DIFFERENTIAL-EFFECTS OF THE ANTIINFLAMMATORY COMPOUNDS HEPARIN, MANNOSE-6-PHOSPHATE, AND CASTANOSPERMINE ON DEGRADATION OF THE VASCULAR BASEMENT-MEMBRANE BY LEUKOCYTES, ENDOTHELIAL-CELLS, AND PLATELETS

Recent studies suggest that heparin, mannose-6-phosphate (M6P), and ca stanospermine (CS) may mediate their anti-inflammatory effects by inhi biting the passage of leukocytes through the subendothelial basement m embrane (BM). In order to test this hypothesis, heparin, M6P, and CS w ere examined for their ability to prevent the in vitro degradation of a (SO4)-S-35-labeled extracellular matrix (ECM) by neutrophils, lympho cytes, endothelial cells (ECs), and platelets, the labeled ECM degrada tion products being analyzed by gel filtration chromatography. ALL thr ee compounds inhibited (SO4)-S-35-labeled ECM degradation, but M6P and CS were cell-type specific in their effects. Heparin inhibited the he paranase activity of all cell types examined, confirming the results o f previous studies using similar in vitro techniques. M6P selectively inhibited lymphocyte heparanase but not that of platelets, neutrophils , or ECs. CS selectively inhibited phorbol myristate acetate (PMA)-ind uced EC heparanase and sulfatase activity but did not affect the const itutive expression of degradative enzymes by nonstimulated ECs. These findings provide important clues to the mode of action of these compou nds and the characteristic inflammatory pathology associated with the use of each anti-inflammatory agent. In particular, the data support t he view that leukocytes markedly differ in the mechanisms they use to degrade BM/ECM to enable extravasation and that some degree of coopera tion with EC is required in this process.