Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans. PLoS Med 2006 Mar;3(3):e46
Date
01/19/2006Pubmed ID
16417407Pubmed Central ID
PMC1334221DOI
10.1371/journal.pmed.0030046Scopus ID
2-s2.0-33645355399 (requires institutional sign-in at Scopus site) 432 CitationsAbstract
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.
Author List
Parikh SM, Mammoto T, Schultz A, Yuan HT, Christiani D, Karumanchi SA, Sukhatme VPAuthor
Tadanori Mammoto MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAngiopoietin-1
Angiopoietin-2
Animals
Blood Vessels
Capillary Permeability
Convalescence
Endothelial Cells
Female
Humans
Intracellular Signaling Peptides and Proteins
Lung
Male
Mice
Pulmonary Gas Exchange
Receptor, TIE-2
Sepsis
Up-Regulation
rho-Associated Kinases
