Exercise stress increases susceptibility to influenza infection.

Exercise stress is associated with an increased risk for upper respiratory tract infection (URTI) while moderate exercise has been associated with a decreased risk. We have shown that exercise stress can increase susceptibility (morbidity, symptom severity and mortality) to HSV-1 respiratory infection, but there is little evidence on the effects of stressful exercise on susceptibility to the principal etiological agents of human respiratory infections, including influenza viruses. This study examined the effects of stressful exercise on susceptibility to influenza virus (A/Puerto Rico/8/34 (H1N1)). Mice were assigned to one of two groups: exercise (Ex) or control (Con). Exercise consisted of a treadmill run to volitional fatigue ( approximately 120 min) performed on three consecutive days. Fifteen minutes after the last bout of exercise or rest, mice (n=20-21/group) were intranasally inoculated with a standardized dose of influenza virus (0.25 HAU). Mice were monitored daily for morbidity (time to sickness), symptom severity and mortality (time to death) for 21 days. Exercise stress was associated with an increase in susceptibility to infection (morbidity, mortality and symptom severity on days 6 and 7; P<0.05). These data from a controlled influenza virus challenge model add significantly to the growing body of evidence that severe exercise can increase susceptibility to URTI.

Benefits of oat beta-glucan on respiratory infection following exercise stress: role of lung macrophages.

Exercise stress is associated with an increased risk for upper respiratory tract infection (URTI). We have shown that consumption of the soluble oat fiber beta-glucan (ObetaG) can offset the increased risk for infection and decreased macrophage antiviral resistance following stressful exercise; however, the direct role of macrophages is unknown. This study examined the effect of macrophage depletion on the benefits of orally administered ObetaG on susceptibility to infection (morbidity, symptom severity, and mortality) following exercise stress. CL(2)MDP (Ex- H(2)O-CL(2)MDP, Ex-ObetaG-CL(2)MDP, Con-H(2)O-CL(2)MDP, Con-ObetaG-CL(2)MDP)-encapsulated liposomes were administered intranasally to deplete macrophages, and PBS (Ex-H(2)O-PBS, Ex-ObetaG-PBS, Con-H(2)O-PBS, Con-ObetaG-PBS)-encapsulated liposomes were given to macrophage-intact groups. Ex mice ran to volitional fatigue on a treadmill for 3 consecutive days, and ObetaG mice were fed a solution of 50% ObetaG in their drinking water for 10 consecutive days before infection. Fifteen minutes following the final bout of Ex or rest, mice were intranasally inoculated with 50 microl of a standardized dose of herpes simplex virus-1. Ex increased morbidity (P < 0.001) and symptom severity (P < 0.05) but not mortality (P = 0.09). The increase in morbidity and symptom severity was blocked by ObetaG consumption for 10 consecutive days before exercise and infection [morbidity (P < 0.001) and symptom severity (P < 0.05)]. Depletion of macrophages negated the beneficial effects of ObetaG on reducing susceptibility to infection following exercise stress, as evidenced by an increase in morbidity (P < 0.01) and symptom severity (P < 0.05). Results indicate that lung macrophages are at least partially responsible for mediating the beneficial effects of ObetaG on susceptibility to respiratory infection following exercise stress.

Susceptibility to HSV-1 infection and exercise stress in female mice: role of estrogen.

Exhaustive exercise has been associated with an increased risk for upper respiratory tract infections in mice and humans. We have previously shown (Brown AS, Davis JM, Murphy AE, Carmichael MD, Ghaffer A, Mayer EP. Med Sci Sports Exerc 36: 1290-1295, 2004) that female mice are better protected from the lethal effects of herpes simplex virus type 1 (HSV-1) infection, both at rest and following exercise stress, but little is known about possible mechanisms. This study tested the effects of estrogen on HSV-1 infection and macrophage antiviral resistance following repeated exhaustive exercise. Female mice were assigned to either exercise (Ex) or control (C): intact female (I-C or I-Ex), ovariectomized female (O-C or O-Ex), or ovariectomized estrogen-supplemented female (E-C or E-Ex). Exercise consisted of treadmill running to volitional fatigue ( approximately 125 min) for 3 consecutive days. Intact female mice had a later time to death than O and E (P < 0.05) and fewer deaths than both O and E (P < 0.05). Exercise stress was associated with increased time to sickness (P < 0.05) and symptom severity at days 6 and 12-21 postinfection (P < 0.05) and decreased macrophage antiviral resistance (P < 0.001) in all groups. E had increased symptom severity at days 6 and 13-21 postinfection (P < 0.05). Results indicate that intact female mice are better protected from the lethal effects of HSV-1 infection and that exercise stress had a similar negative impact in all groups. This protective effect was lost in ovariectomized mice, but it was not reinstated by 17beta-estradiol replacement. This indicates that other ovarian factors, alone or in combination with estrogen, are responsible for the protective effects in females.

