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 criticall y ill patients and is associated with high mortality rates. Neutrophils pla y a central role in sepsis-induced lung and liver injury; however, the mech anism of sepsis-induced cardiac dysfunction remains unclear. Vascular cell adhesion molecule-1 (VCAM-1) has been implicated in neutrophil-mediated liv er injury during endotoxemia and is also expressed in myocardium. The purpo ses of this study were to examine the temporal relationship of myocardial V CAM-1 expression with neutrophil accumulation during endotoxemia and to det ermine whether VCAM-1 mediates neutrophil accumulation and cardiac dysfunct ion during endotoxemia. Methods. Alice were subjected to lipopolysaccharide (LPS; 0.5 mg/kg, intrap eritoneally). Myocardial VCAM-1 expression and neutrophil accumulation were determined by immunofluorescence staining. Cardiac performance with ar wit hout VCAM-1 blocking antibody (5 mg/kg, intravenously) was deters mined by the Langendorff technique. Results. LPS caused a time-dependent increase in both myocardial VCAM-1 exp ression and neutrophil accumulation. At 6 hours after LPS, the immunofluore scent intensity for VCAM-1 increased from 2.5 0.6 x 10(6) in saline solutio n controls to 19.9 +/- 3.5 x 10(6) (P < .05, analysis of variance), and neu trophil 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 de creased maximally at 6 hours after LPS compared with saline solution contro ls (29.1 +/- 1.1 mm Hg vs 53.1 +/- 3.9 mm Hg; P < .05). Treatment with TGAM -1 monoclonal antibody abrogated both myocardial neutrophil accumulation an d cardiac dysfunction during endotoxemia. Conclusions. LPS-induced myocardial dysfunction is associated with increase d expression of VCAM-1 and with neutrophil accumulation. Blockade of VCAM-1 abrogates myocardial neutrophil accumulation and preserves cardiac Junctio n during endotoxemia, which supports a role for VCAM-1 as a therapeutic tar get for myocardial protection during sepsis.