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Department of Health Studies and Gerontology, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Submitted 24 November 2003 ; accepted in final form 30 January 2004
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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+, CD3
+, CD8+, CD8+, CD4+, and NK+ phenotypic markers. ADX mice had significantly more intestinal CD45+ leukocytes (P < 0.05) and CD3+ (P < 0.05), CD3+ (P < 0.01), CD8+ (P < 0.001), and NK+ (P < 0.05) intestinal lymphocytes than Sham mice. There was a significant effect of exercise condition on total intestinal CD45+ leukocytes (P < 0.01) and CD3+ (P < 0.05), CD8+ (P < 0.001), and CD4+ (P < 0.05) intestinal lymphocytes, with fewer cells at 24 h postexercise compared with the other treatment conditions. There were no surgical x exercise interaction effects on the CD3 and CD8 phenotype numbers. Plasma corticosterone was virtually nil in ADX mice regardless of exercise condition but was significantly elevated in Sham mice immediately postexercise (P < 0.001). The data indicate that ADX does not prevent the loss of lymphocytes from the intestinal mucosa 24 h after strenuous exercise and GCs are not directly causal in the leukopenia of exercise. treadmill running; adrenal glands; glucocorticoids
The intestinal intraepithelial lymphocytes (IELs) are a unique population of T cells that function as a first line of defense against exogenous pathogens, many of which develop independently of the thymus gland [i.e., T cells with the form of the T cell receptor (TCR)] (35). IELs play an important role in protection from epithelial tumor cells through their function as cytolytic agents (37). Lamina propria lymphocytes (LPLs), also mainly T cells, are derived from the thymus; they constitute primarily the form of the TCR (12) and have some cytolytic activity against tumor cell lines (38). CD8 T lymphocytes, compromising two subpopulations of - and -chain phenotypes, have cytolytic functions and are found in both the intraepithelial and lamina propria regions (4). CD4 (helper) T cells and natural killer (NK) cells make up a smaller component of the IEL and LPL compartments.
There is only limited research on the impact of exercise on intestinal IELs and LPLs. We have previously shown that 90 min of heavy exercise is associated with reduced numbers of CD3+ lymphocytes in mouse intestine (19), a phenomenon similar to the blood lymphocytopenia observed after heavy duration exercise (41). Because exercise triggered a sharp increase in the secretion of corticosterone, we hypothesized that the loss of intestinal lymphocytes was due to apoptosis mediated through GC as demonstrated by an increase in the expression of phosphatidylserine (annexin V). In this present study, we further characterize the contribution of GCs on the intestinal lymphocyte numerical response to exercise stress. Because the GC response can be abrogated by excision of the adrenal glands, we examined the effect of acute exercise on the number and phenotype distribution of intestinal lymphocytes from mice after adrenalectomy (ADX). We show in this study that ADX, which eliminates systemic GCs, fails to buffer the reduction in the total number of T lymphocytes in the mouse intestine after acute exercise.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Thirty-six female C57BL/6 mice, purchased from Harlan Sprague Dawley (Indianapolis, IN, colony 217), age 4–5 wk and weighing 
14 g at arrival, were housed in groups of three under temperature- and humidity-controlled conditions with a 12:12-h reversed light-dark cycle. Mice were given food (Laboratory Rodent Chow, PMI Feeds, Richmond, IN) and tap water ad libitum and allowed to acclimate to our vivarium for at least 1 wk before use in the experiments. All procedures involving mice concurred with guidelines established by the Canadian Council on Animal Care and were approved by the university IRB.
Adrenalectomy
Mice were randomly assigned to one of two surgical conditions: bilateral ADX (n = 18) or sham surgery (Sham; n = 18). Mice were anesthetized by intraperitoneal injection of a ketamine-xylazine mixture (128 mg/kg and 8.5 mg/kg, respectively); buprenorphine (Temsgesic, 0.003 mg/100 g body wt) was administered subcutaneously as an analgesic. A 0.5-cm skin incision was made in the back, the skin on both sides of the incision was moved to the side, and a 2-mm muscle incision was made on the top of each adrenal gland. The entire adrenal gland was removed with a pair of sterile fine curved forceps. The incision was closed with surgical staples, and 0.8 ml of 0.9% sterile saline solution was injected subcutaneously to restore body fluid. The mice were placed into individual clean cages and recovered under a heat lamp. After recovery, the mice were maintained by providing food and drinking water containing 0.9% sodium chloride ad libitum. Control mice (Sham) underwent the same surgical procedure as the ADX group, except their adrenal glands were not excised. Experiments were performed 2–3 wk after ADX.
