title: Modulating phosphatidic acid metabolism decreases oxidative injury in rat lungs.
abstract: We determined that lisofylline, a potent inhibitor of oleate- and linoleate-containing phosphatidic acid formation (half-maximal inhibitory concentration = 40 nM), prevented oxidant-mediated capillary leak in isolated rat lungs given interleukin-8 (IL-8) intratracheally and perfused with human neutrophils. Lung leak was prevented by lung, but not neutrophil, lisofylline pretreatment. Furthermore, although lisofylline inhibited IL-8-stimulated neutrophil production of phosphatidic acid in vitro, it did not prevent IL-8-stimulated neutrophil adherence, chemotaxis, or intracellular calcium mobilization or N-formyl-Met-Leu-Phe (fMLP)-stimulated oxidant production in vitro. Lisofylline also prevented acute capillary leak in isolated rat lungs perfused only with the oxidant generator purine-xanthine oxidase but did not scavenge O2-(+) or H2O2 in vitro. Finally, lisofylline-mediated protection against lung leak in both models was associated with alterations in lung membrane free fatty acid acyl composition (as reflected by the decreased ratio [linoleate + oleate]/[palmitate]). We conclude that lisofylline prevented both neutrophil-dependent and neutrophil-independent oxidant-induced capillary leak in isolated rat lungs and that protection appears to be mediated by blocking intrinsic lung linoleoyl phosphatidic acid metabolism. We speculate that lisofylline, in addition to our previously reported effects on cytokine signaling by intrapulmonary mononuclear cells, alters intrinsic pulmonary capillary membrane composition and renders this barrier less vulnerable to oxidative damage.
authors.affiliation: Webb Waring Institute for Biomedical Research, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Guidot
authors.forename: S L
authors.initials: SL
authors.lastname: Bursten
authors.forename: G C
authors.initials: GC
authors.lastname: Rice
authors.forename: R B
authors.initials: RB
authors.lastname: Chaney
authors.forename: J W
authors.initials: JW
authors.lastname: Singer
authors.forename: A J
authors.initials: AJ
authors.lastname: Repine
authors.forename: B M
authors.initials: BM
authors.lastname: Hybertson
authors.forename: J E
authors.initials: JE
authors.lastname: Repine
mesh_terms: D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016209:Interleukin-8 / Q000494:pharmacology; D019787:Linoleic Acid / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000502:physiology*; D019301:Oleic Acid / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D010477:Perfusion; D010712:Phosphatidic Acids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013481:Superoxides / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D010712:Phosphatidic Acids; D013481:Superoxides; D019301:Oleic Acid; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019787:Linoleic Acid; D006861:Hydrogen Peroxide; C025189:lisofylline; D010431:Pentoxifylline