Inhibition Of Renal Injury

急性肾损伤（以前称为急性肾功能衰竭）具有很高的发病率和死亡率。在开发了一种新的脓毒症诱导的阿基模型后，该模型在用液体和抗生素治疗的老年小鼠中采用盲肠结扎穿刺，我们正在使用该模型研究损伤的病理生理学，筛选药物，并研究其作用机制，包括通过遥测的清醒血压。 我们通过使用远交系小鼠调整了我们的小鼠模型，这些小鼠在更年轻的时候发生阿基，我们建立了另一种使用合并症的模型，即预先存在的肾功能不全，这被认为会增加患者对阿基的易感性。 我们继续研究脓毒症-AKI模型和“急性慢性”脓毒症-AKI模型。 1)在我们对丙酮酸乙酯的研究之后，我们使用了一种更稳定的类似物，甲基-2-酰胺基丙烯酸酯（M2 AA），我们发现M2 AA可以在诱导脓毒症后长达6小时对小鼠有益。 尽管NF κ B在脾脏中短暂增加，在6小时达到峰值，并且NF κ B是体外M2 AA的已知靶点，但切除脾脏不会降低M2 AA的总体有效性。 然而，因为我们可以排除脾脏作为M2 AA的靶点，并且我们确定脾脏是氯喹有效性所需的，所以我们将M2 AA与氯喹组合使用，取得了一些成功。 2)我们与NIDCR的伊娃梅泽和克里斯蒂安内梅特合作，测试骨髓基质细胞（BMSC，也称为间充质干细胞）对脓毒症的有效性。 我们发现BMSC在抑制脓毒症的器官损伤和死亡率方面是有效的，并研究了其机制。 首先，我们发现BMSC是短暂的，主要靶向肺，暗示了旁分泌效应。 骨髓间充质干细胞在肺内与巨噬细胞相邻，在一系列的机制实验中，我们确定巨噬细胞对骨髓间充质干细胞的益处是必不可少的。 在类似的实验中，我们确定了IL-10对BMSC的有益作用是必不可少的，并且BMSC通过活化的巨噬细胞增加了IL-10的产生。BMSC需要完整的Toll样受体4/MyD 88信号传导，以及环氧合酶2激活和PGE 2产生;巨噬细胞需要EP 2和EP 4来检测PGE 2。 因此，我们得出结论，活化的巨噬细胞似乎触发BMSC局部分泌PGE 2，以下调巨噬细胞的反应。

Acute kidney injury (previously known as acute renal failure) has a high morbidity and mortality. After developing a novel model of sepsis-induced AKI that employs cecal ligation puncture in elderly mice treated with fluids and antibiotics, we are using the model to study the pathophysiology of injury, to screen drugs, and to study their mechanisms of action, including conscious blood pressure by telemetry. We adjusted our mouse model by using outbred mice, which develop AKI at a younger age, and we established another model using comorbidity, namely pre-existing renal dysfunction, which is thought to increase susceptibility to AKI in patients. We continue to study both the sepsis-AKI model and the 'acute-on-chronic' sepsis-AKI model. 1) Following up our studies on ethyl pyruvate, we used a more stable analog, methyl-2-amidoacrylate (M2AA), and we found that M2AA could benefit mice up to 6 hours after induction of sepsis. Although NFkappaB was transiently increased in spleen, peaking at 6 hours, and NFkappaB is a known target of M2AA in vitro, removal of spleen did not decrease the overall effectiveness of M2AA. However, because we could eliminate the spleen as the target of M2AA, and we established that the spleen is required for chloroquine effectiveness, we used M2AA in combination with chloroquine with some success. 2) We collaborated with Eva Mezey and Krisztian Nemeth of NIDCR to test the effectiveness of bone marrow stromal cells (BMSC, also known as mesenchymal stem cells) on sepsis. We found that BMSC were effective in suppressing organ damage and mortality from sepsis, and examined the mechanism. First, we found that BMSCs were short-lived and targeted primarily to the lung, implicating a paracrine effect. The BMSCs were adjacent to macrophages in lung, and in a series of mechanistic experiments we determined that macrophages were essential for the benefit of BMSCs. In similar experiments we determined that IL-10 was essential for beneficial effects of BMSCs, and that BMSCs increased IL-10 production by activated macrophages. BMSCs required intact Toll-like Receptor 4/MyD88 signaling, as well as cyclo-oxygenase 2 activation and PGE2 production; macrophages required both EP2 and EP4 to detect PGE2. Therefore, we concluded that activated macrophages appear to trigger BMSCs to secrete PGE2 locally to downregulate the macrophage response.