T. Furuno et al., THE ROLE OF NEUTROPHIL ELASTASE IN HUMAN PULMONARY-ARTERY ENDOTHELIAL-CELL INJURY, International archives of allergy and immunology, 112(3), 1997, pp. 262-269
Neutrophils are thought to play a key role in tissue injury. We invest
igated the role of human neutrophil-derived elastase in the induction
of injury to human pulmonary artery endothelial cells. Incubation of e
ndothelial cells with neutrophils increased the release of lactate deh
ydrogenase activity, thrombomodulin, and preloaded fura-2 from endothe
lial cells, indicating that neutrophils induce endothelial cell injury
. Attachment alone of neutrophils to endothelial cells appeared to ind
uce activation because elastase release and N-formyl-mentionyl-leucyl-
phenylalanine (fMLP)-induced superoxide (O-2(-)) production from neutr
ophils incubated with endothelial cells were greater than from neutrop
hils only. When endothelial cell were incubated with neutrophils stimu
lated by fMLP or phorbol myristate acetate, the amount of elastase in
the medium and endothelial cell damage was further enhanced. However w
hen neutrophils were blocked from direct attachment to endothelial cel
ls using a membrane filter, endothelial cell damage was ameliorated, w
hile exogenous neutrophil elastase and medium containing neutrophil-re
leased elastase did not induce endothelial cell injury. An inhibitor o
f neutrophil elastase, ONO-5046 Na, as well as erythromycin, which red
uces neutrophil-derived elastase, dramatically inhibited neutrophil-in
duced endothelial cell injury. Superoxide dismutase (SOD) partially in
hibited injury. Injury was completely inhibited by treatment with a co
mbination of ONO-5046 Na and SOD. These results suggest that attachmen
t of neutrophils to endothelial cells is important for endothelial cel
l damage and that neutrophil-derived elastase plays an important role
in endothelial cell injury in combination with O-2(-). In addition, ON
O-5046 Na and erythromycin may be useful in treating diseases worsened
by excessive neutrophil activity.