Intrarenal Arteries Sense N-formyl Peptides Leading to Vascular Injury in Sepsis

肾内动脉感知 N-甲酰肽导致脓毒症血管损伤

• 批准号: 10058843
• 负责人: Camilla Ferreira Wenceslau
• 金额: $ 18.87万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10058843
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Advisory Committees; Affect; Animals; Arteries; Award; Bacteria; Bacterial Infections; Basophils; Biological Markers; Blood; Blood Circulation; Blood Pressure; Blood Vessels; Cardiac; Cause of Death; Cell Communication; Cellular Structures; Cessation of life; Characteristics; Clinical; Clinical Trials; Collaborations; Complication; Data; Development; Diagnosis; Edema; Endothelial Cells; Endothelium; Environment; Enzymes; Extravasation; FPR1 gene; FPR2 gene; Faculty; Femoral vein; Flowmetry; Foundations; Functional disorder; Funding; Future; Germany; Glomerular Filtration Rate; Goals; Growth; Hemorrhagic Shock; Hour; Human; Hyperthermia; Incubated; Infection; Inflammation; Inflammatory Response; Infusion procedures; Injury; Injury to Kidney; Institution; Intensive Care Units; Interlobular Artery; International; Intrinsic factor; Investigative Techniques; Ischemia; Kidney; Kidney Failure; Knockout Mice; Knowledge; Laboratories; Laser-Doppler Flowmetry; Lead; Learning; Leukocytes; Leukocytosis; Leukopenia; Liquid substance; Maintenance; Measurement; Measures; Mediator of activation protein; Mentors; Mitochondria; Modeling; Molecular; Molecular Profiling; Mus; Nephrectomy; Neutrophil Infiltration; Nitric Oxide; Organ; Pathogenesis; Patients; Pattern; Peptides; Perfusion; Pharmacology; Phase; Physiology; Plasma; Play; Positioning Attribute; Prevention; Production; Rattus; Receptor Activation; Renal Blood Flow; Renal Circulation; Renal function; Reperfusion Therapy; Research; Research Personnel; Resistance; Role; Science; Sepsis; Source; Sterility; Symptoms; Syndrome; Systemic Inflammatory Response Syndrome; Tachycardia; Technical Expertise; Testing; Therapeutic; Time; Tissues; Training; Translating; Translational Research; Trauma; Trauma patient; Traumatic injury; Ultrasonography; Universities; Vascular Diseases; Vascular System; Vasodilation; Visit; Wistar Rats; base; career; cell injury; common symptom; experience; fMet-Leu-Phe receptor; formyl peptide; glomerular filtration; hemodynamics; hospital readmission; immunogenic; improved; in vivo; indexing; kidney dysfunction; kidney vascular structure; meetings; natural hypothermia; neutrophil; novel; novel marker; peptide deformylase; pressure; prevent; programs; protein expression; public health relevance; release factor; renal artery; renal ischemia; response to injury; signal recognition particle receptor; success; systemic inflammatory response; tenure track; translational study; two photon microscopy; vascular injury; vasoconstriction

 DESCRIPTION (provided by applicant): Systemic inflammatory response injury (SIRS) and sepsis are the principal causes of death in trauma patients in the USA. The diagnosis of sepsis requires confirmation of bacterial growth in blood cultures, as well as the presence of two or more of the following symptoms: hypothermia or hyperthermia, tachycardia, tachypnea and leukocytopenia or leukocytosis. However, only about one-third to one half of patients meeting these criteria are subsequently diagnosed with an infection. Accordingly, all remaining patients are diagnosed with SIRS. The major pathophysiological characteristic of SIRS and sepsis is vascular collapse. Breakdown of the endothelial barrier function results in the loss of fluid into the extravascular space and may lead to edema in several tissues, including the kidneys. Therefore, a frequent complication that affects more than 35% of patients with SIRS is the development of acute kidney injury (AKI). There is a lack of knowledge about the pathogenesis of AKI during SIRS, specifically as there is no study showing whether intrarenal arteries play a role in the genesis and/or maintenance of AKI during trauma-induced SIRS. Several studies have proposed that renal vasoconstriction and reduced renal blood flow (RBF) are the major causes of AKI in SIRS. However, recent observations have showed that improvements in cardiac index as well as blood pressure did not result in improved renal function and prevention of death. This implies that poor forward flow alone does not account for the development of AKI. Although it has been well established that AKI is a unifying factor of SIRS and sepsis in trauma patients, a common mediator to the many types of sepsis and SIRS has not been discovered. Also, the mechanism by which traumatic injury leads to SIRS is not fully understood. It has been proposed that cell components from traumatized tissue, called damage-associated molecular patterns (DAMPs), are the primary instigators of SIRS in trauma patients. For evolutionary reasons, mitochondria share several characteristics with bacteria and N-formyl peptides are common molecular signatures of both bacteria and mitochondria. We have observed that mitochondrial N-formyl peptides (F-MIT) induce vascular leakage, exacerbated vasodilatation and inflammation in resistance arteries via formyl peptide receptor activation. In a preliminary study, it was observed for the first time that sterile trauma induces the release of F-MIT into the circulation of patients with SIRS. Also, it was observed that F-MIT leads to SIRS, intrarenal artery dysfunction and kidney injury via FPR activation. Therefore, based on our preliminary data, it is clear that F-MIT plays a role in SIRS. However, it is unclear whether these peptides are responsible for the development of AKI due to intrarenal arteries dysfunction (e.g. exacerbated vasodilatation associated with vascular leakage, inflammation and local edema). We propose the novel and intriguing hypothesis that higher levels of F-MIT in the circulation after trauma/ischemia activate FPR leading to intrarenal artery dysfunction, AKI and SIRS. The objective of this K99/R00 application is to reveal an intrinsic factor released after cell damage initiates SIRS and acute inflammation of intrarenal arteries which results in AKI with or without hemodynamic changes. This application will also facilitate the transition of my research career towards an independent investigator position. The training (K99) phase of this award will be mentored by Dr. Clinton Webb, who is internationally recognized leader in the fields of vascular physiology and will be co- mentored by Dr. Paul O´Connor, who has devoted his career to studying whole animal renal physiology and is an expert in kidney injury. Also, during the mentored phase, I will pursue addition training in the laboratory of Dr. Grisk at University of Greifswald, Germany. It is with Dr. Grisk where I plan to learn in vivo techniques for investigating simultaneous recordings of renal perfusion and I will learn how to isolate human intrarenal arteries. These experiences will play a vital role for the completion of the independent phase of this award. My visit to the Dr. Grisk's laboratory not only will expand my technical skill and experience with different models, but it will also initiate collaboration with an expert in the renal field. Such interaction would expand the scope of my current research and improve the potential for success in gaining further independent funding as I establish my own independent research program. My short- term goal is to become an independent investigator in the field of renal vascular physiology and pathophysiology of trauma and SIRS. As an expert in these fields, I hope to obtain a tenure-track faculty position in an academic institution that promotes interdisciplinary biomedical science and has an emphasis on translational research. My long-term career goal is to establish a strong research program using integrative approaches to study the effects of injury-associated vascular dysfunction on renal physiology.