Role of lung macrophages on susceptibility to respiratory infection following short-term moderate exercise training.

Moderate exercise training is associated with a decreased risk for upper respiratory tract infection in human and animal studies, but the mechanisms have not been elucidated. Lung macrophages play an important role in resistance to respiratory infection, and moderate exercise can enhance macrophage antiviral resistance, but no studies have directly tested the role of lung macrophages in this response. This study tested the effect of lung macrophage depletion on susceptibility to infection following short-term moderate exercise training. Mice were assigned to one of four groups: exercise (Ex) and resting controls (Con) with and without clodronate encapsulated liposomes (CL(2)MDP-lip). Ex mice ran for 1 h on a treadmill for 6 days at 36 m/min, 8% grade. Fifteen minutes following exercise or rest on the last day of training, mice were intranasally inoculated with a standardized dose of herpes simplex virus type 1. Clodronate (Ex-CL(2)MDP-lip and Con-CL(2)MDP-lip) or PBS liposomes (Ex-PBS-lip and Con-PBS-lip) (100 microl) were intranasally administered following exercise or rest on the 4th day of training and again on the 4th day postinfection. Morbidity, mortality, and symptom severity were monitored for 21 days. Exercise decreased morbidity by 36%, mortality by 61%, and symptom severity score on days 5-7 (P < 0.05). Depletion of lung macrophages negated the beneficial effects of moderate exercise. This was indicated by no differences between Ex-CL(2)MDP-lip and Con-PBS-lip in morbidity (89 vs. 95%), mortality (79 vs. 95%), or symptom severity. Results indicate that lung macrophages play an important role in mediating the beneficial effects of moderate exercise on susceptibility to respiratory infection.

Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity.

Both moderate exercise and the soluble fiber beta-glucan can have beneficial effects on the initiation and growth of tumors, but the data are limited, and there is no information on their combined effects. This study tested the independent and combined effects of short-term moderate-exercise training and the soluble oat fiber beta-glucan (ObetaG) on the metatastic spread of injected tumor cells and macrophage antitumor cytotoxicity. Male C57BL/6 mice were assigned to one of four groups: exercise (Ex)-H2O, Ex-ObetaG, control (Con)-H2O, or Con-ObetaG. ObetaG was fed in the drinking water for 10 days before tumor administration and death. Exercise consisted of treadmill running (1 h/day) for 6 days. After rest or exercise on the last day of training, syngeneic B16 melanoma cells (2 x 10(5)) were administered via intravenous injection (n = 8-11 per group). Lungs were removed 14 days later, and tumor foci were counted. Additional mice (n = 8 per group) were killed, and peritoneal macrophages were assayed for cytotoxicity against the same mouse tumor cell line at various effector-to-target ratios. Both moderate exercise and ObetaG decreased lung tumor foci and increased macrophage cytotoxicity. However, there were no differences in lung tumor foci and macrophage cytotoxicity between Ex-ObetaG and either Ex-H2O or Con-ObetaG. These data suggest that, although not additive in their effects, both short-term moderate-exercise training and consumption of the soluble ObetaG can decrease the metatastic spread of injected B16 melanoma cells, and these effects may be mediated in part by an increase in macrophage cytotoxicity to B16 melanoma.

Effects of moderate exercise and oat beta-glucan on innate immune function and susceptibility to respiratory infection.

