Human endothelial cells inhibit granulocyte aggregation in vitro.
Granulocyte aggregation in response to circulating or locally released inflammatory mediators may cause vascular injury. The factors that regulate the granulocyte aggregation response and prevent its occurrence are not defined. We found that primary monolayers of human endothelial cells (EC) derived from umbilical veins released products that inhibited granulocyte aggregation. When polymorphonuclear leukocytes (PMN) and EC were incubated together, the subsequent aggregation response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) was inhibited by 40 to 60%, depending in part on the duration of incubation and the concentration of the agonist. Suspension of the granulocytes in albumin-containing buffer that had been rocked with EC monolayers had a similar effect, demonstrating that the EC release a soluble product that modulates the aggregation response. The fMLP concentration-response curve was shifted downward and to the right by EC. Incubation of the granulocytes with endothelial monolayers for various times indicated that the inhibition was maximal at 2 to 3 min, and the PMN responsiveness returned to control over the next 15 min. The inhibiting effect was not selectively directed against fMLP, because incubation of PMN with EC or suspending the PMN in supernatants from endothelial monolayers also inhibited aggregation stimulated by platelet-activating factor, leukotriene B4, and C5a desarg. Release of the inhibitory activity by EC was attenuated by indomethacin, suggesting that the activity is in part due to a cyclooxygenase pathway product. Prostacyclin (PGI2), an eicosanoid produced by EC via the cyclooxygenase pathway, inhibited granulocyte aggregation; however, PGI2 was much less potent as an inhibitor of PMN aggregation than of platelet aggregation. Furthermore, the concentration of PGI2 in buffer that had been incubated with EC was not sufficient to account for the magnitude of the PMN inhibition. The concentration of prostaglandin E2 (PGE2) was also insufficient to completely account for the inhibition. EC that had been treated with indomethacin or aspirin, which blocked the release of PGI2 and PGE2, retained the partial ability to release an activity that blunted granulocyte aggregation; this inhibiting activity was stable at 37 degrees C for 60 min. The results indicate that human EC have the biologic potential to modulate granulocyte aggregation stimulated by inflammatory mediators, and the activity is only partly due to PGI2 and other cyclooxygenase products of arachidonic acid.(ABSTRACT TRUNCATED AT 400 WORDS)
D001779:Blood Coagulation Factors / Q000494:pharmacology; D002449:Cell Aggregation / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone; D004727:Endothelium / Q000502:physiology*; D011464:Epoprostenol / Q000378:metabolism / Q000494:pharmacology; D006098:Granulocytes / Q000166:cytology*; D006801:Humans; D066298:In Vitro Techniques; D007975:Leukotriene B4 / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010972:Platelet Activating Factor; D010974:Platelet Aggregation / Q000187:drug effects; D011458:Prostaglandins E / Q000378:metabolism; D013189:SRS-A / Q000494:pharmacology
D001779:Blood Coagulation Factors; D010972:Platelet Activating Factor; D011458:Prostaglandins E; D013189:SRS-A; D007975:Leukotriene B4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011464:Epoprostenol; D015232:Dinoprostone