Exercise Protocol
Within ADX and sham conditions, mice were randomly assigned to one of three exercise groups (6 mice per surgical x exercise condition): Immediate, which involved 90 min of treadmill running at 28 m/min at a 2° slope and death immediately after completion of the exercise bout; 24 h Post, which involved treadmill running at 28 m/min at a 2° slope and death 24 h after cessation of the exercise bout; and Nonexercised, which involved 90 min of exposure to treadmill laneway noise and vibration without actual running. The Immediate and 24 h Post groups were preconditioned to treadmill running by three prior exposures to the treadmill (Omni-max metabolic small rodent treadmill, Columbus, OH) at 15 m/min for 10 min on day 3, 20 m/min for 15 min on day 2, and 24 m/min for 20 min on day 1 before the experiment.
Tissue Collection
Cardiac blood. Mice were killed by an overdose of sodium pentobarbital sodium (0.06–0.08 ml). On a negative toe pinch response, skin at the midventral position of the body was grasped and a 2 cm incision was made across the chest. The rib cage was exposed and cut along the sides to expose the heart. Blood was collected immediately by cardiac puncture into a 1-ml heparinized syringe and centrifuged for 6 min at 1,500 g. Plasma was frozen at -20°C and stored for analysis of corticosterone.
Isolation of intestine. The skin at the abdominal cavity was cut to expose the gastrointestinal tract. The entire bowel was removed and intestinal lymphocytes were isolated via a modification of the methods of LeFrançois (24) and Todd et al. (44). Briefly, tissue was excised and flushed with PBS to remove fecal matter; visible fat and Peyer's patches were dissected out, and the bowel was cut open longitudinally and separated into 0.5-cm pieces. The samples were gently washed in PBS four times by inversion, discarding the supernatant each time. HBSS (containing 1 mM EDTA and 5% FBS; Ca2+ and Mg2+ free) was added to each sample and incubated at 37°C in a shaking water bath for 20 min. Samples were vortexed, supernatant was collected, and the procedure was repeated with fresh HBSS for 10 min. The supernatants were combined for each sample, centrifuged at 450 g at 4°C for 5 min, decanted, and resuspended in cold RPMI-1640 solution (containing 2.5% FBS, 0.5% HEPES, and 0.2% penicillin). Cell suspensions were passed over a nylon wool column, and then cells were collected, centrifuged at 450 g for 5 min at 4°C, resuspended in buffer (0.5% BSA/PBS containing 2 mM EDTA), and centrifuged again at 450 g for 5 min. Cells were stained with Turk's solution and counted manually by microscopy using a hemocytometer.
Intestinal lymphocyte isolation. CD45 positive cells (leukocyte fraction) were isolated by use of a magnetic separation system (mini-MACS system, Miltenyi Biotec, Auburn, CA). Cell pellets were suspended in 90 µl of buffer and 10 µl MACS CD45 microbeads per 107 total cells, incubated at 6–12°C for 15 min, washed, centrifuged, and resuspended in buffer. Cell suspensions were separated by passing over a separation column with a preseparation filter in the magnetic field using a positive selection protocol.
Antibody Staining Procedure
Intestinal leukocytes were stained with FITC-conjugated monoclonal antibodies (MAbs) against CD3 (clone: GL3), CD8 (clone: H57–597), CD4 (clone: GK1.5), Pan-NK (clone: DX5), and PE-conjugated MAbs against CD3 (clone: 53–5.8) and CD8 (clone: 53–6.7) with all antibodies obtained from PharMingen (Missisauga, ON, Canada). Briefly, 5 x 105 cells suspended in 50 µl of PBS were initially incubated 5 min with 0.5 µl of Fc Block [CD16 FcIII/CD32 FcII (clone: 2.4G2), PharMingen], before specific cell surface phenotype staining to inhibit nonspecific binding via Fc receptors. Cell suspensions were incubated with MAbs for 45 min in the dark at 4°C and washed with 500 µl PBS, and cells were read on a flow cytometer (Epics XL Flow Cytometer, Beckman Coulter, Hialeah, FL) first by gating on the CD45 population using a FITC-conjugated MAb (clone: YW62.3; Cedarlane Laboratories, Hornby, ON, Canada).
