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Modulation of neutrophil apoptosis in septic shock and its regulation by endogenous antimicrobial peptides

脓毒性休克中性粒细胞凋亡的调节及其内源性抗菌肽的调节

基本信息

批准号：
15590400
负责人：
NAGAOKA Isao
金额：
$ 1.98万
依托单位：
JUNTENDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590400/
关键词：
Sepsis Neutrophil Apoptosis Endotoxin Cytokine Monocyte Macrophage Toll-like receptor Integrins

项目摘要

Peptide antibiotics possess potent antimicrobial activities against invading microorganisms and contribute to innate host defense. We previously revealed that antibacterial cathelicidin CAP11 exerts protective actions against endotoxin shock model. During Gram-negative bacterial sepsis, LPS activates neutrophils and their apoptosis is suppressed. Prolonged presence of activated neutrophils causes uncontrolled release of toxic metabolites, leading to the systemic tissue injury. To evaluate a therapeutic potential of CAP11 for Gram-negative sepsis, we here investigated the action of CAP11 on LPS-induced suppression of neutrophil apoptosis.LPS suppressed neutrophil apoptosis, accompanied with NF-kappaB activation, ERK phosphorylation, Bcl-XL expression and caspase 3 inhibition. Interestingly, CAP11 reversed the actions of LPS to trigger these changes, and induced neutrophil apoptosis. Furthermore, LPS activated monocytes to produce anti apoptotic cytokines (IL-1beta, TNF-alpha and IL-8) and suppressed neutrophil apoptosis. Importantly, CAP11 inhibited the cytokine production from monocytes, thereby inducing neutrophil apoptosis. Finally, CAP11 strongly suppressed LPS-binding to neutrophils and monocytes.Thus, CAP11 is able to block the LPS-induced prolongation of neutrophil survival via the suppression of anti apoptotic signaling in neutrophils and cytokine production from monocytes by inhibiting LPS-binding to target cells. CAP11 is expected to have a therapeutic potential in Gram-negative sepsis to induce neutrophil apoptosis, thereby possibly attenuating tissue injury.

肽抗生素具有针对入侵微生物的有效抗菌活性，并有助于宿主的先天防御。我们之前揭示了抗菌导管素 CAP11 对内毒素休克模型具有保护作用。在革兰氏阴性细菌败血症期间，LPS 激活中性粒细胞并抑制其凋亡。活化的中性粒细胞的长期存在会导致有毒代谢物不受控制的释放，从而导致全身组织损伤。为了评估 CAP11 对革兰氏阴性脓毒症的治疗潜力，我们在此研究了 CAP11 对 LPS 诱导的中性粒细胞凋亡抑制的作用。LPS 抑制中性粒细胞凋亡，并伴有 NF-kappaB 激活、ERK 磷酸化、Bcl-XL 表达和 caspase 3 抑制。有趣的是，CAP11 逆转了 LPS 的作用以触发这些变化，并诱导中性粒细胞凋亡。此外，LPS 激活单核细胞产生抗凋亡细胞因子（IL-1β、TNF-α 和 IL-8）并抑制中性粒细胞凋亡。重要的是，CAP11 抑制单核细胞产生细胞因子，从而诱导中性粒细胞凋亡。最后，CAP11 强烈抑制 LPS 与中性粒细胞和单核细胞的结合。因此，CAP11 能够通过抑制 LPS 与靶细胞的结合来抑制中性粒细胞中的抗凋亡信号传导和单核细胞产生细胞因子，从而阻断 LPS 诱导的中性粒细胞存活时间的延长。 CAP11 预计在革兰氏阴性脓毒症中具有治疗潜力，可诱导中性粒细胞凋亡，从而可能减轻组织损伤。