Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition

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Abstract

The primary purpose of this study was to measure the influence of ibuprofen use during the 160-km Western States Endurance Run on endotoxemia, inflammation, and plasma cytokines. Subjects included 29 ultramarathoners who consumed 600 and 1200 mg ibuprofen the day before and on race day, respectively, and 25 controls that competed in the race but avoided ibuprofen and all other medications. Blood and urine samples were collected the morning prior to and immediately following the race, and subjects recorded muscle soreness during the week following the race using a 10-point Likert scale (DOMS). Race time (25.8 ± .6 and 25.6 ± .8 h, respectively) and ratings of perceived exertion (RPE, 6–20 scale) (14.6 ± .4 and 14.5 ± .2, respectively) did not differ significantly between ibuprofen users and nonusers. Ibuprofen use compared to nonuse was linked to a smaller increase in urine creatinine (P = .038), higher plasma levels of lipopolysaccharide (group effect, P = .042), and greater increases (pre-to-post race) in serum C-reactive protein and plasma cytokine levels for interleukin (IL)-6, IL-10, IL-8, IL-1ra, granulocyte colony-stimulating factor, monocyte chemotactic protein 1, and macrophage inflammatory protein 1 beta, but not tumor necrosis factor alpha. Post-race DOMS and serum creatine kinase levels did not differ significantly between ibuprofen users and nonusers (20,621 ± 3565 and 13,886 ± 3068 μcal/L, respectively, P = .163). In conclusion, ibuprofen use compared to nonuse by athletes competing in a 160-km race did not alter muscle damage or soreness, and was related to elevated indicators of endotoxemia and inflammation.

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.

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