Corticosterone
Plasma samples were analyzed for corticosterone via a commercially available 125I radioimmunoassay kit designed for rat and mouse plasma samples (IDS, Bolton, UK) according to the manufacturer's protocol, with a 1:10 dilution and extraction under methylene chloride. Radioactivity was counted with a Gamma 5500 counter (Beckman Coulter).
Statistical Analysis
Results are given as group means ± SE unless otherwise stated. All data were tested for normal distribution to satisfy the assumptions of analysis of variance. Total number of intestinal lymphocytes, percent of intestinal lymphocyte phenotypes, and plasma corticosterone were analyzed by a two-way analysis of variance with exercise condition (Nonexercised, Immediate, 24 h Post) and surgical treatment (ADX, Sham) as the independent factors. In cases of significant main or interaction effects, Tukey's honestly significant difference post hoc test was performed to identify statistical differences. In all cases, P < 0.05 was accepted as being significantly different from chance alone.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Figure 1A shows the significant main effect of ADX on total intestinal (intraepithelial and lamina propria) lymphocytes from mice [F(1,30) = 5.828, P < 0.05], with ADX mice having 30% more intestinal lymphocytes relative to Sham mice. Figure 1B shows the influence of the acute exercise bout on the total number of intestinal lymphocytes recovered. In the 24 h Post group, there were significantly fewer intestinal lymphocytes compared with the Nonexercised and Immediate exercise groups [F(2,30) = 8.175, P < 0.001]. The number of intestinal lymphocytes at 24 h postexercise was 50% of that obtained from the other exercise conditions. There was no significant interaction between surgical and exercise condition, i.e., the same pattern of a reduction in lymphocyte numbers occurred in both ADX and Sham mice 24 h postexercise compared with Nonexercised mice (Fig. 1C).
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Figure 2A shows that ADX was associated with significantly more CD3-positive intestinal lymphocytes with the -TCR phenotype compared with the Sham condition [F(1,30) = 4.753, P < 0.05]. Nonexercised and Immediate postexercise groups did not differ in the total number of CD3-positive intestinal lymphocytes expressing the -TCR although both were higher than the 24 h Post group (P < 0.05; Fig. 2B). There was no significant interaction between surgical and exercise condition on CD3 T cells (Fig. 2C).
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CD3-positive intestinal lymphocytes with the -TCR are a unique population found in the intestine. Figure 3A presents the effect of ADX on the number of -TCR cells and clearly shows that ADX was associated with more lymphocytes recovered from the bowel compared with the Sham condition [F(1,30) = 7.452, P < 0.01]. Similar to the CD3 T cells, there was a significant main effect of the exercise on the total number of CD3 T cells [F(2,30) = 3.646, P < 0.05] (Fig. 3B). There was no difference in response to exercise as a function of the surgical treatment (i.e., no significant surgical x exercise interaction; Fig. 3C).
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Figure 4 shows the effect of surgery and exercise on CD8 T intestinal lymphocytes. There was a significant effect [F(1,30) = 13.234, P < 0.001] of ADX on the number of intestinal CD8 T cells recovered from mice (Fig. 4A). ADX was associated with more CD8 T cells compared with the Sham surgical treatment. Exercise condition also significantly [F(1,30) = 11.758, P < 0.001] influenced the total number of intestinal CD8 T cells isolated from mice (Fig. 4B). There were fewer intestinal CD8 T cells recovered at 24 h postexercise relative to the Nonexercised and Immediate exercise conditions (P < 0.001). The interaction between surgery and exercise is shown in Fig. 4C (not significant). A representative single parameter flow cytometry histogram depicting the CD8 population for the ADX and Sham conditions at 24 h postexercise is also given in Fig. 5. In contrast with the intestinal CD8 T cell response, no significant main or interaction effects for the CD8 T cell population were observed either for surgical or for exercise condition (Fig. 6).
