Adrenergic Modulation of Hematopoiesis.

Hematopoiesis produce every day billions of blood cells and takes place in the bone marrow (BM) by the proliferation and differentiation of hematopoietic stem cells (HSC). HSC are found mainly adjacent to the BM vascular sinusoids where endothelial cells and mesenchimal stromal cells promote HSC maintenance by producing a variety of factors. Other cell types that regulate HSC niches include sympathetic nerves, non-myelinating Schwann cells and a variety of mature hematopoietic cells such as macrophages, neutrophils, and megakaryocytes. This review will focus on the role of adrenergic signals, i.e. of catecholamines, in the regulation of the HSC niche. The available evidence is rather controversial possibly due to the fact that adrenergic receptors are expressed by many cellular components of the niche and also by the often neglected observation that catecholamines may be produced and released also by the BM cells themselves. In addition one has to consider that, physiologically, the sympathetic nervous system (SNS) activity follows a circadian rhythmicity as driven by the suprachiasmatic nucleus (SCN) of the hypothalamus but may be also activated by cognitive and non-cognitive environmental stimuli. The adrenergic modulation of hematopoiesis holds a considerable potential for pharmacological therapeutic approaches in a variety of hematopoietic disorders and for HSC transplantation however the complexity of the system demands further studies. Graphical Abstract Sympathetic nerve termini may release NE while mature BM cells may release norepinephrine (NE) and / or epinephrine (E). Both may bind to ß-adrenergic receptor (AR) expressed in nestin+MSC in the hematopoietic stem cell (HSC) niche and regulate the physiological trafficking of HSC by modulating the expression of CXCL12 and SCF. Both NE and E may also activate Lin - c-Kit+ Sca-1+ (LKS) cell via another AR. In addition, NE may also signal to α1-AR expressed in pre-B cells which by TGF-ß secretion might regulate proliferation of their lymphoid progenitors in an autocrine manner and/or inhibit myeloid progenitors.

Inter-kingdom signaling between gut microbiota and their host.

The crosstalk between prokaryotic bacteria and eukaryotic gut epithelial cells has opened a new field for research. Quorum sensing system (QS) molecules employed by gut microbiota may play an essential role in host-microbial symbioses of the gut. Recent studies on the gut microbiome will unveil evolved mechanisms of the host to affect bacterial QS and shape bacterial composition. Bacterial autoinducers (AIs) could talk to the host's gut by eliciting proinflammatory effects and modulating the activities of T lymphocyte, macrophage, dendritic cells, and neutrophils. In addition, the gut mucosa could interfere with bacterial AIs by degrading them or secreting AI mimics. Moreover, bacterial AIs and gut hormones epinephrine and noradrenaline may be interchangeable in the crosstalk between the microbiota and human gut. Therefore, inter-kingdom signaling between gut microbiota and host may provide a novel target in the management of gut microbiota-related conditions or diseases in the future.

The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity.

In vitro and ex vivo studies assessing the impact of stress hormones on immune competence commonly replace the natural milieu of leukocytes with an artificial medium, excluding plasma factors, hormones, and cytokines. Given prevalent inconsistencies between in vitro, ex vivo, and in vivo findings, we studied whether such procedures could yield misleading outcomes regarding the impact of stress hormones on NK cell cytotoxicity (NKCC), using fresh human whole blood samples. We found that in the presence of plasma 10-30-fold higher concentrations of cortisol, epinephrine, and prostaglandin-E2 (PGE2) were required to reach suppression levels evident in the context of artificial medium. Importantly, whereas the NK suppressive effects of PGE2 occurred immediately and remained stable upon prolonged exposure, the suppressive effects of cortisol slowly increased over time. Last, to simulate the exclusion of stress factors in the ex vivo approach, we subjected whole blood to stress hormones (as occurs in vivo), and abruptly removed them. We found that the effects of epinephrine and PGE2 quickly disappeared, while the effects of cortisol persisted. Overall, these findings demonstrate the potential misleading nature of in vitro and ex vivo procedures, and specifically suggest that (i) the common in vitro findings of profound suppression of NKCC by stress hormones are overestimation of their direct effects expected in vivo; and (ii) the common ex vivo approach cannot reflect the direct in vivo suppressive effects of epinephrine and PGE2 on NKCC, while inflating the effects of glucocorticoids. Some of these fallacies may be circumvented by using non-delayed whole blood NKCC assays in humans.

