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Significance of polymorphonuclear neutrophil cell death in surgical stress

多形核中性粒细胞死亡在手术应激中的意义

基本信息

批准号：
10557109
负责人：
SAITO Hideaki
金额：
$ 8.77万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557109/
关键词：
neutrophil apoptosis necrosis cytokines bacteria antibiotics endotoxin 外科侵襲 Caspaseファミリー NF-kB

项目摘要

We investigated the significance of polymorphonuclear neutrophil cell death in surgical stress. Obtained results are as follows :(1) Exudative PMN apoptosis was markedly inhibited on postoperative day 1 and then increased in a time-dependent manner. IL-6 and GM-CSF were related to inhibit exudative PMN apoptosis, while TNF-a and IL-10 were related to increase apoptosis. ROI production and CD16 expression of exudative PMNs were augmented when PMN apoptosis was inhibited in the early postoperative period. Understanding the mechanisms of PMN apoptosis and its pathophysiological significance at local inflammatory sites in vivo may help in the design of more rational treatments.(2) In vitro IL-6 and GM-CSF inhibited apoptosis of PMN isolated from healthy volunteers. Moreover, IL-10 reduced the inhibitory effect of IL-6 on PMN apoptosis.(3) Low doses of live E. coli inhibits predominantly PMN apoptosis, whereas a high dose of E. coli increases necrosis. Augmented PMN bactericidal function, via inhibition of PMN cell death, may be beneficial for host defense against bacterial infection and/or sepsis.(4) Antibiotics such as ABPC, CEZ, CPZ and LMOX kill bacteria by a mode of filament formation, leading to excessive endotoxin release, cytokine production and necrosis of PMNs. In contrast, IMP, killing bacteria by a mode of spheroplast, inhibit excessive endotoxin release, PMN cytokine production, and necrosis, and induced PMN apoptosis. Antibiotic choices may be based on their PMN necrosis inducing property as well as their sensitivity spectrum for the clinical improvement of therapy of severe infection and/or sepsis.(5) GH pretreatment downregulates Fas expression on PMNs, inhibits apoptosis and upregulates ROI producdon of PMNs. GH pretreatment also increases monocyte ROI production. Although activated PMNs have potentially harmful aspects, our results suggest that GH may improve host defense mainly through enhancement of the PMN functional life span.

我们研究了多形核中性粒细胞死亡在手术应激中的意义。所得结果如下：(1)渗出性PMN凋亡在术后第1天明显受到抑制，随后呈时间依赖性增加。 IL-6和GM-CSF与抑制渗出性PMN细胞凋亡有关，而TNF-a和IL-10与增加细胞凋亡有关。当术后早期抑制 PMN 凋亡时，渗出性 PMN 的 ROI 产生和 CD16 表达增加。了解PMN细胞凋亡的机制及其在体内局部炎症部位的病理生理意义可能有助于设计更合理的治疗方法。(2)体外IL-6和GM-CSF抑制健康志愿者分离的PMN细胞凋亡。此外，IL-10降低了IL-6对PMN凋亡的抑制作用。(3)低剂量的活大肠杆菌主要抑制PMN凋亡，而高剂量的大肠杆菌则增加坏死。通过抑制中性粒细胞死亡，增强中性粒细胞的杀菌功能，可能有利于宿主防御细菌感染和/或脓毒症。(4)ABPC、CEZ、CPZ和LMOX等抗生素通过细丝形成的方式杀死细菌，导致内毒素过度释放、细胞因子产生和中性粒细胞坏死。相比之下，IMP通过原生质球的方式杀死细菌，抑制内毒素的过度释放、PMN细胞因子的产生和坏死，并诱导PMN凋亡。抗生素的选择可能基于其诱导中性粒细胞坏死的特性以及其对严重感染和/或败血症治疗的临床改进的敏感性谱。(5)GH预处理下调中性粒细胞上的Fas表达，抑制细胞凋亡并上调中性粒细胞的ROI产生。 GH 预处理还可以增加单核细胞 ROI 的产生。尽管激活的 PMN 具有潜在的有害方面，但我们的结果表明 GH 可能主要通过延长 PMN 的功能寿命来改善宿主防御。