Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Sci Transl Med. 2010 Mar 17;2(23):23ra19. doi: 10.1126/scitranslmed.3000678.
The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1beta and tumor necrosis factor-alpha, 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.
先天免疫系统通过释放多种炎症细胞因子（如白细胞介素-1β和肿瘤坏死因子-α）来提供抵御入侵病原体的第一道防线，这些细胞因子直接对抗感染因子并招募额外的免疫反应。这种过度的细胞因子释放通过引发毛细血管渗漏、组织水肿、器官衰竭和休克，反而损害了宿主。目前的医疗疗法针对的是具有抗菌作用的单一病原体，或者直接抑制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 激活一种内皮细胞特异性、Robo4 依赖性信号通路，该通路可增强血管屏障，减少宿主对病原体引起的细胞因子风暴的有害反应。这种方法可降低肺部和其他器官的血管通透性，并提高细菌内毒素暴露、多微生物败血症和 H5N1 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反应的弹性可能为治疗多种感染因子提供一种治疗策略。
