title: Excess circulating angiopoietin-2 may contribute to pulmonary vascular leak in sepsis in humans.
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.
  
  
  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.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Parikh
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.forename: Aylit
authors.initials: A
authors.lastname: Schultz
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Yuan
authors.forename: David
authors.initials: D
authors.lastname: Christiani
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
mesh_terms: 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
chemical_list: 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