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ADX did not influence the CD4 cells isolated from the intestine (ADX: 2.7 ± 0.4 x 106 cells vs. Sham: 2.2 ± 0.2 x 106 cells) (Fig. 7A). There was a significant effect of the exercise on the number of CD4 T cells isolated [F(2,30) = 3.68, P < 0.05], with more CD4 T lymphocytes in the Nonexercised (2.9 ± 0.5 x 106 cells) and Immediate (2.9 ± 0.4 x 106 cells) groups compared with mice at 24 h postexercise (1.5 ± 0.2 x 106 cells) (Fig. 7B). There was no significant interaction between surgical treatment and exercise condition for CD4 lymphocytes (Fig. 7C).
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NK cells normally make up a very small proportion of murine intestinal leukocytes, and the numbers were absolutely less than the other subsets. Nevertheless, there was still a significant effect of the ADX (Fig. 8A) on NK cell number [F(1,30) = 4.127, P < 0.05]. ADX mice had more NK cells recovered (1.7 ± 0.3 x 106 cells) than Sham mice (0.9 ± 0.2 x 106 cells). There was, however, no significant effect of exercise (Fig. 8B) on NK cell numbers from mouse bowel. Similarly, there was no exercise by surgical treatment interaction effect for NK cell numbers (Fig. 8C).
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Phenotype Percentages
Table 1 gives the percentages of the various lymphocyte phenotypes from ADX, Sham, and the various exercise conditions for the mice. ADX mice had a higher percentage of intestinal lymphocytes expressing the CD3 T phenotype (34.6 ± 2.5%) and CD8 T cells (67.4 ± 2.1%) compared with the Sham mice (CD3 T cells: 27.8 ± 1.2% and CD8 T cells: 54.4 ± 3.3%). ADX was associated with a lower percentage of cells expressing the CD8 T phenotype (19.1 ± 1.2%) compared with the percentage of CD8 T cells (27.6 ± 3.9%) in the Sham mice. There were no effects of surgical treatment on the percentage of intestinal CD3 T, CD4 T, and NK cells recovered.
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The effects of the exercise intervention on the phenotype percentages are also shown in Table 1. There were no significant differences by exercise condition on the percentage of intestinal lymphocytes expressing the CD3 T, CD3 T, CD4 T, or NK cell phenotypes. The percentages of intestinal CD8 T and CD8 T cells recovered from mice 24 h postexercise were significantly lower (50.6 ± 4.1%) and significantly higher (30.9 ± 5.7%), respectively, than the percentages found in the Nonexercised mice (64.9 ± 2.9% and 20.0 ± 1.4%, respectively; P < 0.05 in both cases).
There were no significant interaction effects between surgical condition and exercise treatment for any of the lymphocyte phenotype percentages with the exception of CD8 and NK cells (Table 1). ADX-24 h Post mice expressed a higher percentage of NK cells relative to Sham-24 h Post mice [F(2,30) = 3.59, P < 0.05]. Sham-24 h Post mice had a higher percentage CD8 population relative to all other groups [F(2,30) = 5.45, P < 0.01].
Plasma Corticosterone
Plasma corticosterone concentrations were virtually nil in the ADX mice, irrespective of exercise condition, compared with the Sham mice [F(1,29) = 100.1, P < 0.001]. There was a significant effect of exercise, with plasma corticosterone concentrations higher in mice sampled immediately after exercise compared with Nonexercised and 24 h Post animals [F(2,29) = 9.92, P < 0.001]. There was also a significant surgery x exercise interaction [F(2,29) = 8.39, P < 0.001], with Sham mice having a higher plasma corticosterone concentration immediately after exercise compared with all other groups. The corticosterone responses by surgical and exercise condition are shown in Table 2.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Stress activates the hypothalamic-pituitary-adrenal axis with a concomitant release of GCs from the adrenal cortex. In vitro exposure to GCs induces thymocyte apoptosis (18, 26), and blocking GC receptors, inhibiting GC biosynthesis, and ADX reduce lymphocyte cell death (6, 15, 43). Furthermore, surgical removal of the adrenal glands is associated with less DNA fragmentation and lower nitric oxide production of splenic macrophages (5). Thus, if GCs were the primary factor in the depletion of intestinal lymphocytes 24 h after exercise, it would be expected that ADX-24 h Post would have a lower lymphocyte loss than Sham-24 h Post animals relative to their respective nonexercised controls. This was not the case and suggests that other mechanisms contribute to the loss of cellularity in ADX mice 24 h after a physical exercise challenge.
