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

Am J Respir Crit Care Med. 2018 Jul 15;198(2):220-231. doi: 10.1164/rccm.201708-1733OC.


Rationale: During pneumonia, pathogen-host interaction evokes inflammation and lung barrier dysfunction. Tie2 activation by angiopoietin-1 reduces, whereas 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 pathogenic 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 postmortem 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 patients with pneumonia, decreased serum angiopoietin-1 and increased angiopoietin-2 levels were observed as compared with healthy subjects. Higher angiopoietin-2 serum levels were found in patients with community-acquired pneumonia who died within 28 days of diagnosis compared with survivors. Receiver operating characteristic 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 on pneumolysin stimulation. Increased pulmonary angiopoietin-2 and reduced angiopoietin-1 mRNA expression were observed in Streptococcus 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.

Keywords: Streptococcus pneumoniae; acute respiratory distress syndrome; endothelial permeability; pneumolysin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-1 / blood
  • Angiopoietin-1 / therapeutic use*
  • Angiopoietin-2 / blood
  • Angiopoietin-2 / therapeutic use*
  • Endothelial Cells / drug effects*
  • Host-Pathogen Interactions / drug effects*
  • Humans
  • Inflammation / physiopathology*
  • Lung / drug effects*
  • Pneumonia, Pneumococcal / drug therapy*
  • Pneumonia, Pneumococcal / physiopathology*
  • Prognosis


  • Angiopoietin-1
  • Angiopoietin-2