Keel M, Ungethüm U, Steckholzer U, Niederer E, Hartung T, Trentz O, Ertel W
Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
Blood. 1997 Nov 1;90(9):3356-63.
Neutrophils play a key role in the pathophysiology of septic multiple organ dysfunction syndrome (MODS) through excessive release of toxic granule components and reactive oxygen metabolites with consequent tissue destruction. The increase of senescent neutrophils during sepsis indicates a potential breakdown of autoregulatory mechanisms including apoptotic processes to remove activated neutrophils from inflammatory sites. Therefore, neutrophil apoptosis of patients with severe sepsis and its regulatory mechanisms were investigated. Spontaneous neutrophil apoptosis from patients with severe sepsis was significantly reduced in comparison to healthy individuals. Cytokines detected in the circulation during sepsis (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) inhibited neutrophil apoptosis in both groups, though the effect was more distinct in neutrophils from healthy humans. Addition of lipopolysaccharide (LPS) to neutrophils from healthy humans markedly (P < .05) reduced apoptosis which was partially restored through addition of anti-TNF-antibody. Interleukin-10 (IL-10) counteracted (P < .05) inhibition of neutrophil apoptosis induced by LPS, recombinant human (rh) TNF-alpha, rhIFN-gamma, rhG-CSF, and rhGM-CSF, whereas rhIL-4 or rhIL-13 were ineffective. Reduced neutrophil apoptosis during sepsis was concomitant with increased tyrosine phosphorylation, while IL-10 markedly inhibited tyrosine phosphorylation in LPS-stimulated neutrophils. These results identify proinflammatory cytokines and IL-10 as strong regulators of spontaneous neutrophil apoptosis during sepsis. Inhibition as well as acceleration of neutrophil apoptosis seems to be associated with alterations of signal transduction pathways.
中性粒细胞在脓毒症多器官功能障碍综合征（MODS）的病理生理学中起关键作用，其通过过度释放有毒颗粒成分和活性氧代谢产物，进而导致组织破坏。脓毒症期间衰老中性粒细胞的增加表明包括凋亡过程在内的自身调节机制可能出现故障，而凋亡过程是从炎症部位清除活化中性粒细胞的机制。因此，对重症脓毒症患者的中性粒细胞凋亡及其调节机制进行了研究。与健康个体相比，重症脓毒症患者的中性粒细胞自发凋亡显著减少。脓毒症期间循环中检测到的细胞因子（肿瘤坏死因子-α [TNF-α]、干扰素-γ [IFN-γ]、粒细胞集落刺激因子 [G-CSF]、粒细胞-巨噬细胞集落刺激因子 [GM-CSF]）在两组中均抑制中性粒细胞凋亡，尽管在健康人中性粒细胞中的作用更明显。向健康人中性粒细胞中添加脂多糖（LPS）可显著（P <.05）降低凋亡，通过添加抗TNF抗体可部分恢复凋亡。白细胞介素-10（IL-10）可抵消（P <.05）LPS、重组人（rh）TNF-α、rhIFN-γ、rhG-CSF和rhGM-CSF诱导的中性粒细胞凋亡抑制作用，而rhIL-4或rhIL-13则无效。脓毒症期间中性粒细胞凋亡减少与酪氨酸磷酸化增加同时出现，而IL-10可显著抑制LPS刺激的中性粒细胞中的酪氨酸磷酸化。这些结果表明促炎细胞因子和IL-10是脓毒症期间中性粒细胞自发凋亡的强调节因子。中性粒细胞凋亡的抑制和加速似乎都与信号转导途径的改变有关。
