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: 9284449
• 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/9284449
• 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; 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）：报告的急性肾损伤（AKI）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，肾脏具有显著的，但不是无穷无尽的自我修复能力。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细胞增殖和修复中的来源和作用尚不清楚。大量研究表明，浸润细胞在小管功能障碍和结构损伤的发生和发展中起着重要作用。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，大致特征为促炎（M1或“经典激活”）和组织修复（M2或“选择性激活”）表型。缺血/再灌注模型1小时内可见巨噬细胞浸润。这些巨噬细胞在缺血/再灌注损伤后早期浸润，具有与“炎性”或“M1”巨噬细胞一致的独特表型。巨噬细胞是AKI后检测到的促炎细胞因子如IL-1、IL-6和TNF-的来源之一。缺血/再灌注损伤前单核细胞的消耗提供了重要的功能和结构保护。相反，有越来越多的