Both moderate exercise and the soluble oat fiber beta-glucan can increase immune function and decrease risk of infection, but no information exists on their possible combined effects. This study tested the effects of moderate exercise and oat beta-glucan on respiratory infection, macrophage antiviral resistance, and natural killer (NK) cell cytotoxicity. Mice were assigned to four groups: exercise and water, exercise and oat beta-glucan, control water, or control oat beta-glucan. Oat beta-glucan was fed in the drinking water for 10 days before intranasal inoculation of herpes simplex virus type 1 (HSV-1) or euthanasia. Exercise consisted of treadmill running (1 h/day) for 6 days. Macrophage resistance to HSV-1 was increased with both exercise and oat beta-glucan, whereas NK cell cytotoxicity was only increased with exercise. Exercise was also associated with a 45 and 38% decrease in morbidity and mortality, respectively. Mortality was also decreased with oat beta-glucan, but this effect did not reach statistical significance. No additive effects of exercise and oat beta-glucan were found. These data confirm a positive effect of both moderate exercise and oat beta-glucan on immune function, but only moderate exercise was associated with a significant reduction in the risk of upper respiratory tract infection in this model.

Tissue expression and plasma concentrations of TNFalpha, IL-1beta, and IL-6 following treadmill exercise in mice.

Exercise can increase plasma inflammatory cytokine concentrations in humans, but tissue responses are not well studied. We examined plasma concentrations and tissue expression of TNFalpha, IL-1beta, and IL-6 following treadmill running in mice. C57B1/6 mice were randomly assigned to: non-exercise control (CON), sacrifice at 0 or 1.5 h after 60 min running (MOD0, MOD 1.5), sacrifice at 0, 1.5, or 3 h after fatiguing running (approximately 3 h) (EX0, EX1.5, EX3), or lipopolysaccharide (25 microg) with no exercise (LPS). Lung, liver, muscle, and brain mRNA expression was analyzed (n = 4-6/group) using reverse transcriptase-rapid polymerase chain reaction (RT-RPCR). Plasma cytokine concentrations were determined (n =4-10/group) by ELISA. Plasma IL-6 was higher in EX1.5, and lung TNFalpha mRNA was higher in EX1.5 and EX3 compared to CON (P < 0.05). No significant increases in plasma cytokine concentrations or tissue cytokine expression were found in other EX groups. LPS significantly increased these cytokine measures in tissues and plasma, with the exception of plasma IL-1beta which was undetectable. The source of the plasma IL-6 following exercise does not appear to be lung, liver, muscle, or brain tissue, and remains to be determined. These data also suggest that tissue level cytokine expression may not necessarily lead to increased plasma cytokine concentrations.

The collagenous domain of class A scavenger receptors is involved in macrophage adhesion to collagens.

Class A macrophage scavenger receptors (MSRs) have a remarkably broad ligand specificity and are well-known for their roles in atherogenesis and host defense. Recently, we demonstrated that these receptors also recognize and mediate adhesion to denatured forms of type I collagen. In this study, the involvement of the collagenous domain of MSRs in binding to denatured type I collagen was investigated. Transient expression of full-length, native type II MSR in COS-1 cells conferred adhesion to denatured type I collagens, whereas expression of a truncated receptor lacking the distal portion of the collagenous domain did not. Further, a synthetic peptide derived from the collagenous domain was effective in abrogating Mphi adhesion to denatured forms of type I collagen. We also addressed collagen-type specificity by examining MSR affinity for type III and type IV collagens. As with type I collagen, Mphis adhered only to denatured forms of type III collagen. Moreover, the adhesion was mediated by MSRs. In contrast, adhesion to denatured type IV collagen was not shown to be MSR-dependent, but adhesion to the native form was. MSR-mediated adhesion to types III and IV collagens was also shown to be dependent on the collagenous domain. Taken together, these data strongly suggest that the collagenous domain is involved in MSR-mediated adhesion to denatured forms of types I and III collagens and native, but not denatured, type IV collagen.

Exercise and tumor development in a mouse predisposed to multiple intestinal adenomas.

