Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition
Introduction
Athletes competing in marathons and ultramarathons experience large increases in plasma cytokine levels including interleukin (IL)-6, IL-10, IL-1ra, IL-8, granulocyte colony-stimulating factor or G-CSF, monocyte chemotactic protein 1 or MCP-1, and macrophage inflammatory protein 1 beta or MIP-1β) (Nieman et al., 2001, Nieman et al., 2002, Nieman et al., 2003, Nieman et al., 2005, Ostrowski et al., 2000, Suzuki et al., 2000, Suzuki et al., 2002).
Exercise-induced increases in these cytokines vary substantially between athletes (Nieman et al., 2001, Nieman et al., 2005). Potential triggers of cytokine release during exercise include leakage of endotoxins (lipopolysaccharide or LPS) from the intestines during exercise, elevation in catecholamines and cortisol, high core body temperature, glycogen deficiency, and other metabolic demands, oxidative stress, and muscle damage (Bruunsgaard et al., 1997, Camus et al., 1997, Camus et al., 1998, Jeukendrup et al., 2000, Nieman et al., 2001, Nieman et al., 2002, Nieman et al., 2003, Nieman et al., 2005, Ostrowski et al., 2000, Steensberg, 2003, Steinacker et al., 2004, Suzuki et al., 2000, Suzuki et al., 2002).
We recently reported that muscle damage, perceptions of muscle soreness, and plasma levels of several inflammatory cytokines were positively correlated in ultramarathon athletes following a 160-km race event (Nieman et al., 2005). Unexpectedly, pre-to-post race changes in IL-6, IL-8, G-CSF, MCP-1, and MIP-1β were two to three times greater in runners reporting use of non-steroidal anti-inflammatory drugs (NSAIDs) during the race compared to nonusers. Plasma creatine kinase (CK) levels and post-race delayed onset of muscle soreness (DOMS) did not differ between NSAID users and nonusers. A majority of other investigators have also reported no beneficial effect of NSAIDs in alleviating muscle soreness and damage after contraction-induced muscle injury (Donnelly et al., 1990, Peterson et al., 2003, Trappe et al., 2002).
We are unaware of other published studies indicating elevated cytokines in NSAID users compared to nonusers following ultramarathons. Increased gastrointestinal permeability and translocation of bacterial lipopolysaccharide (LPS) from the intestines into the circulation (i.e., endotoxemia) due to splanchnic ischemia and hyperthermia have been reported in athletes following prolonged endurance events (Bosenberg et al., 1988, Brock-Utne et al., 1988, Jeukendrup et al., 2000, Lambert, 2004, Lambert et al., 2001, Van Nieuwenhoven et al., 2004). Gastrointestinal permeability is amplified in marathoners using ibuprofen and other NSAIDS compared to nonusers (Ryan et al., 1996, Smetanka et al., 1999). Camus et al. (1998) demonstrated a relationship between exercise-induced endotoxemia and TNF-α. Thus NSAID use during ultramarathons may augment cytokine increases by inducing endotoxemia, but these relationships have not yet been verified using appropriate research designs. Ibuprofen ingestion has a small but significant effect in decreasing glomerular filtration rate during exercise suggesting that kidney clearance of various factors including cytokines is reduced (Farquhar et al., 1999).
In our previous study showing a linkage between ibuprofen use and elevated plasma cytokines, the ibuprofen dose was not controlled or reported, and the major objective was to establish a relationship between muscle damage and post-race cytokine levels (Nieman et al., 2005). As a follow-up to this study, we designed a study in which athletes used 600 and 1200 mg ibuprofen the day before and during the race, respectively, and compared inflammatory parameters, plasma cytokines, urine creatinine, and LPS with nonusers. We hypothesized that ibuprofen use during a 160-km race would augment endotoxemia leading to increased systemic inflammation and plasma cytokine levels.
Section snippets
Subjects and race description
Sixty-three experienced male and female ultramarathoners from the 2005 Western States 100 Mile Endurance Run were recruited and provided pre-race blood and urine samples. Athletes were placed into ibuprofen (n = 33) and control groups (n = 30) based on their historical use during training and competition, and their willingness to use or avoid ibuprofen before and during the race. Permission for a randomized, placebo controlled research design was not granted by the race medical board because of
Results
Fifty-four of 63 subjects completed the 160-km race event. Air temperature was 10 °C at the start of the race (Squaw Valley, CA), 25 °C by 2:00 pm (Michigan Bluff), 15 °C by 12:00 am (race finish, Auburn, CA), and 11 °C by 10:00 am. The average humidity during the last half of the race was 56%. Subject characteristics for ibuprofen and control groups are compared in Table 1, and indicate no significant differences in age, body composition, training and racing history, and race time. Male (n = 43) and
Discussion
Ibuprofen use compared to nonuse the day before (600 mg) and during (1200 mg) a 160-km race by ultramarathon athletes was associated with 25–88% higher plasma levels of seven cytokines, and significant elevations in blood neutrophils counts and serum CRP, ALT, AST, and BUN. Pre- and post-race plasma LPS combined was 106% higher in the ibuprofen compared to control athletes, and was positively correlated with CRP, cortisol, and three of eight cytokines measured in this study. No differences in
Acknowledgments
Supported by the Gatorade Sports Science Institute, 160-km Western States Endurance Run Medical Board, and National Institutes of Health Grants (to J.D. Morrow) DK-48831, GM-15431, CA-77839, and RR00095. J.D. Morrow is the recipient of a Burroughs Wellcome Fund Clinical Scientist Award in Translational Research. Fischer/Nycom Laboratory.
References (27)
- et al.
Muscle damage is linked to cytokine changes following a 160-km race
Brain, Behavior, and Immunity
(2005) - et al.
Strenuous exercise causes systemic endotoxemia
Journal of Applied Physiology
(1988) - et al.
Endotoxemia in exhausted runners after a long-distance race
South African Medical Journal
(1988) - et al.
Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage
Journal of Physiology
(1997) - et al.
Mild endotoxemia and the inflammatory response induced by a marathon race
Clinical Science (London)
(1997) - et al.
Endotoxemia, production of tumor necrosis factor alpha and polymorphonuclear neutrophil activation following strenuous exercise in humans
European Journal of Applied Physiology and Occupational Physiology
(1998) - et al.
Calculation of percentage changes in volumes of blood, plasma, and red cells in dehydration
Journal of Applied Physiology
(1974) - et al.
Effects of ibuprofen on exercise-induced muscle soreness and indices of muscle damage
British Journal of Sports Medicine
(1990) - et al.
Effect of acetaminophen and ibuprofen on renal function in the stressed kidney
Journal of Applied Physiology
(1999) - et al.
Relationship between gastro-intestinal complaints and endotoxemia, cytokine release and the acute-phase reaction during and after a long-distance triathlon in highly trained men
Clinical Science
(2000)
Role of gastrointestinal permeability in exertional heatstroke
Exercise and Sport Science Review
Gastrointestinal permeability during exercise, effects of aspirin and energy-containing beverages
Journal of Applied Physiology
Immune and oxidative changes during and following the Western States Endurance Run
International Journal of Sports Medicine
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