TRANSENDOTHELIAL NEUTROPHIL MIGRATION - ROLE OF NEUTROPHIL-DERIVED PROTEASES AND RELATIONSHIP TO TRANSENDOTHELIAL PROTEIN MOVEMENT

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.