Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

Abstract

Classical proinflammatory eicosanoids, and more recently discovered lipid mediators with anti-inflammatory and proresolving bioactivity, exert a complex role in the initiation, control, and resolution of inflammation. Using a targeted lipidomics approach, we investigated circulating lipid mediator responses to resistance exercise and treatment with the NSAID ibuprofen. Human subjects undertook a single bout of unaccustomed resistance exercise (80% of one repetition maximum) following oral ingestion of ibuprofen (400 mg) or placebo control. Venous blood was collected during early recovery (0 -3 h and 24 h postexercise), and serum lipid mediator composition was analyzed by LC-MS-based targeted lipidomics. Postexercise recovery was characterized by elevated levels of cyclooxygenase (COX)-1 and 2-derived prostanoids (TXB2, PGE2, PGD2, PGF2␣, and PGI2), lipooxygenase (5-LOX, 12-LOX, and 15-LOX)-derived hydroxyeicosatetraenoic acids (HETEs), and leukotrienes (e.g., LTB4), and epoxygenase (CYP)-derived epoxy/dihydroxy eicosatrienoic acids (EpETrEs/DiHETrEs). Additionally, we detected elevated levels of bioactive lipid mediators with anti-inflammatory and proresolving properties, including arachidonic acid-derived lipoxins (LXA4 and LXB4), and the EPA (E-series) and DHA (D-series)-derived resolvins (RvD1 and RvE1), and protectins (PD1 isomer 10S, 17S-diHDoHE). Ibuprofen treatment blocked exercise-induced increases in COX-1 and COX-2-derived prostanoids but also resulted in off-target reductions in leukotriene biosynthesis, and a diminished proresolving lipid mediator response. CYP pathway product metabolism was also altered by ibuprofen treatment, as indicated by elevated postexercise serum 5,6-DiHETrE and 8,9-DiHETrE only in those receiving ibuprofen. These findings characterize the blood inflammatory lipid mediator response to unaccustomed resistance exercise in humans and show that acute proinflammatory signals are mechanistically linked to the induction of a biological active inflammatory resolution program, regulated by proresolving lipid mediators during postexercise recovery. eicosanoid; exercise; inflammation; nonsteroidal anti-inflammatory drug; resolution LIPID MEDIATORS ARE A DIVERSE class of bioactive autocrine/ paracrine signaling molecules that are synthesized endogenously from essential omega-6 and omega-3 fatty acids. Oxidation of free fatty acid substrates via cyclooxygenase (COX-1 and COX-2), lipoxygenase (5-LOX, 12-LOX, and 15-LOX), epoxygenase (CYP), and nonenzymatic pathways, produces a potential array of more than 100 distinct lipid mediators. Bioactive lipid mediators are involved in a wide range of physiological and pathological processes, one of the best characterized of which is their key role in the inflammatory response (reviewed in Ref. 91). Classical eicosanoids derived from omega-6 arachidonic acid (AA, -6 20:4), including prostaglandins (PGs; synthesized via COX-1 and COX-2) and leukotrienes (LTs, synthesized via 5-LOX), are well established proinflammatory signaling molecules that stimul...

Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro-resolving lipid mediators and their precursors

“…The amounts of SPMs detected in this study would equate to low-mid nanomolar tissue concentrations, which are biologically significant. SPMs and their precursors have also previously been detected in normal human plasma and lymphoid organs (Mas et al 2012, Markworth et al 2013, Colas et al 2014 and in human milk (Weiss et al 2013). Similar to our studies, markedly higher concentrations of the primary Rv precursors, 17-HDHA and 18-HEPE, were detected in these studies compared with their downstream products.…”

“…Circulating SPMs have been measured in healthy subjects (Mas et al 2012), with concentrations shown to be associated with n-3 PUFA intake (Colas et al 2014) and produced in greater amounts after exercise in patients taking ibuprofen (Markworth et al 2013). SPMs have been measured in breast milk (Weiss et al 2013), but to date have not been investigated in the context of human pregnancy.…”

Exercise and the Regulation of Inflammatory Responses

“…Evidence of this stems from studies showing that the nonsteroidal anti-inflammatory drugs disrupt both the early translational responses within skeletal muscle 23 and the resolving lipid mediator response. 24 A dynamic, time-dependent polarization of macrophages during the tissue repair process further exemplifies the importance of the initial inflammatory response to exercise. A switch from an initial M1 proinflammatory phenotype 24 h after eccentric exercise, to an M2, antiinflammatory phenotype 48-72-h after exercise, characterizes this phenomenon.…”

Metabolomics approach to assessing plasma 13- and 9-hydroxy-octadecadienoic acid and linoleic acid metabolite responses to 75-km cycling

“…Little information has been published on the influence of exercise on plasma 13-HODE ϩ 9-HODE, and whether postexercise increases relate to changes in established biomarkers of oxidative stress and inflammation (19,20). Using a metabolomics approach, we recently reported that plasma 13-HODE ϩ 9-HODE increased 5.5-fold in 15 runners following a 3-day period of intensified training (2.5 h/day running at 70% V O 2max ), with levels returning to preexercise levels after 14-h recovery (20).…”