UNLABELLED: Epidemiological evidence suggests that physical activity may be protective against the development of colon cancer. Potential mechanisms remain largely unexplored due to the paucity of appropriate experimental models. PURPOSE: The purpose of this study was to examine the effect of exercise training on polyp development in an induced mutant mouse strain predisposed to multiple intestinal neoplasia (Min mouse). METHODS: Three-week-old male and female heterozygotes were randomly assigned to control (CON; 10 males, 6 females) or exercise (EX; 11 males, 11 females) groups. In the first week, EX mice were acclimated to treadmill running at 10-18 m x min(-1) for 15-60 min x d(-1). From 4-10 wk of age, mice ran at 18-21 m x min(-1) for 60 min. CON mice sat in Plexiglas lanes suspended above the treadmill for the same time periods. At 10 wk of age, the mice were sacrificed and the intestines removed, opened, and counted for polyps. RESULTS: Skeletal muscle oxidative capacity increased with training as shown by a 64% increase in citrate synthase activity in the gastrocnemius/soleus muscle of EX compared with CON (P = 0.009). There were no significant effects of exercise in the males and females combined on small intestine, colon, or total intestinal polyps (P > 0.05). When analyzed separately, however, there were fewer colon and total polyps in the EX than in the CON males, although the difference was not statistically significant (P = 0.06). CONCLUSIONS: These results suggest that seven weeks of exercise training do not affect the development of intestinal polyps in the Min mouse. Further studies are required to determine if a true sex difference exists or if variations on the current training protocol may affect tumor outcomes.

Selective adhesion of macrophages to denatured forms of type I collagen is mediated by scavenger receptors.

Macrophages (Mφs) are multifunctional immune cells which are involved in the regulation of immune and inflammatory responses, as well as in tissue repair and remodeling. In tissues, Mφs reside in areas which are rich in extracellular matrix (ECM), the structural component which also plays an essential role in regulating a variety of cellular functions. A major ECM protein encountered by Mφs is type I collagen, the most abundant of the fibril-forming collagens. In this study, the adhesion of RAW 264.7 murine Mphis to native fibrillar, monomeric, and denatured type I collagen was investigated. Using atomic force microscopy, structural differences between fibrillar and monomeric type I collagen were clearly resolved. When cultured on fibrillar type I collagen, Mphis adhered poorly. In contrast, they adhered significantly to monomeric, heat-denatured, or collagenase-modified type I collagen. Studies utilizing anti-beta1 and -beta2 integrin adhesion-blocking antibodies, RGD-containing peptides, or divalent cation-free conditions did not inhibit Mphi; adhesion to monomeric or denatured type I collagen. However, macrophage scavenger receptor (MSR) ligands and anti-MSR antibodies significantly blocked Mphi; adhesion to denatured and monomeric type I collagen strongly suggesting the involvement of the MSR as an adhesion molecule for denatured type I collagen. Further analysis by Western blot identified the MSR as the primary receptor for denatured type I collagen among Mphi; proteins purified from a heat-denatured type I collagen affinity column. These findings indicate that Mphis adhere selectively to denatured forms of type I collagen, but not the native fibrillar conformation, via their scavenger receptors.

Exercise effects on IFN-beta expression and viral replication in lung macrophages after HSV-1 infection.

Mice exercised to fatigue and exposed to herpes simplex virus type 1 (HSV-1) exhibit greater mortality than control mice. In this study, we examined lung macrophage resistance to HSV-1 after exercise in terms of both viral replication and interferon (IFN)-beta production. We utilized the reverse transcriptase-rapid polymerase chain reaction to measure the IFN-beta mRNA content in alveolar macrophages. IFN release was measured with a bioassay, and viral replication within the macrophage was assessed by plaque titration. Exercised (Ex) mice ran on a treadmill until fatigue while control (Con) mice remained in lanes above the treadmill. After exercise, alveolar macrophages were removed and incubated with HSV-1. Alveolar macrophage IFN-beta mRNA was greater in Ex than in Con mice. Culture supernatant from infected macrophages showed a higher degree of IFN release and a higher number of infectious viral particles in Ex vs. Con mice. It is likely that the increase in IFN-beta mRNA occurs in response to a higher degree of viral replication. These results suggest that macrophages from Ex mice are less resistant to infection with HSV-1.

