Kanangat S, Meduri G U, Tolley E A, Patterson D R, Meduri C U, Pak C, Griffin J P, Bronze M S, Schaberg D R
Department of Medicine, Pulmonary and Critical Care Division, University of Tennessee-Memphis, Memphis, Tennessee 38163, USA.
Infect Immun. 1999 Jun;67(6):2834-40. doi: 10.1128/IAI.67.6.2834-2840.1999.
Patients with unresolving acute respiratory distress syndrome (ARDS) have persistently elevated levels of proinflammatory cytokines in the lungs and circulation and increased rates of bacterial infections. Phagocytic cells hyperactivated with lipopolysaccharide (LPS), which induces high levels of proinflammatory cytokines in monocytic cells, are inefficient in killing ingested bacteria despite having intact phagocytic activity. On the other hand, phagocytic cells that are activated with an analogue of LPS that does not induce the expression of proinflammatory cytokines effectively ingest and kill bacteria. We hypothesized that in the presence of high concentrations of proinflammatory cytokines, bacteria may adapt and utilize cytokines to their growth advantage. To test our hypothesis, we primed a human monocytic cell line (U937) with escalating concentrations of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6 and with LPS. These cells were then exposed to fresh isolates of three common nosocomial pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, and an Acinetobacter sp. In human monocytes primed with lower concentrations of proinflammatory cytokines (10 to 250 pg) or LPS (1 and 10 ng), intracellular bacterial growth decreased. However, when human monocytes were primed with higher concentrations of proinflammatory cytokines (1 to 10 ng) or LPS (1 to 10 micrograms), intracellular growth of the tested bacteria increased significantly (P <0.0001). These results were reproduced with peripheral blood monocytes obtained from normal healthy volunteers. The specificity of the cytokine activity was demonstrated by neutralizing the cytokines with specific antibodies. Our findings provide a possible mechanism to explain the frequent development of bacterial infections in patients with an intense and protracted inflammatory response.
急性呼吸窘迫综合征（ARDS）未缓解的患者肺部和循环中的促炎细胞因子水平持续升高，且细菌感染率增加。用脂多糖（LPS）过度激活的吞噬细胞，虽吞噬活性完好，但在单核细胞中诱导高水平促炎细胞因子后，杀灭摄入细菌的效率却很低。另一方面，用不诱导促炎细胞因子表达的LPS类似物激活的吞噬细胞能有效摄取并杀灭细菌。我们推测，在高浓度促炎细胞因子存在的情况下，细菌可能会适应并利用细胞因子来获得生长优势。为验证这一假说，我们用浓度递增的促炎细胞因子肿瘤坏死因子α、白细胞介素-1β（IL-1β）和IL-6以及LPS对人单核细胞系（U937）进行预处理。然后将这些细胞暴露于三种常见医院病原体的新鲜分离株：金黄色葡萄球菌、铜绿假单胞菌和不动杆菌属。在用较低浓度促炎细胞因子（10至250 pg）或LPS（分别为1和10 ng）预处理的人单核细胞中，细胞内细菌生长减少。然而，当用人单核细胞用较高浓度促炎细胞因子（1至10 ng）或LPS（1至10 μg）预处理时，受试细菌的细胞内生长显著增加（P <0.0001）。从正常健康志愿者获得的外周血单核细胞也得到了同样的结果。用特异性抗体中和细胞因子证明了细胞因子活性的特异性。我们的研究结果提供了一种可能的机制，来解释炎症反应强烈且持久的患者频繁发生细菌感染的现象。
