Role of the innate immune system in acute kidney injury

先天免疫系统在急性肾损伤中的作用

• 批准号: 10655797
• 负责人: RAYMOND C. HARRIS
• 金额: $ 63.08万
• 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 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655797
• 关键词: Acceleration; Acute; Acute Renal Failure with Renal Papillary Necrosis; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Arachidonic Acids; Area; Cell Communication; Cells; Communities; Detection; Diabetic Nephropathy; Dinoprostone; Disparate; Enterobacteria phage P1 Cre recombinase; Enzymes; Event; Extracellular Matrix; Fibrosis; Goals; Hour; Immune; Inflammation; Inflammation Mediators; Inflammatory; Injury; Injury to Kidney; Innate Immune System; Investigation; Ischemia; Kidney; Lipoxins; Macrophage; Mediating; Metabolism; Methodology; Modeling; Myelogenous; Natural regeneration; Neutrophil Activation; Neutrophil Infiltration; Phase; Phenotype; Play; Pleurisy; Process; Prostaglandin E Receptor; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Recovery; Regulation; Reperfusion Therapy; Reporting; Resolution; Role; Sterility; System; Tissues; WFDC2 gene; autocrine; chemokine; cyclooxygenase 2; cytokine; ischemic injury; kidney cell; lipid mediator; migration; monocyte; neutrophil; pharmacologic; prevent; renal ischemia; repaired; response

Following the immediate injury to intrinsic kidney cells induced by ischemia/reperfusion, we and others have demonstrated an important role for innate immune cells in both propagation of injury and subsequent recovery. There is an initial renal influx of neutrophils after ischemic injury, followed a few hours later by accumulation of proinflammatory monocytes and activation of resident renal macrophages. Within days after the injury, the majority of renal macrophages shift from a proinflammatory to an anti-inflammatory and pro- resolution phenotype, which is essential for effective repair and resolution of the injury. Meanwhile, with moderate ischemic injury, neutrophil numbers in the injured kidney progressively decrease, and relatively few neutrophils remain after 72 hours. Although neutrophil apoptosis and efferocytosis by macrophages is an important mechanism of neutrophil clearance, in addition, in other tissues, studies have shown that intact neutrophils may also exit the tissue through “reverse migration”. Mechanisms underlying the resolution of inflammation are an area of active investigation. The question of what mediates resolution of inflammation, and specifically what mediates the resolution of the inflammation resulting from ischemic AKI, remains unresolved. Cyclooxygenase (COX) is the rate-limiting enzyme that metabolizes arachidonic acid to prostaglandin G2 and subsequently to prostaglandin H2, thereby serving as the precursor for subsequent metabolism by prostaglandin synthases. More than 20 years ago, Gilroy et al. reported a paradox in sterile inflammation. Pharmacologic COX-2 inhibition at the early phase (2h) accelerated recovery while the same pharmacologic inhibition prevented recovery when applied 24h later, suggesting that COX-2 may have different roles in neutrophils and macrophages in inflammation resolution. We have recently we have reported that COX-2 expression increased in renal macrophages following ischemic injury, and selective deletion of COX-2 or the PGE2 receptor subtype 4 (EP4) with myeloid-specific Cre recombinases delayed recovery, resulting in persistent inflammation in the post-ischemic kidney and subsequent tubulointerstitial fibrosis. In our new preliminary results, we now surprisingly find that selective deletion of neutrophil COX-2 expression results in decreased injury in response to an ischemic insult. We propose that the macrophage COX-2/PGE2 axis promotes recovery from AKI, but the neutrophil COX-2/PGE2 axis has the opposite effect and is important for the initial injury induced by neutrophil infiltration. The goal of our proposed studies is to further our understanding of mechanisms of resolution from AKI by characterizing the disparate roles and mechanisms played by the COX-2/prostaglandin system in neutrophils and macrophages following acute ischemic kidney injury. We have two specific aims: Specific Aim 1 Determine the role of the macrophage COX-2-PGE2-axis in recovery from ischemic AKI Specific Aim 2 Determine the role of COX-2 in neutrophil function in response to ischemic AKI

在缺血/再灌注引起的内在肾细胞立即损伤后，我们和其他人 先天免疫细胞在损伤传播和随后的损伤中发挥着重要作用 缺血性损伤后，最初有中性粒细胞流入肾脏，几个小时后又开始流入肾脏。 促炎单核细胞积聚并激活常驻肾巨噬细胞。 损伤后，大多数肾巨噬细胞从促炎细胞转变为抗炎和促炎症细胞。 解决表型，这对于有效修复和解决损伤至关重要。 中度缺血性损伤，受伤肾脏中中性粒细胞数量逐渐减少，且相对较少 72 小时后，中性粒细胞仍然存在，尽管中性粒细胞凋亡和巨噬细胞胞吞作用是一种现象。 中性粒细胞清除的重要机制，此外，在其他组织中，研究表明完整的 中性粒细胞也可能通过“反向迁移”的机制离开组织。 炎症是一个正在积极研究的领域，即是什么介导炎症消退的问题。 具体来说，是什么介导了缺血性 AKI 引起的炎症的消退，目前仍未解决。 环加氧酶 (COX) 是将花生四烯酸代谢为前列腺素 G2 的限速酶， 随后产生前列腺素 H2，从而作为后续代谢的前体 20 多年前，Gilroy 等人报道了无菌性炎症的悖论。 早期（2小时）的药理COX-2抑制加速了恢复，而相同的药理 24 小时后，抑制作用会阻止恢复，这表明 COX-2 可能在 中性粒细胞和巨噬细胞在炎症消退中的作用。 我们最近报道了肾巨噬细胞中COX-2表达增加 缺血性损伤，以及具有骨髓特异性的 COX-2 或 PGE2 受体亚型 4 (EP4) 的选择性缺失 Cre 重组酶延迟恢复，导致缺血后肾脏持续炎症， 在我们新的初步结果中，我们现在令人惊讶地发现选择性的。 中性粒细胞 COX-2 表达的缺失可减少对缺血性损伤的反应。 提出巨噬细胞 COX-2/PGE2 轴促进 AKI 的恢复，但中性粒细胞 COX-2/PGE2 轴具有相反的作用，并且对于中性粒细胞浸润引起的初始损伤很重要。 我们提出的研究是通过表征 AKI 的特征来进一步了解 AKI 的解决机制 COX-2/前列腺素系统在中性粒细胞和巨噬细胞中发挥的不同作用和机制 急性缺血性肾损伤后，我们有两个具体目标： 具体目标 1 确定巨噬细胞 COX-2-PGE2 轴在缺血性 AKI 恢复中的作用 具体目标 2 确定 COX-2 在响应缺血性 AKI 的中性粒细胞功能中的作用