Immune system activation and fatigue during treadmill running: role of interferon.

UNLABELLED: Extreme fatigue often accompanies infection and other diseases, but the causal mechanisms are unknown. Recent research has focused on various cytokines as potential immune system mediators of fatigue during illness. Interferon-alpha/beta (IFN-alpha/beta) has attracted the most interest in this regard. PURPOSE: The purpose of this research was to study the effect of IFN-alpha/beta on fatigue during treadmill running in mice. METHODS: Mice (male CD-1) were acclimated to treadmill running for 4 d before experimental sessions. In experiment 1 (EXP 1), mice were injected with either polyI:C (pI:C) (5 mg.kg-1 body weight) or saline (CON) 12 or 24 h before the exercise session. These sessions consisted of treadmill running to fatigue (approximately 3 h, 19-24 m.min-1, 5% grade, no shock). In experiment 2 (EXP 2), mice were injected 24 h before exercise with normal rabbit serum (CON), pI:C, or pI:C + anti-IFN-alpha/beta antibody (pI:C + Ab). RESULTS: The results of EXP 1 showed that the plasma IFN-alpha/beta titer was much higher at 24 h than at 12 h after pI:C injection (P < 0.001) and that run time to fatigue was significantly reduced only when the exercise occurred 24 h after injection (P < 0.05). In EXP 2, administration of the anti-IFN-alpha/beta antibody attenuated both the pI:C-induced increase in plasma IFN-alpha/beta (P < 0.001) and the decrease in run time to fatigue (r = -0.81, P < 0.001). CONCLUSIONS: These results suggest that immune system activation by pI:C was associated with early fatigue during prolonged treadmill exercise and that this effect may, at least partially, result from increased IFN-alpha/beta.

Exercise effects on lung tumor metastases and in vitro alveolar macrophage antitumor cytotoxicity.

This study examined the effects of moderate and prolonged exercise on 1) lung tumor metastases and 2) alveolar macrophage antitumor response in vitro. C57B1/6 mice were assigned to either Ex-30 (30-min run), Ex-F (run to fatigue), Ex-F-24 h (run to fatigue 24 h before tumor injection), or Con (rested in lanes above the treadmill). Mice received intravenous injections of syngeneic B16 melanoma cells 30 min postexercise. Lungs were removed 7 or 10 days later, and tumor foci were counted. Ex-F had fewer tumors than either Ex-30 or Con, whereas Ex-F-24 h also showed a strong trend toward fewer tumors. The initial localization of tumor cells in the lungs after injection was not different among groups. For the in vitro experiment, mice were killed immediately after exercise or 8 h later. Alveolar macrophages were removed and cultured in vitro with B16 melanoma cells. The growth of the tumors cultured with macrophages from Ex-F was lower than Con after exercise and, to a lesser extent, 8 h later. In Ex-30, this effect was only found immediately after exercise. The data suggest that prolonged exercise has a protective effect on lung tumor metastases and enhances alveolar macrophage antitumor cytotoxicity.

Galectin-3 expression in human atherosclerotic lesions.

The expression of galectin-3, a beta-galactoside-binding lectin, was studied in atherosclerotic lesions from specimens obtained from carotid endarterectomies, lower limb amputations, and thoracic aortas from autopsies of young adult trauma victims. Immunohistochemical staining with the monoclonal antibody M3/38 demonstrated the presence of galectin-3 in advanced atherosclerotic lesions from each of 13 cases of carotid endarterectomy and 16 lower limb amputations and in the thoracic aorta of 4 of 20 cases of trauma victim adults. Immunostaining did not detect galectin-3 in umbilical cord and normal thoracic aorta arteries and limb veins. Dual immunostaining with monoclonal antibodies M3/38 for galectin-3 and clone 1A4 for smooth muscle alpha-actin or HAM56 for human macrophage antigen showed that galectin-3 was localized predominantly in foam cells and macrophages and rarely (<5%) in the smooth muscle cells of atherosclerotic lesions. The incidence of galectin-3-positive cells was higher in the carotid artery atherosclerotic lesions, which are richer in foam cells, than in the lower limb atherosclerotic lesions, which are more fibrotic. Reverse transcription polymerase chain reaction showed a significantly higher ratio of galectin-3/beta-actin transcripts in 20 atherosclerotic arteries compared with that of 5 umbilical cord arteries. Western blot analysis confirmed a higher level of galectin-3 in atherosclerotic carotid and lower limb arteries compared with that of umbilical cord arteries. The increased expression of galectin-3 in atherosclerotic lesions suggests the involvement of this multifunctional protein in atherogenesis.

