Vascular cell adhesion molecule--1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction.
BACKGROUND
Sepsis-induced cardiac dysfunction occurs commonly in critically ill patients and is associated with high mortality rates. Neutrophils play a central role in sepsis-induced lung and liver injury; however, the mechanism of sepsis-induced cardiac dysfunction remains unclear. Vascular cell adhesion molecule-1 (VCAM-1) has been implicated in neutrophil-mediated liver injury during endotoxemia and is also expressed in myocardium. The purposes of this study were to examine the temporal relationship of myocardial VCAM-1 expression with neutrophil accumulation during endotoxemia and to determine whether VCAM-1 mediates neutrophil accumulation and cardiac dysfunction during endotoxemia.


METHODS
Mice were subjected to lipopolysaccharide (LPS; 0.5 mg/kg, intraperitoneally). Myocardial VCAM-1 expression and neutrophil accumulation were determined by immunofluorescence staining. Cardiac performance with or without VCAM-1 blocking antibody (5 mg/kg, intravenously) was determined by the Langendorff technique.


RESULTS
LPS caused a time-dependent increase in both myocardial VCAM-1 expression and neutrophil accumulation. At 6 hours after LPS, the immunofluorescent intensity for VCAM-1 increased from 2.5 +/- 0.6 x 10(6) in saline solution controls to 19.9 +/- 3.5 x 10(6) (P <.05, analysis of variance), and neutrophil count increased from 2.4 +/- 1.7/mm(2) in saline solution controls to 13.0 +/- 2.5/mm(2) (P <.05). Left ventricular developed pressure was decreased maximally at 6 hours after LPS compared with saline solution controls (29.1 +/- 1.1 mm Hg vs 53.1 +/- 3.9 mm Hg; P <.05). Treatment with VCAM-1 monoclonal antibody abrogated both myocardial neutrophil accumulation and cardiac dysfunction during endotoxemia.


CONCLUSIONS
LPS-induced myocardial dysfunction is associated with increased expression of VCAM-1 and with neutrophil accumulation. Blockade of VCAM-1 abrogates myocardial neutrophil accumulation and preserves cardiac function during endotoxemia, which supports a role for VCAM-1 as a therapeutic target for myocardial protection during sepsis.
Raeburn
C D
CD
Department of Surgery, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Calkins
C M
CM
Zimmerman
M A
MA
Song
Y
Y
Ao
L
L
Banerjee
A
A
Meng
X
X
Harken
A H
AH
D000818:Animals; D000906:Antibodies; D005455:Fluorescent Antibody Technique; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis / Q000096:biosynthesis* / Q000276:immunology; D016277:Ventricular Function, Left
D000906:Antibodies; D008070:Lipopolysaccharides; D019010:Vascular Cell Adhesion Molecule-1