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Dual Pharmacological Inhibition of Angiopoietin-2 and VEGF-A in Murine Experimental Sepsis.
Hauschildt, Janine; Schrimpf, Claudia; Thamm, Kristina; Retzlaff, Jennifer; Idowu, Temitayo O; von Kaisenberg, Constantin; Haller, Hermann; David, Sascha.
Afiliação
  • Hauschildt J; Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
  • Schrimpf C; Department of Cardiothoracic, Transplant and Vascular Surgery, Hannover Medical School, Hannover, Germany.
  • Thamm K; Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
  • Retzlaff J; Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
  • Idowu TO; Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
  • von Kaisenberg C; Department of Gynaecology and Obstetrics, Hannover Medical School, Hannover, Germany.
  • Haller H; Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.
  • David S; Division of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany, david.sascha@mh-hannover.de.
J Vasc Res ; 57(1): 34-45, 2020.
Article em En | MEDLINE | ID: mdl-31726451
ABSTRACT

BACKGROUND:

Sepsis is a pathological host response to infection leading to vascular barrier breakdown due to elevated levels of angiopoietin-2 (Angpt-2) and vascular endothelial growth factor-A (VEGF-A). Here, we tested a novel heterodimeric bispecific monoclonal IgG1-cross antibody of Angpt-2 and VEGF - termed "A2V."

METHODS:

Cecal ligation and puncture was used to induce murine polymicrobial sepsis. Organs and blood were harvested for fluorescence immunohistochemistry and RT-PCR, and survival was recorded. In vitro endothelial cells were stimulated with plasma from septic shock patients costimulated with A2V or IgG antibody followed by immunocytochemistry and real-time transendothelial electrical resistance.

RESULTS:

Septic mice treated with A2V had a reduced induction of the endothelial adhesion molecule ICAM-1, leading to a trend towards less transmigration of inflammatory cells (A2V 42.2 ± 1.0 vs. IgG 48.5 ± 1.7 Gr-1+ cells/HPF, p = 0.08) and reduced tissue levels of inflammatory cytokines (e.g., IL-6 mRNA A2V 9.4 ± 3.2 vs. IgG 83.9 ± 36.7-fold over control, p = 0.03). Endothelial permeability was improved in vivo and in vitro in stimulated endothelial cells with septic plasma. Survival was improved by 38% (p = 0.02).

CONCLUSION:

Dual inhibition of Angpt-2 and VEGF-A improves murine sepsis morbidity and mortality, making it a potential therapeutic against vascular barrier breakdown.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sepse / Angiopoietina-2 / Fator A de Crescimento do Endotélio Vascular Limite: Animals / Humans / Male Idioma: En Revista: J Vasc Res Assunto da revista: ANGIOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Alemanha

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sepse / Angiopoietina-2 / Fator A de Crescimento do Endotélio Vascular Limite: Animals / Humans / Male Idioma: En Revista: J Vasc Res Assunto da revista: ANGIOLOGIA Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Alemanha