The role of stress hormones in exercise-induced suppression of alveolar macrophage antiviral function.

We hypothesized that a previously observed exercise-induced suppression of alveolar macrophage antiviral resistance results from increases in corticosterone and/or epinephrine. Mice (CD-1) were run to fatigue on a treadmill (exercise), or placed in Plexiglas lanes above the treadmill (control). The role of corticosterone was assessed by further dividing mice into groups receiving one of the following treatments; sham surgery, adrenalectomy, or adrenalectomy plus corticosterone replacement. Macrophage antiviral function was suppressed in the exercised mice compared to the control mice. However, macrophage antiviral function was not suppressed in the exercised mice that underwent adrenalectomy or adrenalectomy plus corticosterone replacement. We tested whether another adrenal factor (epinephrine) may be involved by dividing mice into exercise and control groups treated with either saline or propranolol. Macrophage antiviral function was again suppressed in the saline-treated exercised mice compared to saline-treated control mice, but no differences were found between the exercised mice receiving propranolol, control mice receiving propranolol, or saline-treated control mice. Isoproterenol, when added to alveolar macrophages in culture, also suppressed antiviral resistance. These findings suggest that decreased macrophage antiviral function following exercise may be due to increased release of adrenal catecholamines.

Transformation of rabbit vascular smooth muscle cells by human cytomegalovirus morphological transforming region I.

The association of human cytomegalovirus with atherosclerosis and the monoclonal hypothesis of atherogenesis suggested that transformation of vascular smooth muscle cells may be an outcome of the virus-host cell interaction. To test this hypothesis, rabbit aorta smooth muscle cells were transfected with the morphological transforming region I (mtrI) of human cytomegalovirus (HCMV) linked to the neomycin resistance gene. Foci of neomycin-resistant and morphologically transformed cells were isolated and expanded into fourteen RCMV strains. Eight of these strains acquired immortalization, but only one strain (RCMV-21) retained recombined viral sequences integrated in the cellular DNA. RCMV strains were heterogeneous in their morphology, expression of smooth muscle alpha-actin, growth, and mitogenic response to serum and fibroblast growth factor (FGF)-2 and -4. All RCMV strains assayed except RCMV-3 showed DNA synthesis in low serum medium and, with the exception of RCMV-1 cells, all showed a significant mitogenic response to FGF-2 and FGF-4, Maintenance of the transformed phenotype appeared independent of the retention of the transforming viral sequences, which was suggestive of a "hit-and-run" mechanism. These results suggested that morphological transformation by HCMV DNA sequences could enhance the mitogenic response of vascular smooth muscle cells to fibroblast growth factors.

Exercise, alveolar macrophage function, and susceptibility to respiratory infection.

The effects of exercise on susceptibility to respiratory infection were determined by using a murine model of intranasal challenge with herpes simplex type 1 virus (HSV-1). Two doses of treadmill exercise were assessed: moderate short-term (30 min) exercise and prolonged strenuous exercise to voluntary fatigue (2.5-3.5 h). Morbidity and mortality among exercised and control mice were compared after intranasal challenge with HSV-1. We also assessed the ability of alveolar macrophages to restrict HSV-1 viral replication (intrinsic resistance) among exercise and control groups of mice at several time points postexercise. Exercise to fatigue followed by exposure to viral infection resulted in greater morbidity and mortality than either no exercise or short-term moderate exercise. In addition, antiviral resistance of macrophages obtained from the lungs of both exercised groups was suppressed, albeit for a longer duration in the fatigued group. These data are particularly important in that they identify an exercise-induced decrease in antiviral resistance of a specific component of the immune system within the lungs, in conjunction with increased susceptibility to respiratory infection in vivo. The specific mechanism of decreased antiviral resistance of alveolar macrophages and its role in respiratory infection after exercise remains to be determined.

