Intrarenal Arteries Sense Trauma-derived Mitochondrial N-formyl Peptides Leading to Kidney Injury in SIRS

肾内动脉感知创伤源性线粒体 N-甲酰肽导致 SIRS 肾损伤

• 批准号: 9333390
• 负责人: Camilla Ferreira Wenceslau
• 金额: $ 8.09万
• 依托单位: AUGUSTA UNIVERSITY
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333390
• 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; 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; Microscopy; 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; Sepsis Syndrome; Source; Sterility; Symptoms; 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; immunogenic; improved; in vivo; indexing; 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; tenure track; translational study; two-photon; 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（由申请人提供）：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。脓毒症的诊断需要确认血培养中的细菌生长，以及是否存在两种或多种细菌。更多的以下症状：体温过低或体温过高、心动过速、呼吸急促以及白细胞减少或白细胞增多，但只有约三分之一到二分之一的患者会出现这些症状。因此，所有剩余患者均被诊断为 SIRS。SIRS 和脓毒症的主要病理生理学特征是血管塌陷，导致液体流失到血管外空间。包括肾脏在内的多个组织出现水肿，因此，影响超过 35% 的 SIRS 患者的常见并发症是急性肾损伤 (AKI)。 SIRS 期间 AKI 的发病机制，特别是因为没有研究表明肾内动脉是否在创伤诱发的 SIRS 期间 AKI 的发生和/或维持中发挥作用，一些研究提出肾血管收缩和肾血流量 (RBF) 减少与肾血管收缩和肾血流量 (RBF) 减少有关。然而，最近的观察表明，心脏指数和血压的改善并不能改善肾功能和预防死亡，这意味着前向血流不良并不能解释这一情况。尽管已明确 AKI 是创伤患者中 SIRS 和脓毒症的共同因素，但多种类型脓毒症和 SIRS 的共同介导因素尚未被发现。 SIRS 尚不完全清楚，有人提出，来自创伤组织的细胞成分（称为损伤相关分子模式 (DAMP)）是创伤患者 SIRS 的主要诱发因素，线粒体与创伤患者具有一些共同特征。细菌和 N-甲酰基肽是细菌和线粒体的常见分子特征，我们初步观察到线粒体 N-甲酰基肽 (F-MIT) 通过甲酰基肽受体激活诱导血管渗漏、加剧血管舒张和动脉炎症。研究中首次观察到无菌创伤诱导 F-MIT 释放到 此外，还观察到 F-MIT 通过 FPR 激活导致 SIRS、肾内动脉功能障碍和肾损伤。因此，根据我们的初步数据，很明显 F-MIT 在 SIRS 中发挥作用。然而，尚不清楚这些肽是否与肾内动脉功能障碍（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 AKI 的发生有关。有趣的假设是，创伤/缺血后循环中较高水平的 F-MIT 会激活 FPR，导致肾内动脉功能障碍、AKI 和 SIRS。K99/R00 应用的目的是揭示细胞损伤引发 SIRS 和急性肾损伤后释放的内在因子。肾内动脉炎症，导致伴有或不伴有血流动力学变化的 AKI。该申请也将促进我的研究生涯向独立研究者职位的转变，该奖项的培训 (K99) 阶段将由我指导。克林顿·韦伯 (Clinton Webb) 博士是血管生理学领域国际公认的领导者，他的导师是保罗·奥康纳 (Paul O´Connor) 博士，后者致力于研究整个动物肾脏生理学，是肾损伤方面的专家。在指导阶段，我将在德国格赖夫斯瓦尔德大学 Grisk 博士的实验室接受额外培训，我计划与 Grisk 博士一起学习研究肾灌注同步记录的体内技术，并将学习如何进行。来隔离人类这些经验将对肾内动脉的独立完成起到至关重要的作用。 我对 Grisk 博士实验室的访问不仅将扩展我在不同模型方面的技术技能和经验，而且还将启动与该领域专家的合作。 当我建立自己的独立研究计划时，这种互动将扩大我当前的研究范围，并提高成功获得进一步独立资助的潜力。我的短期目标是成为肾血管领域的独立研究者。作为创伤生理学和病理生理学以及 SIRS 的专家，我希望在促进跨学科生物医学科学并强调转化研究的学术机构中获得终身教职。建立一个强大的研究计划，利用研究损伤相关血管功能障碍对肾脏生理学影响的综合方法。