CHEMOTACTIC 5-OXO-EICOSATETRAENOIC ACIDS INDUCE OXYGEN RADICAL PRODUCTION, CA2-MOBILIZATION, AND ACTIN REORGANIZATION IN HUMAN EOSINOPHILS VIA A PERTUSSIS-TOXIN-SENSITIVE G-PROTEIN()

The arachidonic acid metabolites 5-oxo-[6E,8Z,11Z,14Z]-eicosatetraenoi c acid (5oETE) and 5-oxo-15-hydroxy-[6E,8Z,11Z,13E]-eicosatetraen acid (5oHETE) are potent eosinophil chemotaxins. Here, the activation prof ile of 5-oxo-eicosanoids in eosinophils was further characterized and compared to other eosinophil activators such as complement fragment C5 a (C5a), platelet-activating factor (PAF), interleukin-5 (IL-5), and p horbol ester (PMA), Flow cytometric studies revealed a rapid and trans ient actin polymerization upon stimulation by both 5-oxo-eicosanoids. Desensitization studies using actin polymerization as the parameter in dicated cross-desensitization between the two 5-oxo-eicosanoids but re vealed no interference with the response to other chemotaxins. Fluores cence measurements with Fura-2-labeled eosinophils in the presence of EGTA indicated Ca2+-mobilization from intracellular stores by 5oETE an d 5oHETE, Both 5-oxo-eicosanoids stimulated the production of reactive oxygen metabolites as demonstrated by lucigenin-dependent chemilumine scence, superoxide dismutase-inhibitable cytochrome C reduction, and h ow cytometric dihydro-rhodamine-123 analysis. At optimal concentration s the changes induced by 5-oxo-eicosanoids were comparable to those ob tained by C5a and PAF, whereas IL-5 and PMA induced only a restricted pattern of cell responses, Cell responses elicited by 5-oxo-eicosanoid s were inhibited by pertussis toxin, indicating coupling of the putati ve 5-oxo-eicosanoid-receptor to G-proteins. These results indicate tha t 5-oxo-eicosanoids are stong activators of eosinophils with comparabl e biologic activity to the eosinophil chemotaxins C5a and PAF. These f indings point to a role of 5-oxo-eicosanoids in the pathogenesis of eo sinophilic inflammation as chemotaxins as well as activators of pro-in flammatory activities.