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: 9067144
• 负责人: RAYMOND C. HARRIS
• 金额: $ 34.37万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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/9067144
• 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; Health; 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; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Signal Transduction; Source; Surface; TNF gene; Tissues; autocrine; cytokine; insight; interest; macrophage; monocyte; paracrine; 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（由适用提供）：报告的急性肾脏损伤事件（AKI）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，肾脏的潜力具有显着但没有取之不尽的修复能力。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尚不确定。许多研究表明，浸润细胞在管功能障碍和结构损伤的主动性和传播中起重要作用。巨噬细胞的作用尤其令人感兴趣，因为它们可以表现出明显不同的功能表型，该表型被广泛地表征为促炎（M1或“经典激活”）和组织修复（M2或“替代激活”）表型。在缺血/再灌注模型的再灌注后一小时内，可以看到巨噬细胞浸润。这些巨噬细胞在缺血/再灌注损伤后早期浸润的表型与“炎症”或“ M1”巨噬细胞一致。巨噬细胞是AKI后检测到的促炎细胞因子（例如IL-1，IL-6和TNF-）的来源。缺血/再灌注损伤之前单核细胞的耗竭可提供明显的功能和结构保护。相比之下，有所增加 单核细胞衍生的细胞在其他器官中可能在组织修复中起着至关重要的作用，并且最近的数据表明在急性肾损伤后修复中起重要作用。我们建议居民巨噬细胞和树突状细胞介导从急性组织损伤中恢复的重要作用。常驻巨噬细胞和组织树突状细胞在表面标记表达中与M2巨噬细胞表现出显着的重叠。要解决的总体问题是：浸润巨噬细胞与居民巨噬细胞和/或树突状细胞在从AKI中恢复中的相对作用是什么？这些单核细胞衍生的细胞促进肾上皮细胞修复的信号和机制是什么？为了回答这些问题，我们提出了三个具体目标：具体目的我将确定肾脏巨噬细胞/树突状细胞在急性肾脏损伤中增加的机制；具体目标2将确定凋亡细胞的驻留巨噬细胞/树突状细胞吞噬作用（“吞噬作用”）在促进AKI后促进上皮再生中的作用；具体的目标II将确定居民巨噬细胞/树突状细胞刺激上皮细胞再生的机制。我们建议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AKI的新治疗方式发展，这是非常需要的。