Role of Renal Macrophages in Recovery from Acute Kidney Injury

肾巨噬细胞在急性肾损伤恢复中的作用

• 批准号: 8713987
• 负责人: RAYMOND C. HARRIS
• 金额: $ 34.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713987
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Apoptotic; Cells; Data; Dendritic Cells; Development; Endocrine; Epithelial; Epithelial Cells; Exhibits; Failure; Functional disorder; Goals; Growth Factor; Hour; Incidence; Infiltration; Inflammation; Inflammatory; Injury; Intensive Care Units; Interleukin-1; Interleukin-6; Ischemia; Kidney; Lead; Mediating; Mediation; Modality; Modeling; Natural regeneration; Nephrons; Organ; Patients; Phagocytosis; Phenotype; Play; Population; Recovery; Relative (related person); Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Signal Transduction; Source; Surface; TNF gene; Tissues; autocrine; cytokine; insight; interest; macrophage; monocyte; paracrine; public health relevance; repaired; response; tissue repair

DESCRIPTION (provided by applicant): The reported incidence of acute kidney injury (AKI) varies from 5% in all hospitalized patients to 30-50% in intensive care units. Following acute injury, the kidney possesses a remarkable, but not inexhaustible capacity to repair itself. The factors stimulating this repair, and the source and role of autocrine, paracrine and/or endocrine growth factors in mediating the epithelial proliferation and repair remain uncertain. Numerous studies have indicated that infiltrating cells play an important role in the initiation and propagation of the tubule dysfunction and structural injury. The role of macrophages is of particular interest because they can exhibit distinctly different functional phenotypes, broadly characterized as proinflammatory (M1 or "classically activated") and tissue reparative (M2 or "alternatively activated") phenotypes. Macrophage infiltration is seen within one hour of reperfusion in ischemia/reperfusion models. These macrophages infiltrating early after ischemia/reperfusion injury have a distinct phenotype consistent with "inflammatory" or "M1" macrophages. Macrophages are one source of proinflammatory cytokines such as IL-1, IL-6 and TNF-¿ that are detected following AKI. Depletion of monocytes prior to ischemia/reperfusion injury provides significant functional and structural protection. In contrast, there is increasing evidence that monocyte-derived cells may play an essential role in tissue repair in other organs and recent data suggest an important role in repair following acute kidney injury. We propose that there is an important role for resident macrophages and dendritic cells to mediate recovery from acute tissue injury. Resident macrophages and tissue dendritic cells demonstrate significant overlap in surface marker expression with M2 macrophages. The overall questions to be addressed are: What are the relative roles of infiltrating macrophages vs. resident macrophages and/or dendritic cells in recovery from AKI and what are the signals and mechanisms by which these monocyte-derived cells promote renal epithelial cell repair? To answer these questions, we propose three specific aims: Specific Aim I will determine the mechanisms by which renal macrophages/dendritic cells increase in response to acute kidney injury; Specific Aim 2 will determine the role of resident macrophage/dendritic cell phagocytosis of apoptotic cells ("Efferocytosis") in promoting epithelial regeneration after AKI; Specific Aim II will determine mechanisms by which resident macrophages/dendritic cells stimulate epithelial cell regeneration. We propose that these studies will provide new and important insights into mechanisms of renal epithelial repair following acute injury and may lead to development of new treatment modalities for AKI, which are greatly needed.

描述（由申请人提供）： 据报道，急性肾损伤 (AKI) 的发生率从所有住院患者的 5% 到重症监护病房的 30-50% 不等。 急性损伤后，肾脏具有显着但并非取之不尽用之不竭的能力。刺激这种修复的因素，以及自分泌、旁分泌和/或内分泌生长因子在介导上皮增殖和修复中的来源和作用仍然不确定。浸润细胞在肾小管功能障碍和结构损伤的引发和传播中发挥重要作用，巨噬细胞的作用特别令人感兴趣，因为它们可以表现出明显不同的功能表型，广泛表征为促炎性（M1或“经典激活”）和组织。在缺血/再灌注模型中，再灌注后一小时内可见修复性（M2 或“替代激活”）表型。缺血/再灌注损伤具有与“炎症”或“M1”巨噬细胞一致的独特表型。巨噬细胞是促炎细胞因子（例如 IL-1、IL-6 和 TNF-¿）的来源之一。 AKI 后检测到的单核细胞在缺血/再灌注损伤之前的消耗提供了显着的功能和结构保护。 有证据表明单核细胞衍生的细胞可能在其他器官的组织修复中发挥重要作用，并且最近的数据表明在急性肾损伤后的修复中发挥重要作用，我们认为常驻巨噬细胞和树突状细胞在介导急性肾损伤的恢复中发挥着重要作用。常驻巨噬细胞和组织树突细胞与 M2 巨噬细胞的表面标志物表达存在显着重叠。需要解决的总体问题是：浸润性巨噬细胞与常驻巨噬细胞和/或巨噬细胞的相对作用是什么。为了回答这些问题，我们提出了三个具体目标： 具体目标 我将确定肾巨噬细胞/树突状细胞的机制。细胞响应急性肾损伤而增加；具体目标 2 将确定常驻巨噬细胞/树突状细胞吞噬凋亡细胞（“胞吞作用”）在促进AKI 后的上皮再生；特定目标 II 将确定驻留巨噬细胞/树突状细胞刺激上皮细胞再生的机制，我们认为这些研究将为急性损伤后肾上皮修复机制提供新的重要见解，并可能导致新疗法的开发。 AKI 的治疗方式是非常需要的。