Coagulation-inflammation crosstalk in placental abruption

胎盘早剥中的凝血-炎症串扰

• 批准号: 10656840
• 负责人: Rashmi Sood
• 金额: $ 59.65万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-20 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656840
• 关键词: Abruptio Placentae; Acute; Animal Model; Antibodies; Birth; Blood Platelets; Blood coagulation; Cells; Chromatin Structure; Chronic; Classification; Coagulation Process; Cre lox recombination system; Data; Decidua; Dendritic Cells; Development; Diagnosis; Disease Progression; Endothelium; Enzymes; Evaluation; Event; Exhibits; Fetal Growth Retardation; Fetus; Flow Cytometry; Genetic; Goals; Health; Hematological Disease; Hemorrhage; Histones; Human; Immune; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Ischemia; Knock-out; Knowledge; Label; Leucocytic infiltrate; Leukocytes; Life; Low Birth Weight Infant; Macrophage; Mediating; Mediator; Medical; Mission; Molecular; Mothers; Mus; Natural Killer Cells; Neutrophil Infiltration; Onset of illness; Outcome; Oxidants; Oxidative Stress; Pathogenesis; Pathology; Perinatal mortality demographics; Peroxidases; Phenotype; Placenta; Placentation; Platelet Activation; Play; Population; Post-Translational Protein Processing; Pregnancy; Pregnancy Complications; Premature Birth; Process; Production; Public Health; Reaction; Receptor Activation; Research; Risk; Role; T-Lymphocyte; Testing; Thrombin Receptor; Thrombophilia; Tissues; United States National Institutes of Health; Uterus; Vascular Endothelium; Work; activated protein C receptor; cell type; fetal; high dimensionality; histone modification; inhibitor; maternal morbidity; monocyte; mortality; neutrophil; novel; perinatal morbidity; pharmacologic; pregnant; prevent; receptor expression; recruit; stillbirth; therapeutic target; tool; trafficking; transcriptomics

PROJECT SUMMARY/ABSTRACT: Placental abruption is a life-threatening pregnancy complication where the placenta completely or partially separates from the uterus before the birth of the baby. Abruption complicates 1 to 2% of all births; two-thirds are classified as severe based on associated maternal and perinatal morbidity and mortality. Numerous studies suggest that abruption is a culmination of early ischemic pathology involving blood coagulation and inflammation. However, disease onset and mechanisms involved in its progression into abruption are poorly understood and constitute an important gap in knowledge. A well-recognized barrier is that human placental tissue cannot be obtained until pregnancy is over, making early pathology and its progression challenging to investigate. Our preliminary data demonstrate that mice deficient in Endothelial Protein C Receptor (EPCR), an endogenous inhibitor of blood coagulation, exhibit decidual blood clots that progress into placental abruption. We have discovered that this process requires thrombin receptor Par4 and is accompanied by infiltration of leukocytes and evidence of their acute inflammatory reaction involving (1) release of myeloperoxidase (MPO), an enzyme that generates toxic oxidants, and (2) histone citrullination, a posttranslational modification of histones that changes chromatin structure and drives inflammation. Importantly, our data shows that MPO- release and citrullination of histones also occur in human placental abruption, supporting the relevance of our findings. Taken together, these new findings suggest that activation of the blood clotting cascade results in recruitment of immune cells to the decidua, and that their ensuing inflammatory response mediates placental abruption. The long-term goal of this research is to identify cellular and molecular components of this coagulation-inflammation crosstalk in the setting of maternal thrombophilia, and to identify potential therapeutic targets to inhibit progression into placental abruption. The objective of this application is to test the hypothesis that onset of decidual blood clots and progression into placental abruption requires thrombin receptor activation, recruitment of MPO-expressing leukocytes and activation of their downstream mechanism of injury. Specific aim 1 will identify and phenotype altered immune cell populations in the decidua, and their trafficking to and from the decidua during onset and development of placental abruption. Specific aim 2 will dissect the roles of coagulation components and the vascular endothelium in onset and progression to placental abruption. Specific aim 3 will identify mediators of inflammation in the pathogenesis of placental abruption with particular emphasis on the roles of neutrophils and MPO, and their destructive cycle of oxidative stress and chronic inflammation. The expected outcome is a comprehensive understanding of immune cells that are recruited to the decidua in the context of activated coagulation and identification of their downstream mechanisms of injury. This work will have a positive impact by unraveling the mechanisms mediating coagulation-associated abruption and will likely have implications for a broader set of placental complications.

项目摘要/摘要： 胎盘早剥是一种危及生命的妊娠并发症，胎盘完全或部分脱落 在婴儿出生前与子宫分离。 1% 至 2% 的分娩因胎停而变得复杂；三分之二 根据相关的孕产妇和围产期发病率和死亡率被分类为严重。大量研究 表明胎早剥是早期缺血性病理的最终结果，涉及血液凝固和 炎。然而，疾病的发病及其进展为早剥的机制尚不清楚。 理解并构成了重要的知识差距。一个公认的障碍是人类胎盘 直到妊娠结束才能获得组织，这使得早期病理学及其进展具有挑战性 调查。我们的初步数据表明，小鼠缺乏内皮蛋白 C 受体 (EPCR)，这是一种 内源性凝血抑制剂，表现出蜕膜血凝块，进展为胎盘早剥。 我们发现这个过程需要凝血酶受体Par4，并且伴随着凝血酶受体Par4的浸润。 白细胞及其急性炎症反应的证据涉及（1）髓过氧化物酶（MPO）的释放， 一种产生有毒氧化剂的酶，以及（2）组蛋白瓜氨酸化，一种翻译后修饰 改变染色质结构并引发炎症的组蛋白。重要的是，我们的数据表明 MPO- 组蛋白的释放和瓜氨酸化也发生在人类胎盘早剥中，支持我们的相关性 发现。总而言之，这些新发现表明凝血级联的激活会导致 免疫细胞募集到蜕膜，随后的炎症反应介导胎盘 早剥。这项研究的长期目标是确定这种物质的细胞和分子成分 母亲血栓形成倾向中的凝血-炎症串扰，并确定潜在的治疗方法 目标是抑制进展为胎盘早剥。该应用程序的目的是检验假设 蜕膜血栓的发生和胎盘早剥的进展需要凝血酶受体 表达 MPO 的白细胞的激活、募集及其下游损伤机制的激活。 具体目标 1 将识别蜕膜中免疫细胞群的表型改变及其运输 在胎盘早剥发生和发展期间往返于蜕膜。具体目标 2 将剖析 凝血成分和血管内皮在胎盘早剥的发生和进展中的作用。 具体目标 3 将确定胎盘早剥发病机制中的炎症介质，特别是 强调中性粒细胞和 MPO 的作用，以及它们的氧化应激和慢性破坏性循环 炎。预期的结果是对被招募的免疫细胞有一个全面的了解 蜕膜在激活凝血的背景下并确定其下游损伤机制。 这项工作将通过揭示凝血相关的介导机制产生积极影响 胎盘早剥并可能对更广泛的胎盘并发症产生影响。