MEDIATION OF ENDOTHELIAL INJURY FOLLOWING NEUTROPHIL ADHERENCE TO EXTRACELLULAR-MATRIX

Since polymorphonuclear leukocytes (PMN) rapidly migrate across the en dothelial barrier and attach to extracellular matrix components, we te sted the hypothesis that adhesion of PMN to matrix proteins can mediat e endothelial injury following PMN activation. Studies were made using gelatin- and fibronectin-coated polycarbonate microporous filters (10 mum thick) on which confluent monolayers of bovine pulmonary microves sel endothelial cells were grown. PMN were layered either directly ont o endothelial cells (at a ratio of 10:1) (''upright system'') or onto gelatin- and fibronectin-coated filters with the endothelial monolayer grown on the underside of the filter without contact between PMN and endothelial cells (''inverted system''). PMN were activated with phorb ol 12-myristate 13-acetate (PMA; 5 x 10(-9) M) in both systems. PMN ac tivation increased endothelial permeability to I-125-labeled albumin i n upright as well as inverted systems. Pretreatment of PMN with anti-C D18 monoclonal antibodies IB4 or R15.7, which inhibited PMN adherence to matrix constituents as well as to endothelial cells, prevented the permeability increase in both configurations. This effect of anti-CD18 monoclonal antibodies (mAbs) was not ascribed to a reduction in PMN a ctivation, since PMA-induced superoxide generation was unaffected. We conclude that activation of PMN adherent to extracellular matrix prote ins increases endothelial permeability to albumin and that this respon se is dependent on PMN adhesion to the matrix. The results support the concept that PMN-mediated increase in endothelial permeability is the result of ''targeted'' release of PMN products independent of whether the PMN are adherent to the extracellular matrix or the endothelium.