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Regulation of biodefense system by neutrophil apoptosis

中性粒细胞凋亡调节生物防御系统

基本信息

批准号：
08672139
负责人：
KIZAKI Harutoshi
金额：
$ 1.41万
依托单位：
TOKYO DENTAL COLLEGE
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

Under steady-state conditions, the large daily production of neutrophils is balanced by their disappearance and apoptosis in the tissues without eliciting an inflammatory response. Normally, neutrophils disappear into the lung, oral cavity and gastrointestinal tract, where they may be lost from mucosal surfaces or die and become sequestered by macrophages. Infiltrated and activated neutrophils in periodontal tissues release enzymes, oxygen radicals, cytokines, and mediators of inflammation, and their persistent accumulation is associated with the destruction of tissue matrix or organ function, resulting in an exasperation of periodontal diseases. Thus, neutrophil elimination by apotosis is indeed a potentially injury-limiting cell disposal mechanism for the cessation of inflammation. In the present studies, we examined the mechanism of apoptosis of peripheral and oral neutrophils.When the nuclei from peripheral neutrophils were incubated with calcium and magnesium, internucleosomal DNA … More fragmentation was observed, but not in oral neutrophils. Peripheral neutrophil apoptosis was induced by actinomycin D and TNF-alpha, revealing internucleosomal DNA fragmentation, but oral neutrophils were resistant to the stimuli. When peripheral neutrophils were treated by TPA or FMLP which prime the cells, and cultured for an additional time, they underwent apoptosis with DNA fragmentation and did not become insensitive to apoptosis as oral neutrophils. Other signals which are aquired during migration to the oral cavity from the vessels may participate in the resistancy to apoptosis in oral neutrophils. A variety of modulators of intracellular signaling pathways, including protein kinase C and caspases, have been shown to participate in the regulation of neutrophil survival and apoptosis.However, H-7, an inhibitor of PKC,and AcY VADcmK,a caspase inhibitor, did not affect the DNA fragmentation in peripheral neutrophils.HL-60 cells which differentiate to granulocytes, underwent apoptosis by the inhibitor of proteasome which inhibited thymocytes apoptosis. It is difficult to measure neutrophil apoptosis quantitatively, therefor the apoptosis specific molecules such as Fas-FasL and Bcl-2 should be considered to elucidate the mechanism of neutrophil apoptosis.In the periodontal lesions, apoptosis of inflammatory cells including macrophages, neutrophils and lymphocytes is regulated by different mechanisms and modulates periodontitis. Less

在稳态条件下，中性粒细胞的大量日生产通过其在组织中的消失和凋亡来平衡，而不引起炎症反应。正常情况下，中性粒细胞消失在肺、口腔和胃肠道中，在那里它们可能从粘膜表面丢失或死亡并被巨噬细胞隔离。牙周组织中浸润和活化的中性粒细胞释放酶、氧自由基、细胞因子和炎症介质，它们的持续积累与组织基质或器官功能的破坏有关，导致牙周病的恶化。因此，通过细胞凋亡消除中性粒细胞确实是停止炎症的潜在损伤限制性细胞处置机制。在本研究中，我们研究了外周和口腔中性粒细胞凋亡的机制。当外周中性粒细胞的核与钙和镁孵育时， ...更多信息在口腔嗜中性粒细胞中未观察到碎裂。放线菌素D和TNF-α诱导外周中性粒细胞凋亡，揭示核小体间DNA片段化，但口腔中性粒细胞对刺激有抵抗力。当用TPA或FMLP处理外周中性粒细胞并培养额外的时间时，它们经历了DNA片段化的凋亡，并且不会像口服中性粒细胞那样对凋亡不敏感。在从血管迁移到口腔的过程中获得的其他信号可能参与口腔中性粒细胞对凋亡的抵抗。多种细胞内信号通路的调节剂，包括蛋白激酶C和半胱天冬酶，已被证明参与调节中性粒细胞的存活和凋亡。然而，PKC抑制剂H-7和半胱天冬酶抑制剂AcY VADcmK并不影响外周中性粒细胞的DNA片段化。HL-60细胞分化为粒细胞，蛋白酶体抑制剂抑制胸腺细胞凋亡。由于中性粒细胞凋亡的定量检测比较困难，因此需要从凋亡特异性分子如Fas-FasL、Bcl-2等来阐明中性粒细胞凋亡的机制。在牙周病变中，炎症细胞包括巨噬细胞、中性粒细胞和淋巴细胞的凋亡受不同机制的调控，从而调节牙周炎的发生。少