Because vascular smooth muscle cells (SMC) can be exposed to platelets at sites of significant arterial injury, we studied whether cultured rat aorta SMC can utilize platelet-derived arachidonate and prostaglandin (PG) endoperoxides (PGG2/PGH2) in the synthesis of prostacyclin (PGI2). SMC converted exogenous PGH2 to PGI2, measured by radioimmunoassay (RIA) of 6-keto-PGF1 alpha, despite cyclooxygenase inhibition or PGH2-receptor blockade. SMC produced increasing amounts of PGI2 in the presence of an increasing number of platelets when the two cell types were coincubated with arachidonate. Furthermore, aspirin-pretreated SMC produced PGI2 in response to arachidonate, ionophore A23187, or thrombin in the presence of platelets but not in their absence. SMC, by themselves unresponsive to thrombin, produced PGI2 during coincubation with thrombin-stimulated aspirin-pretreated platelets. Separation of the SMC monolayer and platelets with a filter did not prevent platelet-dependent PGI2 formation by the SMC. Finally, aspirin-pretreated SMC, in cosuspension with platelets, inhibited platelet aggregation in association with PGI2 production. These data indicate that 1) SMC can synthesize PGI2 from exogenously added PGH2 and from platelet-derived arachidonate or endoperoxides, 2) direct cell-cell contact is not required for intercellular endoperoxide transfer, and 3) SMC can inhibit platelet aggregation possibly through PGI2 production from platelet-derived endoperoxides.
IL-8 has been characterized primarily as a polymorphonuclear leukocyte (PMN) chemoattractant and proinflammatory mediator. Recently, we have reported that [Ala-IL-8]77 is secreted by activated cultured human endothelial cells and can function as a potent inhibitor of PMN adhesion to these monolayers. The pathophysiologic relevance of this in vitro observation was examined by determining the effects of intravascular or extravascular administration of IL-8 on PMN emigration at sites of acute inflammation in the skin of NZW rabbits. An i.v. bolus of [Ala-IL-8]77 (12 micrograms/kg) produced a marked and selective reduction of circulating PMN within 3 min, which returned toward preinjection levels within 30 min, and subsequently exceeded this level. A similar response was observed for circulating radiolabeled PMN, and gamma-scintigraphy determined that the lungs were the primary site of leukosequestration. During the 30- to 150-min interval after i.v. infusion of [Ala-IL-8]77, PMN emigration into acute inflammatory sites, elicited by various chemoattractants or cytokines, was significantly reduced, as judged histologically and quantitated with 51Cr-labeled PMN and myeloperoxidase measurements. Intravenous administration of [Ser-IL-8]72 yielded similar results. This inhibitory effect of i.v. IL-8 was transient and reinducible and did not reflect a suppression of the responsiveness of circulating PMN to chemoattractants. Intradermal injections of [Ala-IL-8]77 or [Ser-IL-8]72 induced dose-dependent PMN accumulation, which also was significantly reduced by i.v. administration of either form of IL-8. These results indicate that i.v. IL-8 can function as a PMN-directed leukocyte adhesion inhibitor and suggest that local secretion of IL-8 by activated endothelium may differentially modulate leukocyte-endothelial interactions at sites of acute inflammation.
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