Chemical sympathectomy increases numbers of inflammatory cells in the peritoneum early in murine listeriosis.

Here, we investigated the effects of sympathectomy on systemic bacterial loads following infection with Listeria monocytogenes, and on innate and specific immune responses in the peritoneum. Sympathectomy decreased systemic bacterial loads, and increased the number of peritoneal leukocytes and the percentage of peritoneal macrophages three days postinfection. This suggests that sympathectomy-induced decreases systemic bacterial loads are associated with increased recruitment of inflammatory cells into tissues during the innate immune response.

Chemical sympathectomy alters numbers of splenic and peritoneal leukocytes.

Sympathectomy of BALB/c mice that were injected with either Listeria monocytogenes or saline did not affect the total number of splenic leukocytes measured 1-3 days after injection, but sympathectomy did increase the percentages of neutrophils in the spleens of both infected and uninfected mice. By contrast, sympathectomy was associated with increased numbers of peritoneal exudate cells (PEC) and peritoneal macrophages in both groups of mice. Sympathectomy did not affect tumor necrosis factor-alpha, interleukin-12, or interferon-gamma production in cultured splenocytes or PEC in either infected or uninfected mice.

Moderate exercise is associated with enhanced antigen-specific cytokine, but not IgM antibody production in aged mice.

It has been suggested that moderate exercise may modulate the immune response in the elderly. We investigated whether moderate exercise had an effect on the immune response to viral infection in both young (2-4 months) and older (16-18 months) male BALB/cJ mice. Exercised (EX) mice ran on a treadmill for 8 weeks at a gradually increasing speed and duration whereas control (CON) mice were only handled briefly during each exercise session and then returned to their cages. Mice were infected with herpes simplex virus type 1 (HSV-1) 24 h post-exercise. Serum IgM anti-HSV antibody, HSV-1 specific Th1/Th2 cytokine production by spleen cells, and cytokine production by alveolar cells were measured 7 days post-infection. In the aged mice, exercise was associated with an enhanced production of the HSV-1 specific Th1-associated cytokines, interleukin (IL)-2 and interferon (IFN)-gamma, but had no effect on the Th2-associated cytokine IL-10 or IgM antibody. No effect of exercise was observed in young mice. IL-12 production was not altered by exercise, but aging was associated with altered IL-12 production in a tissue-specific manner. In conclusion, moderate exercise was associated with increased antigen-specific IL-2 and IFN-gamma production in response to viral challenge in older mice.

Heart rate, neuroendocrine, and immunological reactivity in response to an acute laboratory stressor.

OBJECTIVE: The primary objective of the present study was to identify neuroendocrine and immunological correlates of cardiovascular reactivity to an acute laboratory stressor. METHODS: Subjects were 56 healthy volunteers. Heart rate and blood pressure were assessed at regular intervals during a 30-minute adaptation period and a 6-minute videotaped speech task. Blood was drawn before and after the task and was assayed for natural killer cell activity (NKCA), cortisol production, in vitro interferon gamma (IFN-gamma) and interleukin 10 production by peripheral blood mononuclear cells (PBMC), and antibody titers to the Epstein-Barr virus. Psychological measures were also administered. RESULTS: NKCA increased significantly in response to the task, and this increase was significantly and positively correlated with heart rate reactivity. IFN-gamma production by PBMC also increased in response to the task, but these increases were unrelated to heart rate reactivity. In addition, baseline cortisol levels were found to be predictive of heart rate reactivity. Finally, questionnaire data were modestly related to various aspects of stress-induced reactivity. CONCLUSIONS: Consistent with the task-related increases in NKCA and IFN-gamma, acute stress may signal an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Furthermore, the finding that heart rate reactivity was related in part to baseline individual differences in cortisol production suggests that short-term cardiovascular responses to stress may be directly related to longer-term neuroendocrine modulation. Finally, the present results also help to highlight the influence of both sympathetic and nonsympathetic pathways in the response to acute stressors and suggest tentative links between certain psychological traits and various aspects of stress-induced reactivity.

Expression of Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness and association with multiorgan dysfunction severity and survival.

OBJECTIVE: This was an exploratory study with three goals: a) to quantify the expression of the apoptotic receptor Fas and its ligand (FasL) on peripheral blood mononuclear cells (PBMCs) in patients with, or at risk for, multiple organ dysfunction syndrome (MODS); b) to compare this expression with the respective expression in matched controls; and c) to explore the association with MODS severity and survival. DESIGN: Repeated-measures correlational and cross-sectional design. SETTING: The surgical, medical, and the trauma/burn intensive care unit of an academic institution. PATIENTS: Thirty-five adult, critically ill patients meeting the diagnostic criteria for systemic inflammatory response syndrome (SIRS) with MODS, or at risk for MODS, were followed for 14 days. Thirty-five non-SIRS controls matched with patients for age, gender, and race comprised the control group. INTERVENTIONS: Peripheral blood sampling every 48 hrs. MEASUREMENTS/MAIN RESULTS: T cells were considerably depleted in SIRS/MODS patients (p <.001), and Fas and FasL expression on PBMCs (flow cytometric analysis) was elevated significantly compared with controls (p <.001). In contrast to controls, non-T cells were the major sources of Fas and FasL in SIRS/MODS patients (p <.01). Expression of Fas and FasL exhibited a bimodal correlation with severity (p <.03). High severity patients demonstrated increasing Fas and FasL expression with increasing severity in contrast to declining expression in moderately severe patients. Fas and FasL measurements were significantly and positively associated with the likelihood of survival (p <.05). CONCLUSIONS: Dysregulation in the expression of apoptotic receptors Fas and FasL, at least in PBMCs, may be involved in the pathophysiology of SIRS, the related lymphocytopenia, and the onset of MODS and the related morbidity and mortality rates.

Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes.

Many investigators have shown that ablation of the sympathetic nervous system (SNS) with 6-hydroxydopamine (6-OHDA) can alter cell-mediated and humoral immune responses to antigenic challenge. Fewer studies have examined 6-OHDA-induced changes in natural immunity. In this study, we have examined the effect of chemical sympathectomy on the nonspecific and specific phases of the response to infection with Listeria monocytogenes. Sympathectomy decreased splenic bacterial loads 3 and 5 days post-infection and increased splenic neutrophils 3 days post-infection. Sympathectomy decreased splenocyte numbers and antigen-stimulated cytokine secretion from splenocytes. These results suggest that the SNS influences specific responses by modulating innate responses.

Serum leptin levels are higher but are not independently associated with severity or mortality in the multiple organ dysfunction/systemic inflammatory response syndrome: a matched case control and a longitudinal study.

OBJECTIVE: Hypercatabolism and immune dysfunction are closely associated with the development of systemic inflammatory response--multiple organ dysfunction (SIRS/MODS) in critical illness. It remains unclear however, whether leptin, an adipocyte-derived hormone whose levels are influenced by several cytokines and which regulates immune function, food-intake and energy expenditure is independently related to the development of and/or severity and mortality from SIRS/MODS. DESIGN AND PATIENTS: To assess the role of leptin in SIRS/MODS we performed a matched case control and a longitudinal study (14 days) in 35 critically ill patients with SIRS/MODS and 35 matched controls. RESULTS: Baseline leptin levels were positively associated with body mass index (BMI) and TNF-alpha (P < 0.01) in patients and with IGF-1 and IL-6 levels (P < 0.05) in controls. Furthermore, leptin levels exhibited a progressive increase from the first to the last day of the study and although baseline levels were not different, peak leptin levels as well as leptin levels on the last day of the study were significantly higher in cases than in controls (P < 0.05). TNF-alpha levels, IL-6 and cortisol levels were also higher, whereas IGF-1 levels were lower in cases (P < 0.05). To assess whether leptin levels are independently associated with SIRS/MODS we performed multivariate logistic regression analysis which revealed that leptin up-regulation in cases is mediated by elevated TNF-alpha and cortisol levels. Finally, there was no independent association between leptin and survival in this group of critically ill patients. CONCLUSION: We conclude that cytokines and cortisol upregulate leptin levels, which may contribute to the development of the hypercatabolism, wasting and immune dysfunction but leptin levels are not independently associated with severity or mortality of patients with systemic inflammatory response-multiple organ dysfunction.

