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

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

Author information

1
1 Division of Pulmonary Inflammation and.
2
2 Department of Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
3
3 Silence Therapeutics AG, Berlin, Germany.
4
4 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
5
5 Excellence Cluster Cardiopulmonary System, University of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University, Giessen, Germany.
6
6 Pathology, Healthcare Center Fuerstenberg-Karree, Berlin, Germany.
7
7 Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
8
8 Department of Pathophysiology and Transplantation, University of Milan, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico, Milan, Italy; and.
9
9 CAPNETZ STIFTUNG, Hannover, Germany.

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 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

PMID:
29447449
DOI:
10.1164/rccm.201708-1733OC

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