Amelioration of sepsis by TIE2 activation-induced vascular protection

Sangyeul Han, Seung Jun Lee, Kyung Eun Kim, Hyo Seon Lee, Nuri Oh, Inwon Park, Eun Ko, Seung Ja Oh, Yoon Sook Lee, David Kim, Seungjoo Lee, Dae Hyun Lee, Kwang Hoon Lee, Su Young Chae, Jung Hoon Lee, Su Jin Kim, Hyung Chan Kim, Seokkyun Kim, Sung Hyun Kim, Chungho KimYoshikazu Nakaoka, Yulong He, Hellmut G. Augustin, Junhao Hu, Paul H. Song, Yong In Kim, Pilhan Kim, Injune Kim, Gou Young Koh

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Protection of endothelial integrity has been recognized as a frontline approach to alleviating sepsis progression, yet no effective agent for preserving endothelial integrity is available. Using an unusual anti-angiopoietin 2 (ANG2) antibody, ABTAA (ANG2-binding and TIE2-activating antibody), we show that activation of the endothelial receptor TIE2 protects the vasculature from septic damage and provides survival benefit in three sepsis mouse models. Upon binding to ANG2, ABTAA triggers clustering of ANG2, assembling an ABTAA/ANG2 complex that can subsequently bind and activate TIE2. Compared with a conventional ANG2-blocking antibody, ABTAA was highly effective in augmenting survival from sepsis by strengthening the endothelial glycocalyx, reducing cytokine storms, vascular leakage, and rarefaction, and mitigating organ damage. Together, our data advance the role of TIE2 activation in ameliorating sepsis progression and open a potential therapeutic avenue for sepsis to address the lack of sepsisspecific treatment.

Original languageEnglish
JournalScience Translational Medicine
Volume8
Issue number335
DOIs
Publication statusPublished - 2016 Apr 20

ASJC Scopus subject areas

  • Medicine(all)

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    Han, S., Lee, S. J., Kim, K. E., Lee, H. S., Oh, N., Park, I., Ko, E., Oh, S. J., Lee, Y. S., Kim, D., Lee, S., Lee, D. H., Lee, K. H., Chae, S. Y., Lee, J. H., Kim, S. J., Kim, H. C., Kim, S., Kim, S. H., ... Koh, G. Y. (2016). Amelioration of sepsis by TIE2 activation-induced vascular protection. Science Translational Medicine, 8(335). https://doi.org/10.1126/scitranslmed.aad9260