MIGRATION OF NEUTROPHILS FROM BLOOD TO TISSUE - ALTERATION OF MODULATORY EFFECTS OF PROSTANOID ON SUPEROXIDE GENERATION IN RABBITS AND HUMANS

Alteration of neutrophil function is associated with their migration f rom blood into tissue. We evaluted this alteration in both human and r abbit neutrophils, by comparing the inhibitory effects of prostanoids on formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide g eneration in human circulating blood neutrophils with those in saliva, and also comparing rabbit circulating blood neutrophils with those ex udated into peritoneal cavity. We showed that EP-receptor agonists (PG E(1)), EP(2)/EP(3) agonist (misoprostol), EP(2)-receptor agonist (buta prost) and DP-receptor agonist (PGD(2)) inhibited fMLP-stimulated supe roxide production from human blood neutrophils in a concentration-depe ndent manner. In contrast, these prostanoids produced a significantly smaller maximum inhibition of fMLP-stimulated superoxide production in salivary neutrophils compared to those in blood neutrophils. Similar differences were observed for rabbit blood and peritoneal neutrophils. The inhibitory effect of EP(2) agonist (butaprost) on the fMLP-stimul ated superoxide generation in human blood neutrophils was significantl y higher than that of EP(3) agonist (ONO-AP-324). The EP(1) antagonist (SC-51322) and EP(4) antagonist (AH23848B) employed in this study cou ld not antagonize the inhibitory effect of PGE(2). TP agonist (U-46619 ) failed to show any inhibitory effect in either blood or salivary neu trophils. These results indicated that EP(2) and DP receptors are the primary receptors mediating the prostanoids inhibition of fMLP-stimula ted superoxide generation from neutrophils. Furthermore, it can be con cluded that neutrophils become less responsive to prostanoids in terms of fMLP-stimulated superoxide production in association with their mi gration from blood to tissue.