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Cited by 38Sepsis Diagnosis and TreatmentCell Adhesion Molecules ResearchInflammation biomarkers and pathways

Effective Treatment of Mouse Sepsis With an Inhibitory Antibody Targeting Integrin αvβ5*

Su, George, Atakilit, Amha, Li, John T., Wu, Nanyan, Luong, Jacky, Chen, Robert, Bhattacharya, Mallar, Sheppard, Dean·2013·Critical Care Medicine
DOI 10.1097/ccm.0b013e3182711b1e
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Abstract

OBJECTIVE: Integrin αvβ5 has been identified as a regulator of vascular leak and endothelial permeability. We hypothesized that targeting αvβ5 could represent a viable treatment strategy for sepsis. DESIGN: Integrin β5 subunit knockout and wild-type 129/svJae mice and wild-type mice treated with αvβ5 blocking or control antibodies were tested in models of intraperitoneal lipopolysaccharide and cecal ligation and puncture. Human umbilical vein endothelial cell and human lung microvascular endothelial cell monolayers were treated with αvβ5 antibodies to assess for effects on lipopolysaccharide-induced changes in transendothelial resistance and on patterns of cytoskeletal reorganization. SETTING: Laboratory-based research. SUBJECTS: Mice and endothelial cell monolayers. INTERVENTIONS, MEASUREMENTS, AND MAIN RESULTS: Measurements taken after intraperitoneal lipopolysaccharide and/or cecal ligation and puncture included mortality, vascular leak, hematocrit, quantification of a panel of serum cytokines/chemokines, and assessment of thioglyccolate-induced leukocyte migration. β5 knockout mice had decreased mortality after intraperitoneal lipopolysaccharide and cecal ligation and puncture and decreased vascular leak, as measured by extravasation of an I-labeled intravascular tracer. Treating clinically ill mice with αvβ5 antibodies, up to 20 hrs after intraperitoneal lipopolysaccharide and cecal ligation and puncture, also resulted in decreased mortality. αvβ5 antibodies attenuated lipopolysaccharide-induced transendothelial resistance changes and cytoskeletal stress fiber formation in both human umbilical vein endothelial cell and human lung microvascular endothelial cell monolayers. αvβ5 antibodies had no effect on cytokine/chemokine serum levels after cecal ligation and puncture. β5 knockout mice and wild-type controls did not exhibit differences in thioglyccolate-induced leukocyte migration. CONCLUSIONS: Our studies suggest that αvβ5 is an important regulator of the vascular endothelial leak response in sepsis and that αvβ5 blockade may provide a novel approach to treating this devastating disease syndrome.

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Crossref · 10.1097/ccm.0b013e3182711b1e

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  • Antibodies inhibiting αvβ5-integrin are able to decrease vascular leakage in a mouse sepsis model.

    “antibodies inhibiting αvβ5-integrin are able to decrease vascular leakage in a mouse sepsis model (31)”

    From Targeting β1-integrin inhibits vascular leakage in endotoxemia (2018) · cites this paper as [31]

  • Integrin αvβ5 is localized around the cell nucleus in confluent BECs, but is associated with cell adhesions at the ends of actin stress fibres in few Tie2-silenced cells.

    “Integrin αvβ5 was localized around the cell nucleus in confluent BECs, in line with previous results37, but was associated with cell adhesions at the ends of actin stress fibres in few Tie2-silenced cells (Supplementary Fig. 3c).”

    From Endothelial destabilization by angiopoietin-2 via integrin β1 activation (2015) · cites this paper as [37]

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Authors
Su, G., Atakilit, A., Li, J. T., Wu, N., Luong, J., Chen, R., Bhattacharya, M., & Sheppard, D.
Affiliations
University of California, San Francisco (US)
ORCID
Venue
Critical Care Medicine
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2013-02
Volume
41
Issue
2
Pages
546-553
ISSN
0090-3493 (ISSN-L)
DOI
10.1097/ccm.0b013e3182711b1e
OpenAlex
W1970325164
Cited by
36
References
35
Citations by year
2025: 2 · 2024: 3 · 2023: 1 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 4 · 2017: 3 · 2016: 1 · 2015: 2 · 2014: 5 · 2013: 1
FWCI
2.19
Type
journal article
Language
en
Open access
closed
Locations
  • Critical Care Medicine (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (R01HL083950, K08HL083097, HL53949, 5K08HL83097-2, HL083950)
Topics
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords
sepsis, integrin αvβ5, integrin blockade, antibody therapy, vascular leakage, endothelial permeability, lipopolysaccharide, cecal ligation and puncture, endothelial cytoskeleton, stress fibers, leukocyte migration
MeSH terms
Animals, Antibodies, Cecum, Cell Movement, Disease Models, Animal, Humans, Injections, Intraperitoneal, Leukocytes, Ligation, Lipopolysaccharides, Punctures, Cytokines, Mice, Knockout, Sepsis, Chemokines, Receptors, Vitronectin, Endothelial Cells, Mice, Mice, 129 Strain

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