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。在用液体和抗生素治疗老年小鼠后，我们开发了一种新的脓毒症诱导的AKI模型，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，筛选药物，并研究其作用机制，包括通过遥测意识血压。我们通过使用近亲繁殖的小鼠来调整我们的小鼠模型，这些小鼠在更年轻的时候发生AKI，我们建立了另一个模型，使用合并症，即先前存在的肾功能障碍，这被认为会增加患者对AKI的易感性。我们继续研究败血症- aki模型和“急性-慢性”败血症- aki模型。

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.