Acute renal failure after whole body ischemia

描述(申请人提供)：急性肾功能衰竭(ARF)在天然肾脏具有很高的死亡率和发病率。尽管在ARF的发病机制方面取得了重大进展，但还没有特效的治疗方法。大多数关于缺血性ARF的实验工作都使用了孤立的肾损伤模型。然而，当患者在自然肾脏发生缺血性ARF时，例如在休克或脓毒症期间，这几乎总是全身事件的结果，而不是单独的肾脏事件。全身缺血再灌注损伤(WBIRI)造成一种独特的状态，同时影响肾脏和许多器官，包括肺、心、肠等。体内环境的整体变化很难在体外器官模型和体外制剂中模拟。鉴于目前对ARF缺乏特异的治疗方法，以及需要开发更多更接近人类疾病复杂性的临床模型，我们已经开始开发一种新的小鼠全身IRI导致ARF的动物模型。我们用氯化钾注射进行了WBIRI，由于心脏停止跳动，导致血压完全丧失。在心脏骤停后，小鼠接受心肺复苏。幸存的动物统一发展成ARF。在初步研究中，我们发现血清肌酐升高，肾小管坏死，白细胞渗入肾脏。基于我们在这个新的ARF小鼠模型中的初步数据，我们建议更好地描述炎症、细胞凋亡、氧化应激和腺核苷酸等病理生理过程。此外，我们还将检查心脏、肺、肝脏和肠道的肾外功能变化，这些变化可能与WBIRI期间的肾脏损伤相互作用。第二个目标是直接比较WBIRI模型和经典的孤立性肾脏缺血模型中的肾脏病理生理过程。我们的长期目标是开发一种临床相关的实验模型，可用于开发ARF的新疗法。

DESCRIPTION (provided by applicant): Acute renal failure (ARF) in the native kidney is associated with a high mortality and morbidity. Despite major advances in the pathogenesis of ARF, there is no specific treatment. Most experimental work on ischemic ARF has used isolated renal injury models. However, when a patient develops ischemic ARF in the native kidney, such as during shock or sepsis, this is almost always a consequence of a whole body event rather than an isolated kidney event. Whole body ischemia reperfusion injury (WBIRI) creates a unique state that affects kidney and many organs simultaneously including lung, heart, intestine, etc. The global changes to the internal milieu are difficult to mimic in isolated organ models and in vitro preparations. In view of the current lack of specific therapy for ARF, as well as the need for the development of more "clinical" models that are closer to the complexity of human disease, we have started to develop a new animal model of whole body IRI in the mouse that leads to ARF. We have performed WBIRI with potassium chloride injection, which results in complete loss of blood pressure due to stoppage of the heart. After cardiac arrest, the mouse undergoes cardiopulmonary resuscitation. The surviving animals uniformly develop ARF. In preliminary studies, we have found that serum creatinine rises, tubular necrosis occurs, and leukocytes infiltrate into the kidney. Based on our preliminary data in this novel murine model of ARF, we propose to better characterize pathophysiologic processes such as inflammation, apoptosis, oxidative stress and adenine nucleotides. In addition, we will examine extra-renal functional changes in heart, lungs, liver and gut that likely interplay with kidney injury during WBIRI. The second aim will be to directly compare the renal pathophysiological processes in the WBIRI model with the classic isolated kidney ischemia model. Our long-term goals are to develop a clinically relevant experimental model which can be used to develop novel therapies for ARF.