Cardiac Surgery With Extracorporeal Circulation: Neutrophil Transendothelial Migration Is Mediated by β1 Integrin (CD29) in the Presence of TNF-Alpha

Abstract

Cardiac surgery with extracorporeal circulation is associated with neutrophil activation, inflammation, and edema. Endothelial hyperpermeability elicited by the interaction of activated neutrophils and/or cytokines with endothelial cells may be critical in this regard. However, the immune and cellular mechanisms involved are not fully understood. Cocultures with human endothelial cells and neutrophils from cardiac surgery patients were used to evaluate the role of β1 integrin activity and the proinflammatory cytokine tumor necrosis factor (TNF)-α in neutrophil transendothelial migration and in impairment of the integrity of endothelial cell-to-cell contacts. Blocking of CD29 (heavy chain of β1 integrins) totally prevented neutrophil adhesion and transendothelial migration. Pretreatment of neutrophils with either a CD29-stimulating monoclonal antibody or the addition of TNF-α (0.1–10 U/ml) to the coculture failed to induce transendothelial migration. However, coculture of endothelial cells with CD29-stimulated neutrophils in the presence of 0.1–10 U/ml TNF-α strongly induced neutrophil transmigration. CD29/TNF-α-mediated transmigration was associated with intracellular redistribution of endothelial β-catenin. We further showed that CD29/TNF-α-mediated effects involved PI3K and tyrosine kinase-dependent signaling via MAPK but were independent of nuclear transcription factor (NF)-κB activity. Inhibition of CD29/TNF-α might be a therapeutic option to limit endothelial dysfunction following cardiac surgery with extracorporeal circulation.

KEYWORDS:

• extracorporeal circulation
• integrins
• neutrophils