title: 5-Hydroxyeicosatetraenoic acid (HETE)-induced neutrophil transcellular migration is dependent upon enantiomeric structure.
abstract: The 5(R) and 5(S) hydroxyeicosatetraenoic acids (5[R]-HETE, 5[S]-HETE) are important inflammatory mediators in lung diseases: they increase mucus, induce airway contraction, and potentiate neutrophil chemotaxis. Neutrophils are important cells in allergic and inflammatory lung diseases. Therefore, we examined the effects of both 5(R)-HETE and 5(S)-HETE on human neutrophil migration across naked filters and human umbilical vein endothelial (HUVE) cell and human type II-like pulmonary epithelial cell (A549) monolayers cultured on these filters. Time courses for both 5(R)-HETE and 5(S)-HETE show significant neutrophil migration at 40 min and maximal migration at 60 to 90 min through all three barriers. Checkerboard analysis showed that migration was chemotactic. Dose-response curves for both isomers through cellular monolayers had the same shapes, but 5(R)-HETE was more potent than 5(S)-HETE. There was greater migration through cellular barriers than through naked filters. Actinomycin D pretreatment of the cellular monolayers slightly inhibited the neutrophil transcellular chemotactic response to both 5-HETEs equally. Enhanced transcellular migration was not due to the production of a soluble chemotactic factor. Thus, although both isomers of 5-HETE were potent chemotactic agents, 5(R)-HETE was slightly more potent. Moreover, relevant endothelial and epithelial monolayers enhance both dose- and time-dependent neutrophil migration stimulated by 5(R)-HETE and 5(S)-HETE. These data indicate that (1) both 5(R)-HETE and 5(S)-HETE are important in mediating lung inflammatory processes, and (2) 5(R)-HETE may play a more important role in neutrophil-rich lung inflammatory responses than 5(S)-HETE because it is a more potent inducer of neutrophil migration through endothelial and epithelial barriers.
authors.affiliation: Department of Internal Medicine, VA Medical Center, Iowa City, Iowa.
authors.forename: D B
authors.initials: DB
authors.lastname: Bittleman
authors.forename: T B
authors.initials: TB
authors.lastname: Casale
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry* / Q000494:pharmacology; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects*; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D003609:Dactinomycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid