Background: Bacterial pneumonia is a major cause of morbidity and mortality worldwide despite the use of antibiotics, and novel therapies are urgently needed. Building on previous work, we aimed to 1) develop a baboon model of severe pneumococcal pneumonia and sepsis with organ dysfunction; and 2) test the safety and efficacy of a novel extracorporeal blood filter to remove pro-inflammatory molecules and improve organ function. Methods: After a dose-finding pilot study, twelve animals were inoculated with S. pneumoniae (5x10⁹ CFU), given ceftriaxone at 24 hours post-inoculation, and randomized to extracorporeal blood purification using a filter coated with surface-immobilized heparin sulfate (n=6) or sham treatment (n=6) for 4 hours at 30 hours post-inoculation. For safety analysis, four uninfected animals also underwent purification. At 48 hours, necropsy was performed. Results: Inoculated animals developed severe pneumonia and septic shock. Compared with sham animals, septic animals treated with purification displayed significantly less kidney injury, metabolic acidosis, hypoglycemia, and shock (P<0.05). Purification blocked the rise in peripheral blood S. pneumoniae DNA, attenuated BAL CCL4, CCL2, and IL-18 levels, and reduced renal oxidative injury and classical NLRP3-inflammasome activation. Purification was safe in both uninfected and infected animals and produced no adverse effects. Conclusions: We demonstrate that heparin-based blood purification significantly attenuates levels of circulating S. pneumoniae DNA and BAL cytokines, and is renal-protective in baboons with severe pneumococcal pneumonia and septic shock. Purification was associated with less severe acute kidney injury, metabolic derangements, and shock. These results support future clinical studies in critically ill septic patients.

中文翻译：

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基于肝素的血液净化可减轻感染肺炎链球菌的狒狒的器官损伤

背景：尽管使用了抗生素，但细菌性肺炎是全球发病率和死亡率的主要原因，迫切需要新的治疗方法。在先前工作的基础上，我们的目标是 1) 开发一种狒狒模型，用于严重肺炎球菌性肺炎和伴有器官功能障碍的败血症；2) 测试新型体外血液过滤器去除促炎分子和改善器官功能的安全性和有效性。方法：经过剂量探索试验研究，12 只动物接种了肺炎链球菌（5x10 ⁹CFU)，在接种后 24 小时给予头孢曲松，并在接种后 30 小时使用涂有表面固定化硫酸肝素 (n=6) 或假处理 (n=6) 4 小时的过滤器随机进行体外血液净化. 对于安全性分析，四只未感染的动物也进行了净化。在 48 小时时，进行了尸检。结果：接种动物出现严重肺炎和感染性休克。与假手术组相比，经纯化处理的脓毒症组大鼠的肾损伤、代谢性酸中毒、低血糖和休克显着减少（P<0.05）。纯化阻止了外周血肺炎链球菌 DNA 的升高，降低了 BAL CCL4、CCL2 和 IL-18 水平，并减少了肾氧化损伤和经典的 NLRP3 炎性体激活。纯化在未感染和受感染的动物中都是安全的，并且没有产生不利影响。结论：我们证明，基于肝素的血液净化可显着降低循环肺炎链球菌 DNA 和 BAL 细胞因子的水平，并且对患有严重肺炎球菌性肺炎和感染性休克的狒狒具有肾脏保护作用。纯化与不太严重的急性肾损伤、代谢紊乱和休克有关。这些结果支持未来对重症脓毒症患者的临床研究。代谢紊乱和休克。这些结果支持未来对重症脓毒症患者的临床研究。代谢紊乱和休克。这些结果支持未来对重症脓毒症患者的临床研究。