Development and Use of an Isolated Perfused Kidney Model to Investigate Mechanisms of Renal Dysfunction Related to B. anthracis Edema and Lethal Toxins

开发和使用离体灌注肾模型来研究与炭疽杆菌水肿和致命毒素相关的肾功能障碍的机制

• 批准号: 9154053
• 负责人: Peter Eichacker
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9154053
• 关键词: Adenylate Cyclase; American; Animal Model; Anthrax disease; Antigens; Azotemia; Bacillus anthracis; Calmodulin; Canis familiaris; Chest; Cholera Toxin; Collection; Creatinine clearance measurement; Cyclic AMP; Development; Disease; Disease Outbreaks; Diuresis; Edema; Excretory function; Functional disorder; Future; Glomerular Filtration Rate; Glucose; Health; Infection; Injecting drug user; Injury; International; Investigation; Kidney; Liquid substance; Measures; Mediating; Metalloproteases; Mitogen-Activated Protein Kinase Kinases; Modeling; Organ; Patients; Production; Rattus; Renal function; Resistance; Role; Serum; Shock; Societies; Sodium; Toxin; Tubular formation; Vasoconstrictor Agents; Water; Work; Zinc; anthrax lethal factor; base; edema factor; hemodynamics; improved; insight; interstitial; outcome forecast; renal toxin; symposium; uptake

In the present study, we first developed an isolated perfused rat kidney model to examine the direct effects of ET and LT on renal function. This model allows investigation of the toxins' renal effects independent of their potential influence on systemic hemodynamic function. The model will permit measures of the effects of ET and LT on glomerular filtration rate; tubular function including sodium and glucose excretion as well as reabsorption, concentration and acidification; and interstitial changes. In studies completed thus far, we have discovered that ET, rather than stimulating renal tubular sodium losses as we originally hypothesized, this toxin actually promotes free water uptake and to a lesser degree sodium uptake. This increase in free water uptake provides one basis for the reduced sodium levels noted in patients with severe anthrax infection and may also contribute to the marked extravascular fluid collections patients develop. Studies are presently underway determining the mechanisms that mediate the free water uptake ET. Work from this study was presented at the 2015 International Conference of the American Thoracic Society.

在本研究中，我们首先建立了一个离体大鼠肾脏灌流模型，以研究ET和LT对肾功能的直接影响。该模型允许研究毒素对肾脏的影响，而不依赖于其对全身血流动力学功能的潜在影响。该模型将允许测量ET和LT对肾小球滤过率的影响;肾小管功能，包括钠和葡萄糖排泄以及重吸收、浓缩和酸化;以及间质变化。 在迄今为止完成的研究中，我们已经发现，ET，而不是刺激肾小管钠损失，因为我们最初的假设，这种毒素实际上促进自由水的吸收和钠的吸收程度较低。这种游离水吸收的增加为严重炭疽感染患者中注意到的钠水平降低提供了一个基础，也可能有助于患者发展出明显的血管外液体收集。目前正在研究确定介导自由水吸收ET的机制。 这项研究的成果在2015年美国胸科学会国际会议上发表。