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.

项目总结/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 在婴儿出生前就与子宫分离了。在所有分娩中，1%至2%的婴儿出现早产;三分之二的婴儿出现早产。 根据相关的孕产妇和围产期发病率和死亡率，被归类为重度。大量研究 提示缺血是早期缺血病理学一个高潮，包括血液凝固， 炎症然而，疾病的发病和机制涉及其进展到预防是穷人 这是一个重要的知识缺口。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，缺乏内皮蛋白C受体（EPCR）的小鼠， 血液凝固的内源性抑制剂，表现出发展为胎盘凝结的蜕膜血凝块。 我们已经发现，这一过程需要凝血酶受体Par 4，并伴随着凝血酶受体Par 4的浸润。 白细胞及其急性炎症反应的证据，包括（1）髓过氧化物酶（MPO）的释放， 一种产生有毒氧化剂的酶，和（2）组蛋白瓜氨酸酶，一种 改变染色质结构并驱动炎症的组蛋白。重要的是，我们的数据显示，MPO- 组蛋白的释放和瓜氨酸化也发生在人类胎盘中，支持我们的研究的相关性。 调查结果。总之，这些新发现表明，凝血级联反应的激活导致 补充免疫细胞的蜕膜，并随后炎症反应介导胎盘 注意。这项研究的长期目标是确定这种细胞和分子组成部分， 凝血-炎症串扰在母体血栓形成倾向的背景下，并确定潜在的治疗 靶点是抑制发展为胎盘早剥。本申请的目的是检验假设 蜕膜血凝块的发生和发展为胎盘血栓需要凝血酶受体 激活、募集表达MPO的白细胞和激活其下游损伤机制。 具体目标1将确定和表型改变的免疫细胞群在蜕膜， 在胎盘脱垂的发生和发展过程中与蜕膜的相互作用。具体目标2将剖析 凝血成分和血管内皮在胎盘早剥发病和进展中的作用。 具体目标3将确定炎症介质的发病机制中的胎盘功能障碍，特别是 强调中性粒细胞和MPO的作用，以及它们在氧化应激和慢性炎症中的破坏性循环。 炎症预期的结果是对免疫细胞的全面了解， 蜕膜在激活凝血的背景下，并确定其下游的损伤机制。 这项工作将有一个积极的影响，通过解开机制，调解凝血相关 这可能会对更广泛的胎盘并发症产生影响。