Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans.
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.


RESULTS
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.
Parikh
Samir M
SM
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
Mammoto
Tadanori
T
Schultz
Aylit
A
Yuan
Hai-Tao
HT
Christiani
David
D
Karumanchi
S Ananth
SA
Sukhatme
Vikas P
VP
D000368:Aged; D042683:Angiopoietin-1 / Q000494:pharmacology; D042702:Angiopoietin-2 / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D003289:Convalescence; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011659:Pulmonary Gas Exchange / Q000502:physiology; D042787:Receptor, TIE-2 / Q000172:deficiency; D018805:Sepsis / Q000097:blood* / Q000150:complications / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D047908:Intracellular Signaling Peptides and Proteins; D042787:Receptor, TIE-2; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases