Increased Levels of Soluble Vascular Endothelial Cadherin are Associated with Poor Outcome in Severe Sepsis

Abstract

Endothelial cells are thought to play a key role in sepsis pathogenesis: vascular endothelial damage occurs in severe sepsis and multiple organ dysfunction. Soluble vascular endothelial cadherin (VE-cadherin) levels were investigated in a prospective study involving 28 consecutive critically ill patients with or without severe sepsis who were admitted to surgical intensive care; 13 healthy age-matched volunteers were included as controls. Soluble VE-cadherin levels increased significantly in patients with severe sepsis compared with ill patients without severe sepsis and healthy controls. There was a significant linear correlation between soluble VE-cadherin levels and illness severity scores. Soluble VE-cadherin levels were significantly higher in patients who died compared with survivors. In vitro cell culture showed that serum from patients with severe sepsis greatly decreased VE-cadherin staining at intercellular junctions and total VE-cadherin expression in human umbilical cord vein endothelial cells. These findings suggest that endothelial cells play an important role in the poor outcome of patients with severe sepsis.

Keywords

Severe sepsis Endothelial dysfunction Soluble marker VE-cadherin

References

Martin

Mannino

Eaton

: The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003; 348: 1546–1554.

Dombrovskiy

Martin

Sunderram

: Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: A trend analysis from 1993 to 2003. Crit Care Med 2007; 35: 1244–1250.

Dellinger

Levy

Carlet

: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296–327.

Hack

Zeerleder

: The endothelium in sepsis: Source of and a target for inflammation. Crit Care Med 2001; 29 (7 suppl): S21–S27.

Vallet

: Bench-to-bedside review: Endothelial cell dysfunction in severe sepsis: A role in organ dysfunction? Crit Care 2003; 7: 130–138.

Aird

: The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 2003; 101: 3765–3777.

Aird

: Endothelium as a therapeutic target in sepsis. Curr Drug Targets 2007; 8: 501–507.

Pober

Sessa

: Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 2007; 7: 803–815.

Lampugnani

Resnati

Raiteri

: A novel endothelial-specific membrane protein is a marker of cell–cell contacts. J Cell Biol 1992; 118: 1511–1522.

10.

Dejana

Orsenigo

Lampugnani

: The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008; 121: 2115–2122.

11.

Corada

Mariotti

Thurston

: Vascular endothelial-cadherin is an important determinant of microvascular integrity in vivo . Proc Natl Acad Sci USA 1999; 96: 9815–9820.

12.

Beckers

García-Vallejo

van Hinsbergh

: Nuclear targeting of β-catenin and p120ctn during thrombin-induced endothelial barrier dysfunction. Cardiovasc Res 2008; 79: 679–688.

13.

Taddei

Giampietro

Conti

: Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol 2008; 10: 923–934.

14.

Sulkowska

Famulski

Wincewicz

: Levels of VE-cadherin increase independently of VEGF in preoperative sera of patients with colorectal cancer. Tumori 2006; 92: 67–71.

15.

American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20: 864–874.

16.

Knaus

Draper

Wagner

: APACHE II: A severity of disease classification system. Crit Care Med 1985; 13: 818–829.

17.

Villasante

Pacheco

Pau

: Soluble vascular endothelial-cadherin levels correlate with clinical and biological aspects of severe ovarian hyperstimulation syndrome. Hum Reprod 2008; 23: 662–667.

18.

Bennett

Jin

: A novel role of vascular endothelial cadherin in modulating c-Src activation and downstream signaling of vascular endothelial growth factor. J Biol Chem 2008; 283: 7261–7270.

19.

Müller

Gruhn

Herwig

: VE-cadherin and ACE: Markers for sepsis in post mortem examination? Leg Med (Tokyo) 2008; 10: 257–263.

20.

Nakamura

Ebihara

Shimada

: Modulation of plasma metalloproteinase-9 concentrations and peripheral blood monocyte mRNA levels in patients with septic shock: Effect of fiber-immobilized polymyxin B treatment. Am J Med Sci 1998; 316: 355–360.

21.

Navaratna

McGuire

Menicucci

: Proteolytic degradation of VE-cadherin alters the blood–retinal barrier in diabetes. Diabetes 2007; 56: 2380–2387.

22.

Ryniers

Stove

Goethals

: Plasmin produces an E-cadherin fragment that stimulates cancer cell invasion. Biol Chem 2002; 383: 159–165.

23.

Noe

Fingleton

Jacobs

: Release of an invasion promoter E-cadherin fragment by matrilysin and stromelysin-1. J Cell Sci 2001; 114: 111–118.

24.

Baumgartner

Schutz

Wiegand

: Cadherin function probed by laser tweezer and single molecule fluorescence in vascular endothelial cells. J Cell Sci 2003; 116: 1001–1011.