Lipopolysaccharide-induced suppression of phagocytosis: effects on the phagocytic machinery.

We have shown previously that Lipopolysaccharide (LPS) can suppress macrophage phagocytosis and that suppression was not mediated by the induction of cytokines (1). In this study we investigated the mechanisms by which LPS may be suppressing phagocytosis in thioglycolate-elicited murine peritoneal macrophages, by evaluating the effect of LPS on various components of the phagocytic machinery. LPS mediated suppression in vitro was not due to reduced Fc gamma receptor gene expression. LPS-treatment did result in a slight reduction in the number of Fc gamma RI receptors but this reduction could not account for the degree of suppression seen following LPS treatment. LPS treatment altered the distribution of microfilaments and microtubules and Møs with such alterations had reduced phagocytic activity, suggesting that LPS may be suppressing phagocytosis via its effects on the cytoskeletal network. LPS administration in vivo also resulted in reduced phagocytic activity.

Effects of exercise on the immune response to cancer.

This study examined the effects of two doses of exercise on tumor incidence and progression, and the number and activity of intratumoral phagocytic cells (80% macrophages [M phi's]). Male mice were randomly assigned to control (CON), moderate (MOD) or exhaustive (EXH) treadmill running. Mice were inoculated subcutaneously with 2.5 x 10(5) mammary adenocarcinoma cells after 3 d of running (3 h after the last run at a point when enhancement in M phi cytotoxicity is observed). This tumor was chosen due to its susceptibility to M phi inhibition in vitro and in vivo. Mice continued daily running for 14 d. Food intakes were higher during the last 3 d in MOD and EXH, but body weights were no different. Flow cytometer analysis of tumor masses revealed that MOD had greater numbers of phagocytic cells (vs EXH) with slightly higher phagocytic activities (vs CON and EXH) (P < 0.05). However, no group differences in tumor appearance were seen except on day 7 when CON had less observable tumors than MOD and EXH (P < 0.05). Tumor size was also not different between groups at any point. These results indicate that moderate exercise can increase the phagocytic capacity of intratumoral phagocytic cells, but these changes had no apparent effect on tumor incidence or progression in this study.

Effects of exercise on macrophage activation for antitumor cytotoxicity.

Recent evidence suggests that exercise affects macrophage functions and that amount of exercise may be important. We determined effects of moderate (MOD) and exhaustive treadmill running (EXH) on 1) ability of macrophages to become activated for antitumor cytotoxicity after injection of heat-inactivated Propionibacterium acnes in vivo, 2) macrophage responsiveness to activating agents lipopolysaccharide and interferon-gamma, and 3) role of glucocorticoids and various macrophage metabolic products in modulating cytotoxicity in exercised animals. Male C3H/HeN mice were randomly assigned to MOD (18 m/min, 5% grade, 30 min/day) or EXH (18-35 m/min, 5%, 2-4 h) on a motor-driven treadmill. Control animals were kept in simulated treadmill lanes located directly over the runners. In general, both MOD and EXH increased cytotoxicity (42 and 22%, respectively, across all experiments; P < 0.05). Enhanced cytotoxicity was not due to altered macrophage adherence, tumor necrosis factor-alpha, interleukin-1 beta, or reactive oxygen species. Reactive nitrogen species were responsible for enhanced toxicity in EXH only. Macrophage cytotoxicity was further increased by lipopolysaccharide and interferon-gamma to a similar maximal level that was the same in all groups. Plasma corticosterone was elevated two- and fourfold in MOD and EXH, respectively, but there was no correlation between plasma corticosterone and macrophage cytotoxicity when compared across all groups even though cells were sensitive to steroid-mediated suppression in vitro. However, consistent with a corticosterone effect, EXH reduced the number of peritoneal macrophages elicited during P. acnes inflammation and abolished the typical exercise-induced increase in cytotoxicity of activated macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)