title: Global assessment of oxidized free fatty acids in brain reveals an enzymatic predominance to oxidative signaling after trauma.
abstract: Traumatic brain injury (TBI) is a major health problem associated with significant morbidity and mortality. The pathophysiology of TBI is complex involving signaling through multiple cascades, including lipid peroxidation. Oxidized free fatty acids, a prominent product of lipid peroxidation, are potent cellular mediators involved in induction and resolution of inflammation and modulation of vasomotor tone. While previous studies have assessed lipid peroxidation after TBI, to our knowledge no studies have used a systematic approach to quantify the global oxidative changes in free fatty acids. In this study, we identified and quantified 244 free fatty acid oxidation products using a newly developed global liquid chromatography tandem-mass spectrometry (LC-MS/MS) method. This methodology was used to follow the time course of these lipid species in the contusional cortex of our pediatric rat model of TBI. We show that oxidation peaked at 1h after controlled cortical impact and was progressively attenuated at 4 and 24h time points. While enzymatic and non-enzymatic pathways were activated at 1h post-TBI, enzymatic lipid peroxidation was the predominant mechanism with 15-lipoxygenase (LOX) contributing to the majority of total oxidized fatty acid content. Pro-inflammatory lipid mediators were significantly increased at 1 and 4h after TBI with return to basal levels by 24h. Anti-inflammatory lipid mediators remained significantly increased across all three time points, indicating an elevated and sustained anti-inflammatory response following TBI.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, United States; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States.
authors.forename: Tamil S
authors.initials: TS
authors.lastname: Anthonymuthu
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, United States; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Kenny
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, United States.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Amoscato
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, United States; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States.
authors.forename: Jesse
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, United States; Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, United States.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, United States.
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15261, United States; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15224, United States; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, United States; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, United States; Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, United States. Electronic address: bayihx@ccm.upmc.edu.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
mesh_terms: D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001923:Brain Chemistry / Q000276:immunology; D000070642:Brain Injuries, Traumatic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D005230:Fatty Acids, Nonesterified; D018836:Inflammation Mediators; D001093:Arachidonate 15-Lipoxygenase
keywords: Cardiolipin; Docosanoids; Eicosanoids; Lipid peroxidation; Octadecanoids; Pro-resolving mediators