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

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

doi:10.1164/rccm.201708-1733OC

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

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

Microbiology and Infection

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

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.

Original language	English
Journal	American Journal of Respiratory and Critical Care Medicine
Volume	198
Issue number	2
Early online date	15 Feb 2018
DOIs	https://doi.org/10.1164/rccm.201708-1733OC
Publication status	E-pub ahead of print - 15 Feb 2018

Keywords

streptococcus pneumoniae
pneumolysin
endothelial permeability
ARDS

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1164/rccm.201708-1733OCLicence: None: All rights reserved

https://www.atsjournals.org/doi/10.1164/rccm.201708-1733OCLicence: None: All rights reserved

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Gutbier, B., Neuhauß, A-K., Reppe, K., Ehrler, C., Santel, A., Kaufmann, J., Scholz, M., Weissmann, N., Morawietz, L., Mitchell, T., Aliberti, S., Hippenstiel, S., Suttorp, N., Witzenrath, M., & CAPNETZ and PROGRESS study groups (2018). Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia. American Journal of Respiratory and Critical Care Medicine, 198(2). Advance online publication. https://doi.org/10.1164/rccm.201708-1733OC

@article{cb1859710dc04888b9f8ad58582a5a74,

title = "Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia",

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.",

keywords = "streptococcus pneumoniae, pneumolysin, endothelial permeability, ARDS",

author = "Birgitt Gutbier and Anne-Kathrin Neuhau{\ss} and Katrin Reppe and Carolin Ehrler and Ansgar Santel and J{\"o}rg Kaufmann and Markus Scholz and Norbert Weissmann and Lars Morawietz and Tim Mitchell and Stefano Aliberti and Stefan Hippenstiel and Norbert Suttorp and Martin Witzenrath and {CAPNETZ and PROGRESS study groups}",

year = "2018",

month = feb,

day = "15",

doi = "10.1164/rccm.201708-1733OC",

language = "English",

volume = "198",

journal = "American Journal of Respiratory and Critical Care Medicine",

issn = "1073-449X",

publisher = "American Thoracic Society",

number = "2",

}

Gutbier, B, Neuhauß, A-K, Reppe, K, Ehrler, C, Santel, A, Kaufmann, J, Scholz, M, Weissmann, N, Morawietz, L, Mitchell, T, Aliberti, S, Hippenstiel, S, Suttorp, N, Witzenrath, M & CAPNETZ and PROGRESS study groups 2018, 'Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia', American Journal of Respiratory and Critical Care Medicine, vol. 198, no. 2. https://doi.org/10.1164/rccm.201708-1733OC

TY - JOUR

T1 - Prognostic and Pathogenic Role of Angiopoietin-1 and -2 in Pneumonia

AU - Gutbier, Birgitt

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, Tim

AU - Aliberti, Stefano

AU - Hippenstiel, Stefan

AU - Suttorp, Norbert

AU - Witzenrath, Martin

AU - CAPNETZ and PROGRESS study groups

PY - 2018/2/15

Y1 - 2018/2/15

N2 - 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.

AB - 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.

KW - streptococcus pneumoniae

KW - pneumolysin

KW - endothelial permeability

KW - ARDS

U2 - 10.1164/rccm.201708-1733OC

DO - 10.1164/rccm.201708-1733OC

M3 - Article

C2 - 29447449

SN - 1073-449X

VL - 198

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

IS - 2

ER -

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

Abstract

Keywords

UN SDGs

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