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Dramatic Elevations of Interleukin-6 and Acute-Phase Reactants in Athletes Participating in the Ultradistance Foot Race Spartathlon: Severe Systemic Inflammation and Lipid and Lipoprotein Changes in Protracted Exercise

Department of Clinical Biochemistry (A.M., E.H., I.P.), Aghia Sophia Children’s Hospital, GR 11527 Athens, Greece; Laboratory of Nutrition and Clinical Dietetics (K.S., A.-L.M.), Harokopio University, GR 17671 Athens, Greece; Department of Internal Medicine (M.T.), Sparta General Hospital, GR 23100 Sparta, Greece; Medical Genetics (C.V., E.K.), Athens University, GR 11527 Athens, Greece; and First Department of Pediatrics (G.C.), Athens University, Medical School, GR 11527 Athens, Greece

Address all correspondence and requests for reprints to: Ioannis Papassotiriou, Ph.D., Department of Clinical Biochemistry, Aghia Sophia Children’s Hospital, GR 115 27 Athens, Greece. E-mail: biochem{at}paidon-agiasofia.gr or jpapasotiriou{at}ath.forthnet.gr.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context and Objective: Plasma IL-6, the serum inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA), and the tissue destruction marker-free plasma DNA, as well as the circulating lipid profile, were examined in athletes participating in the ultradistance foot race of the 246-km Spartathlon.

Setting, Design, and Participants: This race consists of continuous, prolonged, brisk exercise. Blood samples were obtained from 15 male athletes, who finished the race in less than 36 h, taken before, at the end of, and 48 h after the end of the race.

Results: IL-6, CRP, SAA, and free plasma DNA levels markedly increased (by 8000-, 152- 108-, and 10-fold, respectively) over the baseline at the end of the race. However, IL-6 levels returned to normal by 48 h, whereas CRP, SAA, and free plasma DNA remained elevated. The mean values of cholesterol, triglycerides, low-density lipoprotein, and apolipoprotein B decreased to a minimum value at the end of the race and remained low 48 h after the race. High-density lipoprotein levels, on the other hand, were mildly increased at the end of the race (P < 0.015) and decreased to normal 48 h after the race. Apolipoprotein AI levels decreased significantly during the time course of the exercise and remained low 48 h after the race (P < 0.001).

Conclusions: These observations suggest that continuous, prolonged, moderate-intensity exercise is associated with markedly elevated IL-6 and acute-phase reactant concentrations, peripheral tissue damage, and significant changes in serum lipid levels. The biochemical changes observed during the Spartathlon amount to a potent systemic inflammatory response, which might explain severe cardiovascular events that occur during prolonged exercise in compromised individuals.

	Introduction

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STRENUOUS AND/OR PROLONGED physical activity leads to muscle and other tissue damage and, thereby, induces an inflammatory response characterized by secretion of proinflammatory cytokines, chemokines, and other mediators of inflammation (1, 2, 3, 4, 5, 6, 7). On the other hand, physical activity also induces counter-regulation of inflammation through secretion of immunosuppressant mediators, such as cortisol and antiinflammatory cytokines (8). In addition, levels of positive acute-phase proteins, such as C-reactive protein (CRP) and serum amyloid A (SAA), increase during a bout of exercise, whereas levels of negative ones, such as albumin and transferrin, decrease (9). Also, strenuous and/or prolonged physical activity perturbs intermediary metabolism and produces a wide variety of changes in the plasma concentrations of metabolites, including those of lipids and lipoproteins, which in general appear to be antiatherogenic (10, 11). It might be reasonable to hypothesize that the reduced risk of cardiovascular disease achieved in adults engaged in regular physical activity may result from prevention, reduction, or modulation of inflammation and favorable changes in the lipid profile (8, 12, 13, 14, 15, 16).

The beneficial effects of regular exercise on the lipid profile [i.e. lower total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglyceride concentrations and higher concentrations of antiinflammatory, cholesterol-removing high-density lipoprotein (HDL) particles] generally increase with its intensity and duration (17). In contrast to what is observed with exercise though, during an inflammatory response and acute-phase reaction elicited by tissue damage from trauma or surgery, by administration of an irritant, such as croton oil, or because of an infection, HDL particles lose their protective enzymes paraoxonase and platelet-activating factor acetylhydrolase, whereas they concomitantly develop a marked increase in their content of SAA and ceruloplasmin, all changes that result in an overall diminution of their antiatherogenic properties (18). Furthermore, these alterations of the HDL particles might allow increases of monocyte/macrophage trafficking into the arterial wall and predispose to atherosclerosis (19).

