EFFECT OF ENDOTHELIN-1 ON NEUTROPHIL ADHESION TO ENDOTHELIAL-CELLS AND PERFUSED HEART

Background. Based on recent evidence showing that endothelin-1 stimula tes several activation mechanisms on neutrophils, the aim of the prese nt study was to analyze the effects of endothelin-I on neutrophil adhe sion to endothelial cells and neutrophil accumulation in the heart. Me thods and Results. The experiments included (1) adhesion of Cr-51-labe led human neutrophils to bovine endothelial cells in culture both in t he presence and absence of monoclonal antibodies against the alpha- an d beta-subunits of integrins; (2) surface expression of the alpha- and beta-integrin antigens; (3) accumulation of Cr-51-labeled neutrophils on the isolated perfused rabbit heart; (4) in vivo accumulation of au tologous neutrophils in the heart, as assessed by myeloperoxidase acti vity. Endothelin-1 stimulated neutrophil adhesion to endothelial cells (increase of 1x10(5)+/-1x10(4) neutrophils per well). The endothelin- 1-induced adhesion was blocked (83+/-6%) by the anti-CD18 antibody TS1 /18 and by several anti-alpha-subunit antibodies. The expression of CD 18 and CD11b on the neutrophil surface was also increased by endotheli n-1. Endothelin-1 enhanced neutrophil accumulation in the isolated rab bit heart by 4.2 times throughout a TS1/18-inhibitable mechanism. Myel operoxidase activity increased by 4.2 times in hearts infused in vivo with endothelin-1. Conclusions. Endothelin-1 stimulates neutrophil adh esion to endothelial cells by an effect on the expression of adhesive molecules on the neutrophil surface. Endothelin-1 stimulates neutrophi l accumulation in vivo and in vitro in the heart Antibodies against th e integrin complex block the endothelin-1-dependent neutrophil adhesio n. These findings have potential importance in the pathophysiology of endothelin-1-increased states.