Moore Thomas A, Lau Helen Y, Cogen Anna L, Monteleon Christine L, Standiford Theodore J
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA.
Shock. 2003 Oct;20(4):309-15. doi: 10.1097/01.shk.0000087203.34916.45.
Klebsiella pneumoniae is a leading cause of gram-negative bacterial pneumonia, often resulting in bacteremia concurrent with the localized pulmonary infection. The beneficial role of tumor necrosis factor (TNF)-alpha during pulmonary infection has been well documented; however, consequences of TNF-alpha production during systemic bacterial infection are controversial. A murine model of K. pneumoniae was developed to address this important issue. Liver-associated TNF-alpha mRNA was induced within 30 min after intravenous bacterial inoculation and remained elevated through 6 h before returning to near-baseline at 24 h postinfection. Intravenous K. pneumoniae infection induced liver cellular injury that was completely ablated when mice were pretreated with a neutralizing anti-TNF-alpha antibody. Interestingly, this reduction in liver injury failed to translate into improved survival. Mice receiving anti-TNF-alpha continued to succumb to the infection even out to day 10 postinfection. Bacterial clearance after TNF-alpha neutralization was significantly impaired at later time points during infection. Correlating with impaired bacterial clearance was diminished production of liver-associated MIP-2, MIP-1alpha, MCP-1, and interferon-gamma. Further evidence of diminished antibacterial immune responses was noted when the activational status of splenic natural killer cells in anti-TNF-alpha-treated mice was examined 24 h postinfection. Natural killer cells displayed decreased CD69 expression. Combined, these data indicate that the beneficial effects of TNF-alpha during systemic K. pneumoniae infection outweigh the detrimental effects of TNF-alpha-mediated hepatocyte cellular injury. Anti-TNF-alpha therapy, although preventing liver injury during blood-borne bacterial infection, results in a dampened anti-bacterial host response, resulting in decreased bacterial clearance and overall survival.
肺炎克雷伯菌是革兰氏阴性细菌性肺炎的主要病因，常导致菌血症并伴有局部肺部感染。肿瘤坏死因子（TNF）-α在肺部感染期间的有益作用已得到充分证明；然而，全身性细菌感染期间TNF-α产生的后果存在争议。为了解决这个重要问题，建立了肺炎克雷伯菌的小鼠模型。静脉注射细菌后30分钟内，肝脏相关的TNF-α mRNA被诱导，并在6小时内一直升高，感染后24小时恢复到接近基线水平。静脉注射肺炎克雷伯菌感染诱导肝脏细胞损伤，当用中和性抗TNF-α抗体预处理小鼠时，这种损伤完全消除。有趣的是，肝脏损伤的减轻并未转化为生存率的提高。接受抗TNF-α治疗的小鼠甚至在感染后第10天仍继续死于感染。在感染后期，TNF-α中和后细菌清除明显受损。与细菌清除受损相关的是肝脏相关的MIP-2、MIP-1α、MCP-1和干扰素-γ的产生减少。在感染后24小时检查抗TNF-α治疗小鼠脾脏自然杀伤细胞的激活状态时，发现了抗菌免疫反应减弱的进一步证据。自然杀伤细胞显示CD69表达降低。综合这些数据表明，在全身性肺炎克雷伯菌感染期间，TNF-α的有益作用超过了TNF-α介导的肝细胞损伤的有害作用。抗TNF-α治疗虽然在血源性细菌感染期间可预防肝脏损伤，但会导致抗菌宿主反应减弱，从而导致细菌清除率降低和总体生存率下降。
