Differential effects of the anti-inflammatory 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 castanospermine (CS) may mediate their anti-inflammatory effects by inhibiting the passage of leukocytes through the subendothelial basement membrane (BM). In order to test this hypothesis, heparin, M6P, and CS were examined for their ability to prevent the in vitro degradation of a 35SO4-labeled extracellular matrix (ECM) by neutrophils, lymphocytes, endothelial cells (ECs), and platelets, the labeled ECM degradation products being analyzed by gel filtration chromatography. All three compounds inhibited 35SO4-labeled ECM degradation, but M6P and CS were cell-type specific in their effects. Heparin inhibited the heparanase activity of all cell types examined, confirming the results of 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)-induced EC heparanase and sulfatase activity but did not affect the constitutive expression of degradative enzymes by non-stimulated ECs. These findings provide important clues to the mode of action of these compounds and the characteristic inflammatory pathology associated with the use of each anti-inflammatory agent. In particular, the data support the view that leukocytes markedly differ in the mechanisms they use to degrade BM/ECM to enable extravasation and that some degree of cooperation with EC is required in this process.
Division of Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra.
M R
MR
Bartlett
W B
WB
Cowden
C R
CR
Parish
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001485:Basement Membrane / Q000187:drug effects / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology*; D002417:Cattle; D004728:Endothelium, Corneal / Q000166:cytology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D007212:Indolizines / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008360:Mannosephosphates / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D013431:Sulfates / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D054836:Indolizidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006493:Heparin; D007212:Indolizines; D008360:Mannosephosphates; D013431:Sulfates; D013462:Sulfur Radioisotopes; D013755:Tetradecanoylphorbol Acetate; C027693:mannose-6-phosphate; C037806:castanospermine; D054836:Indolizidines