Journal article
Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza
Science translational medicine, Vol.2(23), pp.23ra19-ra19
03/17/2010
DOI: 10.1126/scitranslmed.3000678
PMCID: PMC2875996
PMID: 20375003
Abstract
The innate immune system provides a first line of defense against invading pathogens by releasing multiple inflammatory cytokines, such as interleukin-1 beta 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.
Details
- Title: Subtitle
- Targeting Robo4-Dependent Slit Signaling to Survive the Cytokine Storm in Sepsis and Influenza
- Creators
- Nyall R. London - University of UtahWeiquan Zhu - University of UtahFernando A. Bozza - Fundação Oswaldo CruzMatthew C. P. Smith - University of UtahDaniel M. Greif - Stanford UniversityLise K. Sorensen - University of UtahLuming Chen - University of UtahYuuki Kaminoh - University of UtahAubrey C. Chan - University of UtahSamuel F. Passi - University of UtahCraig W. Day - Utah State UniversityDale L. Barnard - Utah State UniversityGuy A. Zimmerman - University of UtahMark A. Krasnow - Stanford UniversityDean Y. Li - University of Utah
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.2(23), pp.23ra19-ra19
- DOI
- 10.1126/scitranslmed.3000678
- PMID
- 20375003
- PMCID
- PMC2875996
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Publisher
- Amer Assoc Advancement Science
- Number of pages
- 10
- Grant note
- Rocky Mountain Regional Center of Excellence in Biodefense and Emerging Infectious Disease National Institute of Allergy and Infectious Diseases (NIAID); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) Ruth L. Kirschstein National Research Service Award; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA K08 / NIH-NHLBI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Juvenile Diabetes Research Foundation Burroughs Wellcome Foundation; Burroughs Wellcome Fund NO1-AI-15435 / NIAID; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) National Heart, Lung, and Blood Institute (NHLBI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) R01HL065648 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) T32GM007464 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Department of Defense; United States Department of Defense 5R37 HL44525-20 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Sarnoff Cardiovascular Research Foundation Scholar Award American Heart Association N01AI015435 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) UL1-RR025764 / National Center for Research Resources Public Health Services; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) UL1RR025764 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, Brazil); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPQ) HA and Edna Benning Foundation Pulmonary Hypertension Association American Asthma Foundation
- Language
- English
- Date published
- 03/17/2010
- Academic Unit
- Psychiatry; Internal Medicine
- Record Identifier
- 9984280843402771
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