Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia

Research output: Contribution to journalArticle

Authors

  • Birgitt Gutbier
  • Anne-Kathrin Neuhauß
  • Katrin Reppe
  • Carolin Ehrler
  • Ansgar Santel
  • Jörg Kaufmann
  • Markus Scholz
  • Norbert Weissmann
  • Lars Morawietz
  • Timothy Mitchell
  • Stefano Aliberti
  • Stefan Hippenstiel
  • Norbert Suttorp
  • Martin Witzenrath
  • CAPNETZ and PROGRESS study groups

Colleges, School and Institutes

External organisations

  • Charité-Universitätsmedizin Berlin
  • IPPMed – Institut für Pharmakologie und Präventive Medizin GmbH
  • Silence Therapeutics AG
  • University of Leipzig
  • Justus Liebig University Giessen
  • Healthcare Center Fuerstenberg-Karree
  • University of Milan

Abstract

RATIONALE: During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2-activation by Angiopoietin-1 reduces, while Tie2-blockade by Angiopoietin-2 increases inflammation and permeability during sepsis. The role of Angiopoietin-1/-2 in pneumonia remains unidentified.

OBJECTIVES: To investigate the prognostic and pathogenetic impact of Angiopoietins in regulating pulmonary vascular barrier function and inflammation in bacterial pneumonia.

METHODS: Serum Angiopoietin levels were quantified in pneumonia patients of two independent cohorts (n=148, n=395). Human post mortem lung tissue, pneumolysin- or Angiopoietin-2-stimulated endothelial cells, isolated perfused and ventilated mouse lungs, and mice with pneumococcal pneumonia were investigated.

MEASUREMENTS AND MAIN RESULTS: In pneumonia patients, decreased serum Angiopoietin-1 and increased Angiopoietin-2 levels were observed as compared to healthy subjects. Higher Angiopoietin-2 serum levels were found in community-acquired pneumonia patients who died within 28 days after diagnosis compared to survivors. ROC analysis revealed improved prognostic accuracy of CURB-65 for 28-day survival, intensive care treatment and length of hospital stay if combined with Angiopoietin-2 serum levels. In vitro, pneumolysin enhanced endothelial Angiopoietin-2 release, Angiopoietin-2 increased endothelial permeability, and Angiopoietin-1 reduced pneumolysin-evoked endothelial permeability. Ventilated and perfused lungs of mice with Angiopoietin-2-knockdown showed reduced permeability upon pneumolysin stimulation. Increased pulmonary Angiopoietin-2 and reduced Angiopoietin-1 mRNA expression were observed in S. pneumoniae infected mice. Finally, Angiopoietin-1 therapy reduced inflammation and permeability in murine pneumonia.

CONCLUSIONS: These data suggest a central role of Angiopoietin-1/-2 in pneumonia-evoked inflammation and permeability. Increased Angiopoietin-2 serum levels predicted mortality and length of hospital stay, and Angiopoietin-1 may provide a therapeutic target for severe pneumonia.

Details

Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume198
Issue number2
Early online date15 Feb 2018
Publication statusE-pub ahead of print - 15 Feb 2018

Keywords

  • streptococcus pneumoniae, pneumolysin, endothelial permeability, ARDS