Prognostic and pathogenic role of angiopoietin-1 and -2 in pneumonia

CAPNETZ and PROGRESS Study Groups

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 communityacquired 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 pneumolysinevoked 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 serumlevels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.

Original languageEnglish
Pages (from-to)220-231
Number of pages12
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume198
Issue number2
DOIs
Publication statusPublished - Jul 15 2018

Fingerprint

Angiopoietin-2
Angiopoietin-1
Pneumonia
Permeability
Angiopoietins
Length of Stay
Lung
Inflammation
Serum
Pneumococcal Pneumonia
Bacterial Pneumonia
Critical Care
Streptococcus
ROC Curve
Blood Vessels
Survivors
Sepsis
Healthy Volunteers
Therapeutics

Keywords

  • Acute respiratory distress syndrome
  • Endothelial permeability
  • Pneumolysin
  • Streptococcus pneumoniae

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Prognostic and pathogenic role of angiopoietin-1 and -2 in pneumonia. / CAPNETZ and PROGRESS Study Groups.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 198, No. 2, 15.07.2018, p. 220-231.

Research output: Contribution to journalArticle

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abstract = "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 communityacquired 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 pneumolysinevoked 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 serumlevels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.",
keywords = "Acute respiratory distress syndrome, Endothelial permeability, Pneumolysin, Streptococcus pneumoniae",
author = "{CAPNETZ and PROGRESS Study Groups} and Birgitt Gutbier and Neuhau{\ss}, {Anne Kathrin} and Katrin Reppe and Carolin Ehrler and Ansgar Santel and J{\"o}rg Kaufmann and Markus Scholz and Norbert Weissmann and Lars Morawietz and Mitchell, {Timothy J.} and Stefano Aliberti and Stefan Hippenstiel and Norbert Suttorp and Martin Witzenrath",
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AU - Neuhauß, Anne Kathrin

AU - Reppe, Katrin

AU - Ehrler, Carolin

AU - Santel, Ansgar

AU - Kaufmann, Jörg

AU - Scholz, Markus

AU - Weissmann, Norbert

AU - Morawietz, Lars

AU - Mitchell, Timothy J.

AU - Aliberti, Stefano

AU - Hippenstiel, Stefan

AU - Suttorp, Norbert

AU - Witzenrath, Martin

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N2 - 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 communityacquired 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 pneumolysinevoked 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 serumlevels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.

AB - 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 communityacquired 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 pneumolysinevoked 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 serumlevels predicted mortality and length of hospital stay, and angiopoietin-1 may provide a therapeutic target for severe pneumonia.

KW - Acute respiratory distress syndrome

KW - Endothelial permeability

KW - Pneumolysin

KW - Streptococcus pneumoniae

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