和血管封闭。这导致了与氧化应激，缺血/再灌注，内皮细胞激活，炎症和凝结的激活相关的复杂血管病理生理学。我们最近证明，在SCD2的两个小鼠模型中，组织因子（TF）是外部凝结途径的主要引发剂，有助于凝血激活，内皮细胞激活和炎症。 TF和下游凝血蛋白酶因子VIIA（FVIIA），FXA和凝血酶可以通过激活蛋白酶激活受体（PARS）来促进炎症反应。凝血酶和其他蛋白酶激活PAR-1，而TF：FVIIA和FXA激活PAR-2。除了全身性炎症和中性粒细胞激活外，PAR-2信号传导与肺动脉高压（PH）有关，这是SCD患者常见的临床并发症。 SCD中的pH与肺血管收缩有关，由溶血和无依赖性介导。最近提出了一个替代假设，即血栓形成可能有助于pH的发展4-6。有趣的是，FXA7，PAR-28,9和IL-610,11与啮齿动物模型中的pH发病机理有关。因此，我将检验以下假设：FXA介导血栓形成和PAR-2依赖注射，这有助于SCD中的pH。我的建议分为两个目标。在AIM 1中，我将评估PAR-2缺乏症或PAR-2药理抑制对镰状细胞小鼠pH发育的影响。在AIM 2中，我将使用经过临床认可的FXA抑制剂利瓦沙沙班来确定长期FXA抑制剂对镰状细胞小鼠凝结，感染和pH的影响。这些结果将与从用凝血酶抑制剂Dabigatran治疗的小鼠获得的结果进行比较。这些研究将增加我们对SCD中pH病因的理解，并提供对可用于减少患者感染，凝结和pH的治疗靶标的见解。