Department of Laboratory Medicine, The First Affiliated Hospital of Chongqing Medical University Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, China.
Key Laboratory of Diagnostic Medicine Designated by the Ministry of Education, Chongqing Medical University, China.
J Infect Dis. 2015 May 15;211(10):1616-27. doi: 10.1093/infdis/jiu668. Epub 2014 Dec 8.
Interleukin 4 (IL-4) is an important cytokine that may modulate development of secondary bacterial pneumonia during sepsis-induced immunosuppression.
We established an experimental model of cecal ligation and puncture (CLP)-induced sublethal polymicrobial sepsis followed by secondary Pseudomonas aeruginosa pulmonary infection,
IL-4-deficient mice that underwent CLP were resistant to secondary pulmonary P. aeruginosa infection. As compared to wild-type mice, IL-4 knockout (KO) mice displayed improved survival and better bacterial clearance. Furthermore, IL-4 KO mice exhibited enhanced lung inflammation, neutrophil recruitment to airspaces, and elevated pulmonary cytokine production, with significantly increased tumor necrosis factor α (TNF-α) production. Neutralization of TNF-α could reverse the enhanced protection against secondary P. aeruginosa pneumonia in septic IL-4 KO mice, indicating that the resistance of septic IL-4 KO mice to secondary bacterial pneumonia was partially mediated by TNF-α. In addition, IL-4 priming displayed marked impairment of the ability of alveolar macrophages to phagocytose and kill P. aeruginosa in vitro, and this defect was associated with decreased activation of Akt, JNK, p38MAPK, and ERK intracellular signaling pathways by IL-4. Finally, neutralization of IL-4 in septic mice could improve survival and clearance of bacteria from the lungs of septic mice infected with P. aeruginosa.
Our findings provide new insight for immunopathologic mechanisms of sepsis-induced secondary bacterial pneumonia.
白细胞介素 4（IL-4）是一种重要的细胞因子，可能在脓毒症引起的免疫抑制期间调节继发性细菌性肺炎的发展。
我们建立了盲肠结扎和穿刺（CLP）诱导的亚致死性多微生物脓毒症继发铜绿假单胞菌肺部感染的实验模型，
接受 CLP 的 IL-4 缺陷小鼠对继发性肺部铜绿假单胞菌感染具有抗性。与野生型小鼠相比，IL-4 敲除（KO）小鼠表现出更好的生存和更好的细菌清除。此外，IL-4 KO 小鼠表现出增强的肺部炎症、中性粒细胞向气道募集和升高的肺部细胞因子产生，肿瘤坏死因子-α（TNF-α）产生显著增加。TNF-α 的中和可以逆转脓毒症 IL-4 KO 小鼠对继发性铜绿假单胞菌肺炎的增强保护作用，表明 TNF-α 部分介导了脓毒症 IL-4 KO 小鼠对继发性细菌性肺炎的抗性。此外，IL-4 引发显示出肺泡巨噬细胞吞噬和杀死铜绿假单胞菌的能力明显受损，并且这种缺陷与 IL-4 激活 Akt、JNK、p38MAPK 和 ERK 细胞内信号通路的减少有关。最后，脓毒症小鼠中 IL-4 的中和可以提高脓毒症合并铜绿假单胞菌感染小鼠的生存率并清除肺部细菌。
我们的发现为脓毒症引起的继发性细菌性肺炎的免疫病理机制提供了新的见解。