Prolonged exercise suppresses antigen-specific cytokine response to upper respiratory infection.

Fatiguing exercise has been associated with an increased susceptibility to infection. This study examined the antigen-specific T-helper (Th) type 1 and Th type 2 cytokine response to herpes simplex virus (HSV) infection after an acute bout of fatiguing exercise. Male BALB/cJ mice ran on a treadmill (Ex) until voluntary fatigue (approximately 2.5 h), and control mice were handled and remained next to the treadmill. Mice were infected with HSV 20 min after exercise. Mice were killed 2 or 7 days postinfection, and sera and spleens were taken for the determination of HSV-specific serum IgM, splenocyte cytokine production during culture with HSV, and splenocyte natural killer cell cytotoxicity. Both Th type 1 [interleukin (IL)-2, interferon-gamma, IL-12] and Th type 2 (IL-10) cytokine production in spleen cell cultures, as well as natural killer cell cytotoxicity, decreased in Ex on day 2 postinfection. On day 7 postinfection, there was no difference in HSV-specific serum IgM or cytokine production by cells from control and Ex mice, with the exception of decreased IL-12 in Ex mice. These findings suggest that fatiguing exercise may alter the kinetics of antigen-specific cytokine production.

Depression, medical illness, and interleukin-1beta in older cardiac patients.

OBJECTIVE: A model has been proposed in which atherosclerosis contributes to depression in later life by the effects of cytokines on central monoamine systems. We collected pilot data to test the hypothesis that interleukin-1beta (IL-1beta) is associated with depression in a cardiac patient group. METHOD: Thirty-seven subjects completed research evaluations that included depression diagnosis (Structured Clinical Interview for DSM-III-R), depressive symptom severity (Hamilton Rating Scale for Depression), medical illness burden (Cumulative Illness Rating Scale), and serum IL-1beta level measured by enzyme linked immunosorbent assay. RESULTS: Serum IL-1beta level was not significantly associated with depressive symptom severity or depression diagnosis, whether or not controlled for medical illness burden, age, and gender. IL-1beta level was significantly correlated with medical illness burden. CONCLUSIONS: We did not confirm our study hypothesis. The correlation of IL-1beta level with medical illness burden likely reflects its release as part of the "sickness response" in a wide variety of disease states. Further research using a larger sample size and a non-cardiac comparison group is warranted.

Soluble fas levels correlate with multiple organ dysfunction severity, survival and nitrate levels, but not with cellular apoptotic markers in critically ill patients.

Apoptosis is a mode of programmed cell death (PCD). Transduction of apoptotic signals results in cellular suicide. Organ specific apoptosis has been proposed as a factor in multiple organ dysfunction syndrome (MODS). Fas is a widely occurring apoptotic signal receptor molecule expressed by almost any type of cell, which is also released in a soluble circulating form (circulating fas, sfas). In this exploratory study, we investigated the association of sfas with severity, survival, known mediators of multiple organ dysfunction, and cellular apoptotic markers on peripheral blood mononuclear cells (PBMC) in a group of 35 patients with MODS and in 35 matched controls. Critically ill patients with MODS had significantly elevated sfas levels compared to controls over time (P < .001). Increased serum concentration of circulating fas was associated with increased severity of multiple organ dysfunction. Non-survivors exhibited significantly higher sfas levels compared to survivors (P < .01) and increasing sfas was inversely associated with the likelihood of survival (P < .05). Circulating fas levels correlated highly with serum nitrate concentration, but not with fas and fasL expression on PBMC of critically ill patients. TNF-alpha and IL-6, although they appear to be mediators of both apoptosis and MODS, had no association with sfas. These results are suggestive of the need for further investigation on the role of apoptotic signaling in the development of MODS. They also suggest a potential prognostic value of sfas for SIRS/MODS clinical outcomes.