Increases of inflammatory and antiinflammatory cytokines or cytokine inhibitors and alterations of circulating lipids and lipoproteins are detected during and after various types of exercise, just as they occur in other general medical and surgical conditions accompanied by tissue damage (20, 21, 22, 23, 24). The aim of this study was to examine the inflammatory response and lipid profile during a strenuous, unrelenting, and protracted exercise paradigm in healthy adult volunteers. The fatigue-inducing proinflammatory cytokine IL-6 and the serum markers of inflammation CRP and SAA, along with the lipid profile of athletes participating in the ultra-long-distance foot race Spartathlon, i.e. almost 36 h of continuous brisk exercise, were measured and analyzed. The results revealed dramatic systemic inflammatory changes in this form of exercise associated with less impressive but significant changes in the lipid profile.

	Subjects and Methods

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Subjects and exercise protocol

The 2002 Spartathlon race was an ultradistance foot race of continuous, moderate intensity exercise of 246 km distance, during which runners attempted to cover the distance from Athens to Sparta. The ambient daily temperatures during running were maximum 36 C and minimum 8 C, and the mean daytime relative humidity was 60–85%. Before commencement of this study, approval was obtained from the Bioethics Committee of the Harokopio University, Laboratory of Nutrition and Clinical Dietetics, and all experimental procedures conformed to the National Health and Medical Research Council guidelines for experimentation with human subjects. All potential participants (n = 89) were informed of all procedures and purposes of the study and gave their informed written consent before participation in the study. However, 41 athletes did not complete the event. The data of this study were derived from 15 healthy male subjects who participated in the Spartathlon race 2002 (median age, 40 yr; range, 31–46 yr) and finished the race in less than 36 h (mean and median running times were 32 h 8 min and 30 h 2 min, respectively; range, 25 h 17 min to 34 h 43 min).

Sampling and analysis of blood

Blood samples were drawn from an antecubital vein of participants after assuming a sitting position before race start and immediately after (within 15 min) the end of the event, whereas the final sample was obtained at the recovery period at 48 h after the end of the race. The subjects consumed electrolytes and carbohydrate ad libitum before, during, and after running. Peripheral venous blood samples (10 ml) were drawn into plastic syringes under sterile conditions and transferred immediately to nonadditive tubes for serum and allowed to clot at room temperature for 30 min. Serum was separated from whole blood by centrifugation at 1000 x g for 10 min at room temperature. The samples were stored frozen at –80 C until assayed.

Blood chemistry

Serum cholesterol, triglycerides, and HDL cholesterol were performed with the Bayer-Advia 1650 Clinical Chemistry System, whereas SAA, CRP, and the apolipoproteins Apo AI and Apo B were measured by means of particle-enhanced immunonephelometry using the Dade-Behring BN Prospec nephelometer. LDL cholesterol values were determined by calculation, known as Friedewald’s formula, using measured values for total cholesterol, HDL cholesterol, and triglycerides. Quality control procedures relating to the measurements of cholesterol, triglycerides, HDL cholesterol, SAA, CRP, Apo AI, and Apo B were also performed.

IL-6 levels were assayed in duplicate with all values expressed as a mean of the two determinations, using a validated commercial ELISA (Quantikine; R&D Systems, Minneapolis, MN). The intra- and interassay coefficients of variation were less than 5.2 and 7.0%, respectively.