 描述（由申请方提供）：全身炎症反应损伤（SIRS）和脓毒症是美国创伤患者死亡的主要原因。败血症的诊断需要确认血培养中的细菌生长，以及存在以下两种或多种症状：体温过低或体温过高、心动过速、呼吸急促和白细胞减少或白细胞增多。然而，符合这些标准的患者中只有约三分之一到一半随后被诊断为感染。因此，所有剩余的患者都被诊断为SIRS。SIRS和脓毒症的主要病理生理特征是血管塌陷。内皮屏障功能的破坏导致液体流失到血管外空间，并可能导致包括肾脏在内的几种组织水肿。因此，影响超过35%的SIRS患者的常见并发症是急性肾损伤（阿基）的发展。缺乏关于SIRS期间阿基发病机制的知识，特别是因为没有研究表明肾内动脉是否在创伤诱导的SIRS期间阿基的发生和/或维持中起作用。一些研究已经提出，肾血管收缩和肾血流量（RBF）减少是SIRS中阿基的主要原因。然而，最近的观察表明，心脏指数和血压的改善并没有改善肾功能和预防死亡。这意味着仅仅是前向血流不佳并不能解释阿基的发生。虽然已经确定阿基是创伤患者中SIRS和脓毒症的统一因素，但尚未发现许多类型的脓毒症和SIRS的共同介导物。此外，创伤性损伤导致SIRS的机制尚未完全了解。已经提出，来自创伤组织的细胞组分，称为损伤相关分子模式（DAMP），是创伤患者中SIRS的主要引发者。由于进化的原因，线粒体与细菌有几个共同的特征，N-甲酰肽是细菌和线粒体的共同分子特征。我们已经观察到线粒体N-甲酰肽（F-MIT）通过甲酰肽受体激活诱导血管渗漏，加重阻力动脉的血管舒张和炎症。在初步研究中，首次观察到无菌创伤诱导F-MIT释放到 SIRS患者的血液循环。此外，观察到F-MIT通过FPR激活导致SIRS、肾内动脉功能障碍和肾损伤。因此，基于我们的初步数据，很明显F-MIT在SIRS中起作用。然而，尚不清楚这些肽是否是由于肾内动脉功能障碍（例如与血管渗漏、炎症和局部水肿相关的血管舒张加剧）导致阿基发展的原因。我们提出了一个新颖而有趣的假设，即创伤/缺血后循环中较高水平的F-MIT激活FPR，导致肾内动脉功能障碍、阿基和SIRS。本K99/R 00申请的目的是揭示细胞损伤后释放的内在因子引发SIRS和肾内动脉急性炎症，导致阿基伴或不伴血流动力学变化。这个应用程序也将促进我的研究生涯过渡到一个独立的调查员的位置。该奖项的培训（K99）阶段将由Clinton Webb博士指导，他是血管生理学领域的国际公认领导者，并将由Paul O '康纳博士共同指导，他的职业生涯致力于研究整个动物肾生理学，是肾损伤专家。此外，在指导阶段，我将在德国格赖夫斯瓦尔德大学的格里克博士的实验室接受额外的培训。我计划在Grisk博士那里学习研究肾灌注同步记录的体内技术，并学习如何分离人体肾内动脉。这些经验将对独立后的完成起到至关重要的作用 这个奖项的阶段。我对格里克博士实验室的访问不仅将扩大我的技术技能和不同模型的经验，而且还将启动与专家的合作， 肾区这样的互动将扩大我目前的研究范围，并提高成功的潜力，在获得进一步的独立资助，因为我建立自己的独立研究计划。我的短期目标是成为创伤和全身炎症反应综合征的肾血管生理学和病理生理学领域的独立研究者。作为这些领域的专家，我希望在一个促进跨学科生物医学科学并强调转化研究的学术机构获得终身教职。我的长期职业目标是建立一个强大的研究计划，使用综合方法来研究损伤相关的血管功能障碍对肾脏生理的影响。