During exercise, splanchnic blood flow decreases proportional to the rise in heart rate (31). Ardevol et al. (1) found that in the rat gastrointestinal blood flow (17 ml/min) decreases during intense exercise (8 ml/min) but returns to basal levels during the initial recovery period. Therefore, an alternative explanation for the lymphocyte loss observed in the gastrointestinal tract is that cardiovascular dynamics with exercise indirectly affect this lymphocyte pool. However, it remains to be determined whether alterations in blood flow would affect the lymphocyte pool in the gastrointestinal tract at 24 h postexercise because at this time point cardiac output, and consequently splanchnic blood flow, would be expected to return to preexercise levels.
Another factor that could contribute to the loss of intestinal lymphocytes with heavy exercise is ischemia-reperfusion injury. Noda et al. (34) found that occlusion of the rat superior mesenteric artery (to simulate ischemia) induced apoptosis of intestinal epithelial cells, which was further exacerbated after reperfusion. Similarly, Coopersmith et al. (10) found that apoptosis of mouse intestinal epithelial cells was maximal at 24 h after ischemia-reperfusion injury. Apoptosis of intestinal epithelial cells after ischemia-reperfusion injury can be inhibited by overexpression of the antiapoptotic protein Bcl-2 and provision of antioxidants (10, 22). It is reasonable to assume that the mechanisms responsible for ischemia-reperfusion-induced apoptosis in intestinal epithelial cells may also directly induce apoptosis of lymphocytes. A loss of intestinal epithelial cells via apoptosis after ischemia-reperfusion could indirectly induce intestinal lymphocyte apoptosis though growth factor withdrawal because cytokines such as IL-7 and IL-15 are produced by intestinal epithelial cells (23, 36) and these cytokines provide essential survival signals as well as prevent apoptosis of intraepithelial lymphocytes (50). Whether the loss of intestinal lymphocytes represents a direct effect of ischemia and reperfusion on intestinal lymphocytes or an indirect effect due to cytokine withdrawal as a result of atrophy of epithelial cells remains to be determined.
Heavy exercise increases oxidative respiration and the generation of reactive oxygen species (ROS) (32). Oxidative stress during exercise induces apoptosis of lymphocytes and the loss of cellularity of lymphoid tissues by generating ROS with consequent damage directly to DNA (33) or indirectly by rapid consumption of antioxidant defenses resulting in membrane lipid peroxidation (3). ROS production may also play a role in cell loss during exercise by affecting lymphocyte migration (39). The oxidative stress pathway is further supported by the findings that supplementation with dietary antioxidants protected against exercise-induced apoptosis and DNA damage of human and rodent lymphocytes (17, 25). Although we did not measure whole body or cellular respiration in this study, previous work (19) showed that, at the same exercise workload in C57BL/6 mice, there was a significant increase in plasma 8-isoprostanes (a biomarker of oxidative stress) immediately after exhaustive treadmill exercise relative to nonexercised animals. Whether ADX-exercised mice generate equivalent 8-isoprostanes as sham-exercised mice is not known. However, exposure to GCs increases the production of intracellular ROS (8), and it is reasonable to assume that basal intracellular ROS production in intestinal lymphocytes might be lower in the GC-depleted, ADX animals. Because ADX and Sham mice did not differ in the loss of intestinal lymphocytes 24 h after the exhaustive exercise bout, this finding suggests that differences in intracellular ROS production by GCs do not mediate the observed intestinal lymphocyte depletion. Although intracellular ROS via GC signaling may differ between surgical groups, it is unlikely that ROS production via increased oxidative metabolism due to exercise would differ at the active muscle. This raises the possibility that spillover of ROS from the working muscle may be a mechanism for lymphocyte cell loss during exercise.
