Doi Kent, Leelahavanichkul Asada, Hu Xuzhen, Sidransky Karen L, Zhou Hua, Qin Yan, Eisner Christoph, Schnermann Jürgen, Yuen Peter S T, Star Robert A
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1268, USA.
Kidney Int. 2008 Oct;74(8):1017-25. doi: 10.1038/ki.2008.346. Epub 2008 Jul 16.
While it is known that risk of death from sepsis is higher in patients with pre-existing chronic kidney disease its mechanism is unknown. To study this we established a two-stage mouse model where renal disease was first induced by folic acid injection followed by sub-lethal cecal ligation and puncture to induce sepsis. Septic mice with pre-existing renal disease had significantly higher mortality, serum creatinine, vascular permeability, plasma vascular endothelial growth factor (VEGF) levels, bacteremia, serum IL-10, splenocyte apoptosis and more severe septic shock when compared to septic mice without pre-existing disease. To evaluate the contribution of vascular and immunological dysfunction, we treated the folate-septic mice with soluble Flt-1 to bind VEGF and chloroquine to reduce splenocyte apoptosis. These treatments together resulted in a significant improvement in kidney injury, hemodynamics and survival. Our study shows that the sequential mouse model mimics human sepsis frequently complicated by pre-existing renal disease and might be useful in evaluating preventive and therapeutic strategies.
虽然已知患有慢性肾病的患者因败血症死亡的风险更高，但其机制尚不清楚。为了研究这一点，我们建立了一个两阶段小鼠模型，首先通过注射叶酸诱导肾病，然后进行亚致死性盲肠结扎和穿刺以诱导败血症。与没有预先存在疾病的败血症小鼠相比，患有预先存在肾病的败血症小鼠死亡率显著更高，血清肌酐、血管通透性、血浆血管内皮生长因子（VEGF）水平、菌血症、血清IL-10、脾细胞凋亡更高，并且败血症休克更严重。为了评估血管和免疫功能障碍的作用，我们用可溶性Flt-1治疗叶酸-败血症小鼠以结合VEGF，并使用氯喹减少脾细胞凋亡。这些治疗共同导致肾损伤、血流动力学和存活率显著改善。我们的研究表明，该序贯小鼠模型模拟了经常并发预先存在肾病的人类败血症，可能有助于评估预防和治疗策略。
