Role of the innate immune system in acute kidney injury

在缺血/再灌注诱导的固有肾细胞立即损伤后，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免疫反应中的重要作用。 复苏在缺血性损伤后，中性粒细胞最初流入肾脏，几小时后， 促炎性单核细胞的积聚和常驻肾巨噬细胞的活化。后天内 损伤后，大多数肾巨噬细胞从促炎性转变为抗炎性和促炎性。 消退表型，其对于损伤的有效修复和消退至关重要。同时随着 中度缺血性损伤时，损伤肾脏中的中性粒细胞数量逐渐减少， 72小时后仍有中性粒细胞。尽管巨噬细胞引起的中性粒细胞凋亡和嗜中性粒细胞增多是一种重要的免疫学机制， 中性粒细胞清除的重要机制，此外，在其他组织中，研究表明， 嗜中性粒细胞也可以通过“反向迁移”离开组织。问题的解决机制 炎症是一个积极研究领域。什么介导炎症消退的问题，以及 特别是什么介导了由缺血性AKI引起的炎症的消退，仍然没有得到解决。 环氧合酶（考克斯）是将花生四烯酸代谢为前列腺素G2的限速酶， 随后的前列腺素H2，从而作为前体的后续代谢， 前列腺素酶20多年前，Gilroy等人报道了无菌性炎症的悖论。 早期（2小时）的药理学考克斯-2抑制加速恢复，而相同的药理学 24小时后，抑制剂阻止了恢复，这表明考克斯-2可能在 中性粒细胞和巨噬细胞在炎症消退中的作用。 我们最近报道了在肾巨噬细胞中考克斯-2表达增加， 缺血性损伤，选择性缺失考克斯-2或PGE 2受体亚型4（EP 4）， Cre重组酶延迟恢复，导致缺血后肾脏持续炎症， 随后肾小管间质纤维化。在我们新的初步结果中，我们现在惊讶地发现， 嗜中性粒细胞考克斯-2表达的缺失导致响应缺血性损伤的损伤减少。我们 提出巨噬细胞考克斯-2/PGE 2轴促进AKI的恢复，而中性粒细胞考克斯-2/PGE 2轴促进AKI的恢复。 轴具有相反的作用，并且对于由中性粒细胞浸润诱导的初始损伤是重要的。的目标 我们提出的研究是通过表征 中性粒细胞和巨噬细胞中考克斯-2/前列腺素系统的不同作用和机制 急性缺血性肾损伤。我们有两个具体目标： 具体目的1确定巨噬细胞考克斯-2-PGE 2-轴在缺血性AKI恢复中的作用 具体目的2确定考克斯-2在响应缺血性AKI的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