THE REGULATION OF NEUTROPHIL EXTRACELLULAR TRAPS (NETS) BY ADENOSINE IN MYOCARDIAL ISCHEMIA-REPERFUSION

腺苷在心肌缺血再灌注中对中性粒细胞胞外陷阱（NETS）的调节

• 批准号: 10471275
• 负责人: Rebecca Diane Levit
• 金额: $ 43.65万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10471275
• 关键词: 5' -Nucleotidase; ADORA2A gene; Acute Respiratory Distress Syndrome; Adenosine; Adenosine A2 Receptors; Alginates; Animal Model; Anti-Inflammatory Agents; Atherosclerosis; Autoimmune Diseases; Automobile Driving; Blood Platelets; Bone Marrow; Cardiovascular Diseases; Cell Transplantation; Cells; Chromatin; Coagulation Process; Crohn' s disease; Cyclic AMP; Cytoplasmic Granules; DNA; Data; Deaminase; Deep Vein Thrombosis; Diffuse; Dose; Encapsulated; Endothelial Cells; Equilibrium; Extracellular Matrix; Extracellular Space; Functional disorder; Future; Heart; Histone H1; Histones; Hour; Human; Immune; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Interruption; Knockout Mice; Leukocytes; Light; Link; Lymphocyte; Mediating; Mediator of activation protein; Metabolism; Molecular Conformation; Morbidity - disease rate; Multiple Sclerosis; Mus; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocarditis; Myocardium; Necrosis; Pathway interactions; Pharmacology; Physiological; Physiological Processes; Play; Pre-Eclampsia; Process; Production; Protein-arginine deiminase; Purinergic P1 Receptors; Reactive Inhibition; Reactive Oxygen Species; Regulation; Reperfusion Injury; Reperfusion Therapy; Rheumatoid Arthritis; Rodent Model; Role; Septic Shock; Signal Pathway; Signal Transduction; Site; Sterility; Stimulus; Surface; Techniques; Testing; Therapeutic; Thrombin; Thrombosis; Tissues; Transplantation; White Blood Cell Count procedure; acute coronary syndrome; antimicrobial; autoimmune pathogenesis; cost; efficacy evaluation; efficacy testing; experimental study; extracellular; feasibility testing; heart function; hemodynamics; in vivo; inflammatory milieu; inhibitor; macrophage; mesenchymal stromal cell; migration; mortality; myocardial damage; neutrophil; novel; novel therapeutic intervention; nucleoside triphosphate; pathogen; prevent; targeted treatment; treatment strategy

PROJECT SUMMARY/ABSTRACT Reperfusion of the ischemic heart is lifesaving in myocardial infarction, but the physiologic processes triggered by reperfusion can cause subsequent damage. The innate immune system plays a prominent role in reperfusion injury. Neutrophils release multiple toxic mediators and the appreciation of the role of neutrophil extracellular traps (NETs) in MI/R pathophysiology is gaining importance. Adenosine is known to mitigate many pro-inflammatory immune processes while ATP released from dying and necrotic cells, activates immune cells. ATP is metabolized to adenosine by ectonucleotidases expressed on many cells including mesenchymal stromal cells (MSCs). MSCs are known to highly express ecto-nucleoside triphosphate diphosphohydrolase-1 (NTDPase1, CD39) and ecto-5’-nucleotidase (CD73). Modulation of purinergic metabolism may be a powerful mechanism used by MSCs to inhibit inflammation in their native bone marrow as well as when transplanted for therapeutic purpose. Currently little is known about endogenous regulation of NET production and we have hypothesize that adenosine may be a key endogenous regulator. Our preliminary data shows that MSC transplanted to the heart encapsulated in alginate can modulate the innate inflammatory response to MI/R. Furthermore, encapsulated MSCs increase myocardial adenosine levels, reduce reactive oxygen species, and decrease the number of leukocytes and neutrophils in the heart after 24 hours. We will use human neutrophils as well as neutrophils isolated from mice lacking key adenosine receptors to understand the role of adenosine signaling in MI/R. We will also use a rodent model of MI/R to test our novel NET-regulatory strategy in vivo. The results of these studies will identify new therapeutic strategies for treatment of innate immune MI/R injury. It is our aims to 1) delineate the importance of adenosine receptor 2A (A2A) signaling in the regulation of NET formation; 2) evaluate the intracellular signaling pathways involved in NET regulation; 3) test the feasibility of MSC modulation of purinergic metabolism to prevent NETs in MI/R.

项目摘要/摘要 缺血性心脏的再灌注在心肌梗塞中救生，但是生理过程 由再灌注触发会造成后续损坏。先天免疫系统在 再灌注损伤。中性粒细胞释放多种有毒介质和中性粒细胞作用的欣赏 MI/R病理生理学中的细胞外陷阱（网络）变得重要。众所周知腺苷可以减轻许多 ATP从垂死和坏死细胞释放的ATP时，促炎性免疫过程会激活免疫细胞。 ATP通过在许多细胞（包括间充质）上表达的核苷酸酶代谢为腺苷 基质细胞（MSC）。已知MSC高度表达核苷三磷酸双磷酸二磷酸酶-1 （NTDPase1，CD39）和Ecto-5'-核苷酸酶（CD73）。嘌呤能代谢的调节可能是强大的 MSC使用的机制来抑制其天然骨髓的炎症以及移植时 治疗目的。 目前，关于净生产的内源性调节知之甚少，我们假设 腺苷可能是关键的内源调节剂。我们的初步数据表明，MSC已移植到 藻酸盐中包裹的心脏可以调节对MI/R的先天炎症反应。此外， 封装的MSC提高心肌腺苷水平，降低活性氧，并减少 24小时后，心脏中的白细胞和中性粒细胞数量。我们将使用人类中性粒细胞以及 从缺乏关键腺苷受体的小鼠中分离出的中性粒细胞，以了解腺苷信号的作用 在mi/r中。我们还将使用MI/R的啮齿动物模型来测试我们在体内新型的网络调节策略。结果 这些研究将确定治疗先天免疫/R损伤的新治疗策略。 这是我们的目的是1）描述腺苷接收器2A（A2A）信号的重要性 净形成； 2）评估净调控涉及的细胞内信号通路； 3）测试可行性 MSC调节嘌呤能代谢，以防止网中的网。

项目成果

Therapeutic efficacy of intra-articular delivery of encapsulated human mesenchymal stem cells on early stage osteoarthritis.

• DOI: 10.22203/ecm.v037a04
• 发表时间: 2019-01-29
• 期刊: European cells & materials
• 影响因子: 3.1
• 作者: McKinney JM;Doan TN;Wang L;Deppen J;Reece DS;Pucha KA;Ginn S;Levit RD;Willett NJ
• 通讯作者: Willett NJ