Intestinal lymphocytes (especially CD3 and CD8 T cells) are a distinctive population of lymphocytes that function in protection against epithelial tumors, pathogens, allergens, and antigens. Normally, the lymphocyte pool at the gastrointestinal mucosa is maintained at equilibrium between activation during antigen exposure and apoptosis once the challenge is removed (46). Imbalances due to excessive proliferation or insufficient apoptosis could lead to inflammatory bowel disease (7), whereas excessive apoptosis or insufficient proliferation could lead to reduced barrier functions (14). We observed a reduction by 50% in the intestinal lymphocyte cell numbers after a single episode of heavy treadmill exercise in mice. Of note is the loss of CD8 T cells, which include the CD8 homodimer phenotype, unique to the intestinal mucosa (16). Das and colleagues (11) reported that CD8 T cells suppress intestinal inflammation. In contrast to the CD8 T population, which was affected by treadmill exercise, there was no apparent effect on CD8 T cells. Several studies (30, 47) indicate that, although all subsets of intraepithelial intestinal lymphocytes are susceptible to GC-induced apoptosis, some subsets (CD8 and CD3) are more resistant because of higher expression of intracellular Bcl-2 (an antiapoptosis protein). This raises the possibility of differential regulation of intestinal lymphocyte subtypes to those apoptosis-inducing factors associated with heavy exercise.
The presence or lack of GCs may alter the morphology of the intestinal epithelium. Bilateral ADX in rats led to partial atrophy and disorganization of the epithelium with increased villus apoptosis (13); however, it has also been noted that GC administration in vitro increases intestinal epithelial cell apoptosis and inhibits cellular proliferation (21). Although intestinal epithelial cells produce cytokines that regulate apoptosis and cell proliferation of intestinal lymphocytes (50), our experiments demonstrate significantly higher lymphocyte counts for most phenotypes in ADX mice regardless of exercise condition. These findings suggest that basal GC secretion, irrespective of exercise condition, may contribute to intestinal lymphocyte loss either directly or indirectly via loss of intestinal epithelial cells. This latter indirect effect remains to be determined because we did not measure intestinal epithelial cell loss. Regardless of the effect of GC (or lack or GC in the case of ADX mice) on the intestinal epithelial cells, GCs are not the primary mechanism for intestinal lymphoid cell loss 24 h after acute treadmill running because a similar pattern of lower cell numbers was observed in both ADX and sham-treated mice.
There are limitations with this study. Although ADX eliminates GCs, it reduces epinephrine production as well. Catecholamines have apoptosis-inducing effects on lymphocytes (40, 41), and it is possible that the higher lymphocyte numbers observed in ADX compared with Sham mice were due to overall lower epinephrine production. After ablation of the adrenal glands, circulating and tissue epinephrine levels may still be high because of extra-adrenal synthesis of epinephrine by methylation of norepinephrine via tissue phenylethanolamine N-methyltransferase (PMNT) (51). We did not measure plasma epinephrine levels in the ADX mice, and it is possible that the reduction in intestinal lymphocyte numbers 24 h postexercise was due to extra-adrenal epinephrine effects on apoptosis. Whether PMNT induction occurs in mouse intestine after ADX is not known.
The physiological consequences of the overall reduction in intestinal lymphocyte numbers with intense exercise and the apparent greater susceptibility of CD8 relative to CD8 T to contribute to the cell loss remain to be determined. It is likely that the physiological implications will depend, in part, on the time course for reconstitution of this intestinal lymphocyte pool and the environmental exposures during this "open window" period. It is still unclear whether loss of intestinal lymphocytes during exercise represents a direct effect of lymphocyte apoptosis inducing triggers that accompany exercise, an indirect effect due to growth factor withdrawal as a result of atrophy of epithelial cells by these same triggers, or a consequence of cardiovascular readjustments. This study suggests that at least one of the apoptosis-inducing triggers, GCs, does not directly mediate the loss of lymphocytes in the gastrointestinal tract after heavy, dynamic exercise.
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ACKNOWLEDGMENTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This research was supported by a grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada. J. Quadrilatero and J. Boudreau were the recipients of NSERC graduate and undergraduate scholarships, respectively.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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T cells in the intestinal epithelial layer in the prevention of inflammatory bowel disease. Proc Natl Acad Sci USA 100: 5324-5329, 2003. T cells and Peyer's patches. J Exp Med 191: 1569-1580, 2000./ in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus-derived T lymphocytes. J Exp Med 176: 187-199, 1992.This article has been cited by other articles:
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  J. Quadrilatero and L. Hoffman-Goetz N-acetyl-l-cysteine protects intestinal lymphocytes from apoptotic death after acute exercise in adrenalectomized mice Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1664 - R1672. [Abstract] [Full Text] [PDF]
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Significantly (P < 0.01) different compared with Nonexercised and Immediate groups (B). The interaction between surgical and exercise condition was not significant (C). All values are presented as means ± SE. Differences were determined by Tukey's post hoc test.