Catecholamine stress alters neutrophil trafficking and impairs wound healing by ß2-adrenergic receptor-mediated upregulation of IL-6.

Stress-induced hormones can alter the inflammatory response to tissue injury; however, the precise mechanism by which epinephrine influences inflammatory response and wound healing is not well defined. Here we demonstrate that epinephrine alters the neutrophil (polymorphonuclear leukocyte (PMN))-dependent inflammatory response to a cutaneous wound. Using noninvasive real-time imaging of genetically tagged PMNs in a murine skin wound, chronic, epinephrine-mediated stress was modeled by sustained delivery of epinephrine. Prolonged systemic exposure of epinephrine resulted in persistent PMN trafficking to the wound site via an IL-6-mediated mechanism, and this in turn impaired wound repair. Further, we demonstrate that ß2-adrenergic receptor-dependent activation of proinflammatory macrophages is critical for epinephrine-mediated IL-6 production. This study expands our current understanding of stress hormone-mediated impairment of wound healing and provides an important mechanistic link to explain how epinephrine stress exacerbates inflammation via increased number and lifetime of PMNs.

Overnight changes of immune parameters and catecholamines are associated with mood and stress.

OBJECTIVES: To test the hypothesis that a nocturnal decrease of secretion of inflammation markers and catecholamines would be associated with mood and stress variables even after controlling for objective sleep variables. METHODS: A total of 130 healthy volunteers participated in this study, spending 2 nights in the Gillin Laboratory of Sleep and Chronobiology at the University of California, San Diego, General Clinical Research Center. Blood samples were obtained before sleep (10:30 PM) and after awakening (6:30 AM) on the first day, and these samples were assayed for inflammatory biomarkers and catecholamines. On the second night, polysomnographic records were scored for objective sleep variables, e.g., total sleep time and wake after sleep onset. Self-rating scales for mood, stress, depression, and daily hassles were administered the second day. RESULTS: The nocturnal decrease in interleukin-6 was smaller in people who reported more negative mood or fatigue and greater in those who reported more uplift events (e.g., with Profile of Mood States fatigue r(p) = -.25 to -.30). People with high stress or high depression levels had smaller nocturnal decreases of epinephrine. That relationship was even stronger when partial correlations were used to control for morning level and sleep variables. The associations between nocturnal changes of C-reactive protein, soluble tumor necrosis factor-receptor I, and norepinephrine with psychological states were nonremarkable. CONCLUSIONS: The analyses of nocturnal change scores (difference scores) add substantial information compared with the traditional analyses of morning levels of immune variables and catecholamines alone. Subjective well-being is significantly associated with a greater nocturnal decrease of interleukin-6 and epinephrine. More research on nocturnal adaptation processes is warranted.

[Case report : Severe anaphylactic shock followed by positive skin-prick-test to multiple vasoconstrictors].

A 71-year-old woman was scheduled for revision of total hip replacement under general anesthesia. Twenty minutes before entering the operating room, slight urticaria was caused by drop infusion of cefotiam. It was stopped immediately and the patient entered the operating room without any symptoms. Anesthesia was induced and maintained with sevoflurane and remifentanil. After 3 hours, systolic arterial pressure (SAS) dropped to 80 mmHg. Injecting of ephedrine 8 mg was not effective, and we injected a total of 3 mg of methoxamine. Then SAS dropped to 50 mmHg. We injected epinephrine 0.2 mg twice and also started continuous infusion of norepinephrine. Severe skin rash indicated that anaphylactic reaction had occurred. About 20 minutes after starting norepinephrine, the SAS was stabilized. We decided to stop the operation, and the patient was moved to the intensive care unit (ICU). A few hours after entering the ICU, she was extubated and moved to the general ward next day. Skin-prick-tests performed 14 days later indicated that she was allergic to ephedrine, methoxamine, epinephrine, dopamine and a few more drugs.

