Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.
Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza.
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DOI：
10.1126/scitranslmed.3000678
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发表时间：
2010-03-17
影响因子：
17.1
通讯作者：
Li DY
中科院分区：
文献类型：
--
作者：
London NR;Zhu W;Bozza FA;Smith MC;Greif DM;Sorensen LK;Chen L;Kaminoh Y;Chan AC;Passi SF;Day CW;Barnard DL;Zimmerman GA;Krasnow MA;Li DY
先天免疫系统通过释放多种炎性细胞因子（如白细胞介素-1 β和肿瘤坏死因子-α）提供抵抗入侵病原体的第一道防线，所述炎性细胞因子直接对抗感染因子并募集额外的免疫应答。这种旺盛的细胞因子释放矛盾地通过触发毛细血管渗漏、组织水肿、器官衰竭和休克来伤害宿主。目前的医学疗法针对个别病原体与抗菌剂或直接钝或增强宿主的免疫系统。我们探索了第三种方法：用可溶性配体Slit激活增强血管屏障的内皮特异性Robo 4依赖性信号通路，减少宿主对病原体诱导的细胞因子风暴的反应的有害方面。这种方法降低了肺和其他器官的血管通透性，并增加了细菌内毒素暴露、多微生物败血症和H5 N1流感动物模型的存活率。因此，增强宿主血管系统对宿主先天免疫应答的恢复力可以提供用于治疗多种感染因子的治疗策略。
The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1β and tumor necrosis factor–α, which directly combat the infectious agent and recruit additional immune responses. This exuberant cytokine release paradoxically injures the host by triggering leakage from capillaries, tissue edema, organ failure, and shock. Current medical therapies target individual pathogens with antimicrobial agents or directly either blunt or boost the host’s immune system. We explored a third approach: activating with the soluble ligand Slit an endothelium-specific, Robo4-dependent signaling pathway that strengthens the vascular barrier, diminishing deleterious aspects of the host’s response to the pathogen-induced cytokine storm. This approach reduced vascular permeability in the lung and other organs and increased survival in animal models of bacterial endotoxin exposure, polymicrobial sepsis, and H5N1 influenza. Thus, enhancing the resilience of the host vascular system to the host’s innate immune response may provide a therapeutic strategy for treating multiple infectious agents.
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影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
21.3
作者：
Jones CA;Nishiya N;London NR;Zhu W;Sorensen LK;Chan AC;Lim CJ;Chen H;Zhang Q;Schultz PG;Hayallah AM;Thomas KR;Famulok M;Zhang K;Ginsberg MH;Li DY
通讯作者：
Li DY
影响因子：
20.3
作者：
Corada, M;Liao, F;Dejana, E
通讯作者：
Dejana, E
影响因子：
4.4
作者：
Gupta, Naveen;Su, Xiao;Matthay, Michael A.
通讯作者：
Matthay, Michael A.
DOI：
10.1073/pnas.75.5.2458
发表时间：
1978-01-01
影响因子：
11.1
作者：
COLLINS, SJ;RUSCETTI, FW;GALLO, RC
通讯作者：
GALLO, RC