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.

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