G. Cepinskas et al., TRANSENDOTHELIAL NEUTROPHIL MIGRATION - ROLE OF NEUTROPHIL-DERIVED PROTEASES AND RELATIONSHIP TO TRANSENDOTHELIAL PROTEIN MOVEMENT, Circulation research, 81(4), 1997, pp. 618-626
During an acute inflammatory response polymorphonuclear leukocytes (PM
Ns) adhere to and emigrate across the venular microvasculature. There
is general agreement on the mechanisms involved in PMN adhesive intera
ctions. However, the mechanisms by which PMNs migrate across the endot
helial lining remain controversial, particularly with respect to the r
ole of elastase. In the present study, we used human umbilical vein en
dothelial cells (HUVECs) and PMNs to test the hypothesis that the rela
tive role of PMN-derived elastase may be dependent on the degree of HU
VEC retraction within monolayers. A high (10(-7) mol/L), but not a low
(10(-10) mol/L), concentration of platelet-activating factor (PAF) ca
used HUVEC retraction of sufficient magnitude to increase transendothe
lial protein movement. Elastase inhibitors prevented PMN transendothel
ial migration in response to the low, but not the high, concentration
of PAF. These findings suggest that PMN migration across confluent end
othelial cells is elastase dependent, whereas PMN migration across ret
racted endothelial cells is elastase independent. However, under the l
atter condition (high concentration of PAF), the two endogenous protea
ses, alpha(2)-macroglobulin and alpha(1)-antitrypsin, could interfere
with PAF-induced PMN transendothelial migration. Thus, as the concentr
ation of PAF is increased, migrating PMNs use other proteases, in addi
tion to elastase. We also noted that transendothelial protein movement
is closely coupled to PMN migration.