Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans
Samir M. Parikh1, Tadanori Mammoto1, Aylit Schultz1, Hai-Tao Yuan1, David Christiani2, S. Ananth Karumanchi1, Vikas P. Sukhatme1*
1 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America, 2 Occupational Health Program, Harvard School of Public Health, Boston, Massachusetts, United States of America
ABSTRACT
Background
Acute respiratory distress syndrome (ARDS) is a devastating complication of numerous underlying conditions, most notably sepsis. Although pathologic vascular leak has been implicated in the pathogenesis of ARDS and sepsis-associated lung injury, the mechanisms promoting leak are incompletely understood. Angiopoietin-2 (Ang-2), a known antagonist of the endothelial Tie-2 receptor, was originally described as a naturally occurring disruptor of normal embryonic vascular development otherwise mediated by the Tie-2 agonist angiopoietin-1 (Ang-1). We hypothesized that Ang-2 contributes to endothelial barrier disruption in sepsis-associated lung injury, a condition involving the mature vasculature.
Methods and Findings
We describe complementary human, murine, and in vitro investigations that implicate Ang-2 as a mediator of this process. We show that circulating Ang-2 is significantly elevated in humans with sepsis who have impaired oxygenation. We then show that serum from these patients disrupts endothelial architecture. This effect of sepsis serum from humans correlates with measured Ang-2, abates with clinical improvement, and is reversed by Ang-1. Next, we found that endothelial barrier disruption can be provoked by Ang-2 alone. This signal is transduced through myosin light chain phosphorylation. Last, we show that excess systemic Ang-2 provokes pulmonary leak and congestion in otherwise healthy adult mice.
Conclusions
Our results identify a critical role for Ang-2 in disrupting normal pulmonary endothelial function.
Competing Interests: The authors have declared that no competing interests exist.
Author Contributions: SMP, TM, DC, SAK, and VPS were responsible for hypothesis generation. SMP and AS were responsible for human data collection and analysis and for institutional review board applications. SMP and TM were responsible for manuscript preparation. SMP, TM, AS, HTY, DC, SAK, and VPS were responsible for final approval of manuscript. TM was responsible for in vitro and animal studies. AS and HTY were responsible for Ang-2 ELISA data acquisition and analysis. SMP, TM, AS, HTY, DC, SAK, and VPS were responsible for critical revision of the manuscript.
Academic Editor: Peter J. Barnes, National Heart and Lung Institute, United Kingdom
Received: August 19, 2005; Accepted: November 17, 2005; Published: January 24, 2006
DOI: 10.1371/journal.pmed.0030046
Copyright: © 2006 Parikh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abbreviations: Ang-1, angiopoietin-1; Ang-2, angiopoietin-2; APACHE, acute physiology and chronic health evaluation; ARDS, acute respiratory distress syndrome; EC, endothelial cell; FBS, fetal bovine serum; FiO2, fraction of inspired air consisting of oxygen; HMVEC, human microvascular endothelial cell; MLC, myosin light chain; MLCK, myosin light chain kinase; MLC-p, phosphorylated myosin light chain; Pa, permeability coefficient of albumin; PaO2, partial pressure of oxygen in arterial blood; PVDF, polyvinylidene difluoride; VEGF, vascular endothelial growth factor; siRNA, short interfering RNA; W/D, wet-to-dry
* To whom correspondence should be addressed. E-mail: vsukhatm@bidmc.harvard.edu
These authors contributed equally to this work.
Citation: Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D, et al. (2006) Excess Circulating Angiopoietin-2 May Contribute to Pulmonary Vascular Leak in Sepsis in Humans. PLoS Med 3(3): e46
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