Role of the innate immune system in acute kidney injury

在缺血/再灌流对固有肾细胞造成即刻损伤后，我们和其他人 已经证明了先天免疫细胞在损伤的传播和随后的 恢复。在缺血损伤后，中性粒细胞最初进入肾脏，几小时后 促炎症单核细胞积聚和常驻肾巨噬细胞的激活。之后的几天内 在损伤后，大多数肾脏巨噬细胞从促炎转变为抗炎和促炎。 分解表型，这是有效修复和解决损伤所必需的。同时，随着 中度缺血损伤后，受损肾脏中性粒细胞数量进行性减少，且相对较少 中性粒细胞在72小时后仍然存在。尽管巨噬细胞的中性粒细胞凋亡和泡腾作用是一种 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 中性粒细胞也可能通过“反向迁移”的方式离开组织。解决问题的基本机制 炎症是一个积极研究的领域。什么是调节炎症消退的媒介，以及 确切地说，是什么介导了缺血性AKI引起的炎症的消退，至今仍未解决。 环氧合酶(COX)是将花生四烯酸代谢成前列腺素G2和前列腺素G2的限速酶。 在前列腺素H2之后，从而作为后续代谢的前体 前列腺素合成酶。20多年前，吉尔罗伊等人。报道了无菌炎症中的一个悖论。 早期(2小时)药物抑制环氧合酶-2促进恢复，而相同药物 抑制作用阻止了24小时后的恢复，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COX-2在肾巨噬细胞中的表达增加 具有髓系特异性的缺血性损伤和选择性缺失COX-2或PGE2受体亚型4(EP4) Cre重组酶延迟恢复，导致缺血后肾脏持续炎症和 继发的肾小管间质纤维化。在我们新的初步结果中，我们现在令人惊讶地发现， 中性粒细胞COX-2表达缺失可减少对缺血性损伤的反应。我们 提示巨噬细胞COX-2/PGE2轴促进AKI的恢复，而中性粒细胞COX-2/PGE2 AXIS具有相反的作用，在中性粒细胞渗透所致的早期损伤中起重要作用。的目标是 我们建议的研究是为了加深我们对AKI解决机制的理解，通过表征 环氧合酶-2/前列腺素系统在中性粒细胞和巨噬细胞中的不同作用和机制 在急性缺血性肾损伤后。我们有两个具体目标： 特异性目的1确定巨噬细胞COX-2-PGE_2轴在脑缺血后恢复中的作用 特异性目的2确定COX-2在AKI后中性粒细胞功能中的作用

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