Cell adhesion molecule mediates endothelial cell injury caused by activated neutrophils.
Addition of PMA (phorbol myristate acetate)-stimulated neutrophils to an endothelial cell monolayer caused a significant increase in the intracellular peroxide level of the endothelial cells after 15 minutes and endothelial cell injury after 5 hours. Both the early and the late events were abolished in the presence of specific antibodies against CD (cluster of differentiation) 11a, CD11b, CD18 and ICAM (intercellular adhesion molecule) 1, but not CD11c. These antibodies affected neither the production of active oxygen species by the neutrophils nor the rate of adhesion of neutrophils to endothelial cells. Pretreatment of endothelial cells with allopurinol caused significant inhibition of both the early and the late events, suggesting that the binding of adhesion molecules may trigger the activation of XO (xanthine oxidase) of endothelial cells, and have the cells produce more hydrogen peroxide and ferrous ions, followed by producing more hydrogen peroxide. The hydrogen peroxide produced by endothelial cells themselves and by neutrophils may be converted to hydroxyl radicals by ferrous ions, which may cause lethal cell damage. Examination of XO activity in endothelial cells showed that the enzyme activity increased double within 15 minutes after the addition of PMA activated neutrophils. Monoclonal antibodies against CD11a and CD18 significantly inhibited the increased conversion of XD (xanthine dehydrogenase) to XO induced by PMA-activated neutrophils. Moreover, tyrosine kinase inhibitors also inhibited the increased conversion of XD to XO. These results indicate that the adhesion of activated neutrophils to endothelial cells via CD11a/CD18-ICAM-1 is involved in the conversion of XD to XO in endothelial cells, which results in endothelial cell injury.
Department of Physiological Chemistry, Graduate School, Tokyo Medical and Dental University, Japan.
S
S
Murota
H
H
Fujita
Y
Y
Wakabayashi
I
I
Morita
D000818:Animals; D002417:Cattle; D015815:Cell Adhesion Molecules / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D018375:Neutrophil Activation; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D015815:Cell Adhesion Molecules; D013755:Tetradecanoylphorbol Acetate