Quantification of free plasma DNA

Plasma was isolated after a two-step centrifugation protocol comprising a 10-min centrifugation at 800 x g followed by a 10-min centrifugation at 16,000 x g. DNA was extracted from 400 µl plasma with the QIAamp DNA Blood Mini Kit (QIAGEN, Hilden, Germany) according to the manufacturer’s recommendations with minor modifications. DNA was eluted into 50 µl of RNase/DNase-free H₂O. Free DNA was measured by quantitative real-time PCR using the LightCycler (Roche Diagnostics, Mannheim, Germany) with the following primers: forward, 5'-AGG TGA ACG TGG ATG AAG TT-3', and reverse, 5'-AGG GTA GAC CAC CAG CAG CC-3', for the amplification of a 189-bp fragment of the ß-globin gene. PCR amplification reactions were carried out in glass capillary tubes (Roche) in a total reaction volume of 20 µl containing the ready-to-use reaction mixture provided by the manufacturer (LightCycler Fast Start DNA Master SYBR Green I) with 4.5 mM Mg²⁺ and 0.5 µM of each PCR primer. The PCR conditions included a first denaturation step of 95 C for 10 min followed by 40 cycles of 95 C for 10 sec, 58 C for 5 sec, and 72 C for 20 sec with a temperature ramp of 20 C/sec.

Statistical analyses

Data are presented as mean ± SD, and the level of statistical significance was considered at P < 0.05. The paired observation t test was used to analyze time course changes. All the statistical procedures were performed using the STATGRAFICS PLUS version 5.1 for Windows program (Graphic Software System, Statistical Graphics Corp., Englewood Cliffs, NJ), whereas bar charts were prepared using the Sigma plot version 8.0 program (Sigma-Aldrich Chemical Co., Milwaukee, WI).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The biochemical parameters examined, expressed as mean ± SD, and the level of statistical significance before, at the end of, and 48 h after the race are presented in Table 1.

View larger version (27K): [in this window] [in a new window]   FIG. 1. Chart presentation of inflammatory parameters expressed as mean ± SD. SAA (mg/liter), CRP (mg/liter), IL-6 (pg/ml), and free plasma DNA (genome equivalents per milliliter) levels are presented before (pre), at the end of, and 48 h after (post) the race.

CRP levels were significantly increased by 152-fold by the end of the race (P < 0.0002) and by 108-fold at 48 h after the race (P < 0.0004) compared with the low CRP levels found before the race (Fig. 1).

Circulating levels of free plasma DNA were elevated at the end of the race and remained increased 48 h after the race (Table 1 and Fig. 1).

The mean values of cholesterol, triglycerides, LDL, and Apo B presented a similar profile at the time points examined, reaching a minimum value at the end of the race with a tendency for an increase at 48 h after the race (Table 1). Significant differences were found when the above mentioned biochemical parameters before the race were compared with those found at the end (P < 0.001) and at 48 h after the race (P < 0.007). Nonsignificant differences were obtained when comparing levels of cholesterol, triglycerides, LDL, and Apo B at the end of the race with those at 48 h after the race (Table 1).

HDL values were significantly increased at the end of the race compared with those before the race (P < 0.015). At 48 h after the race, however, HDL levels were similar to pre-exercise ones, without presenting any significant difference to either the pre-exercise one or to those at the end of the race (Table 1). The Apo AI levels were continuously decreased during the whole time course of the exercise (P < 0.005), presenting significant differences when compared before, at the end of, and/or at 48 h after the race (Table 1).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study provides evidence that IL-6 is dramatically elevated during prolonged exercise to levels seen only in major trauma, septic shock, systemic inflammation, or near-death states (25, 26, 27, 28, 29). One of the major functions of IL-6 during inflammation has been considered the generation of sickness syndrome manifestations, such as sleepiness and fatigue, that protect the individual from exhaustion and additional tissue damage, the stimulation of the acute-phase reaction to promote healing of the damaged tissues, and the restraint of the inflammatory response through inhibition of TNF- and IL-1ß secretion and through activation of the hypothalamic-pituitary-adrenal axis (30). In the case of the Spartathlon exercise paradigm, tissue damage was expected and confirmed by the elevated levels of circulating free DNA. In our Spartathlon paradigm, we hypothesize damage from all strained organs and tissues, such as the cardiovascular system, the skeletal muscles, and the bones, joints, and ligaments.

SAA and CRP, representative of positive acute-phase reactants that have not been previously studied in such an event, were extremely increased during the time course of the Spartathlon and its aftermath, when, actually, IL-6 levels had already normalized. The earlier normalization of IL-6, which has a relatively short plasma half-life of 20–30 min, than those of SAA and CRP (10 and 20 h, respectively), in the presence of sustained tissue damage markers, indicates that the secretion of this cytokine may develop tolerance to inflammatory stimuli (22, 28, 30).

The acute-phase SAA protein is related to HDL cholesterol and comprises a family of polymorphic apolipoproteins, whose levels are increased up to 1000-fold, within a short period of time (4–8 h), in response to infectious and noninfectious inflammatory processes (31, 32, 33). SAA circulates at low baseline concentrations and is eliminated by renal-independent clearance mechanisms. The early response and the broad dynamic range of SAA contribute to the sensitivity of its plasma concentration as an early indicator of changes in the inflammatory process of a disease (31, 32, 33). CRP, whose serum levels also rise during a general, nonspecific inflammatory reaction in response to both infectious and noninfectious injurious agents, is normally present as a serum or plasma trace constituent. Approximately 18–24 h after the onset of inflammation, i.e. quite later than SAA, plasma CRP values may rise above normal up to 20- to 500-fold.

In the present study, SAA and CRP were extremely elevated, up to 108- and 152-fold respectively, whereas in another study, in a group of ultramarathon runners competing in a 6-d track race, CRP levels were increased 20-fold above baseline, with a peak on d 2 (4). In a 5-km run, regarded as a physiological human exercise pattern, healthy athletes had modest increases (1.5-fold) of SAA and CRP 24 h after the race (22). In a marathon run, a modest increase in CRP (4-fold) was detected after 16 h (34, 35). These data are contrary to the extremely elevated SAA and CRP levels observed in our study. The differences in the inflammation markers among these studies could be attributed to the different duration, intensity, and type of the exercise. In our study, SAA and CRP remained elevated 48 h after the race. Pathological SAA values are often detected in association with normal CRP concentrations, perhaps because the former has an earlier and sharper rise than the latter (31, 32).

Inflammation is associated with lipid metabolism alterations that may be regulated by activated macrophage-derived cytokines (36). The activation of monocytes/macrophages precedes the high SAA levels, as the numbers of these cells increase where tissue damage has occurred, with consequent inflammation (37, 38). Generally, non-exercise-related infection and inflammation produce a wide variety of changes in the plasma concentrations of lipids and lipoproteins, such as increased triglyceride levels caused by an increase in very-low-density lipoprotein production and a reduction in HDL levels (39, 40, 41).

Plasma HDL cholesterol levels are inversely correlated with the risk of coronary artery disease, possibly a result of a direct antiatherogenic effect of this fraction (11). The circulating fraction of HDL is a heterogeneous collection of particles consisting of about 50% protein and 50% lipid, containing mainly Apo AI and Apo AII, and a large number of less abundant proteins, including Apo CI, CII, CIII, E, J, and L, lecithin-cholesterol acyltransferase, paraoxonase 1, and platelet-activating factor acetylhydrolase (42). During inflammation, SAA and ceruloplasmin are incorporated into the HDL, and under certain conditions, this fraction may lose its antiatherogenic properties and might even promote atherogenesis (42). Indeed, SAA inhibits HDL-mediated cholesterol removal from peripheral cells but instead promotes delivery of lipid to macrophages (42). About 5–6 d after an acute inflammatory episode, normal HDL apolipoprotein composition reappears (43). This time course of SAA acquisition and loss by the HDL fraction coincides with both the pattern of infiltration and disappearance of macrophages at sites of inflammation (43). The increased levels of HDL in parallel with a decrease of Apo AI observed at the end of the Spartathlon race may possibly represent decreased antiinflammatory/antiatherogenic behavior of the HDL in the athletes.

Kraus et al. (44) examined the effects of two different amounts (low and high) and intensities of exercise training (moderate and high) on lipoproteins, showing a clear effect of the amount of exercise on lipoproteins and lipoprotein subfractions. The duration of exercise made a greater difference than the intensity of exercise on plasma lipids, suggesting that the duration of daily physical activity is of importance for the improvement of the lipoprotein profile with exercise programs (44). The observed alterations of lipoproteins found in runners participating in the Spartathlon, who exercised continuously for up to 36 h, suggest that the duration of exercise matters mostly for both the degree of systemic inflammation and lipoprotein profile observed. The profound systemic inflammation observed in our Spartathlon athletes may explain the potential cardiovascular adverse effects of strenuous exercise in the context of a cardiovascularly compromised individual.

	Footnotes

 
First Published Online April 26, 2005

Abbreviations: Apo, Apolipoprotein; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; SAA, serum amyloid A.

Received December 1, 2004.

Accepted April 20, 2005.

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