Temporal pattern and effect of sex on lipopolysaccharide-induced stress hormone and cytokine response in pigs.

The temporal pattern and sex effect of immune and stress hormone responses to a lipopolysaccharide (LPS) challenge were assessed using a pig model. Secretion of the pro-inflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 increased in a time-dependent manner following LPS infusion. There was also a time-dependent increase in secretion of the stress-related hormones cortisol, epinephrine (E), and norepinephrine (NE) following LPS, with peak concentrations attained within 30 min. The magnitude of the TNF-alpha and IL-1beta responses were both positively associated (P < 0.05) with the magnitude of cortisol response following LPS, whereas serum IL-1beta and IL-6 were positively correlated with the magnitude of E and NE responses following LPS. Acute-phase protein production was also time-dependently increased following LPS. The concentration of immune cells in circulation was decreased (P < 0.05) at 5.5h post-LPS and negatively correlated with pro-inflammatory cytokine production. By 24h post-LPS, immune cell counts increased (P < 0.05) and were positively associated with both pro-inflammatory cytokine and stress hormone production. The amplitude of pro-inflammatory cytokine response following LPS was affected (P < 0.05) by sex classification; however, the magnitude of elevated cytokine concentrations was not. The magnitude of the NE response, but not of the E and cortisol responses, to LPS was influenced by sex (P < 0.05). Similar to the pro-inflammatory cytokines, the magnitude of exposure to the stress hormones following LPS was not influenced by sex. The production of serum amyloid A (SAA) was influenced by sex, with barrows producing more SAA than gilts at 24h post-LPS (P < 0.05). Collectively, these results demonstrate sex-specific, concomitant temporal changes in innate immune- and stress-related hormones.

[Liver mitochondria in antigenic stress in rats]. / Mitokhondrii pecheni v realizatsii antigennogo napriazheniia organizma u krys.

The penomenon of reciprocal regulation of succinate dehidrogenase activity in rat liver mitochondria was elicited in antigenic strain induced by the administration of activated lymphocytes from animals with allotransplated heart. Two coupled but opposite changes (simultaneous activation and inhibition) in succinate depended ATP synthesis and calcium transport occur. The inhibition was correlated with the activation of synthetic processes in hepatocytes. Similar changes were provoked by epinephrine (either administered i.p. or released endogenously under immobilization stress and in myocardium infarction) as well as in patients with stomach tumor. The physiological significance of the reciprocal regulation of succinate dehydrogenase is discussed.

[Comparative study on the effect of antiatherosclerotic diet enriched with polyunsaturated omega-3 fatty acids of plant and animal origin on the level of natural antibodies against catecholamines in patients with cardiovascular diseases]. / Sravnitel'nyi analiz vliianiia protivoateroskleroticheskikh diet, obogashchennykh PNZhK omega-3 pastitel'nogo i zhivotnogo proiskhozhdeniia na uroven' estestvennykh antitel k katekholaminam u bol'hykh serdechno-sosudistymi zabolevaniiami.

The levels of natural antibodies against catecholamines in 138 patients with cardiovascular diseases was studied and the comparative analysis of influence of antiatherosclerotic diets with different origin of PUFA omega-3 on dynamic of these parameters was made. For the first time discovered universal action of diets with PUFA omega-3 vegetable and animal origin on parameters of humoral immunity: in case of primary excess of norm of the contents of natural antibodies to adrenaline, noradrenaline and dopamine as a result of treatment these parameters were reduced or did not change; and at is primary a low their level--parameters increased in most cases. The greatest immunocorrection effect was rendered by diet, enriched PUFA omega-3 of freshwater fishes fat.

Stress hormones and the immunological responses to heat and exercise.

This review focuses on the response of "stress" hormones to heat, exercise (single or repeated bouts), and combinations of these stimuli, with particular reference to their impact upon immune function. Very hot conditions induce a typical stress response, with secretion of catecholamines and cortisol. The catecholamines induce a demargination of leukocytes, and cortisol subsequently causes cells to migrate to lymphoid tissue. Sustained exercise, even in a thermally comfortable environment, induces a larger hormonal response than moderate thermal stress. With moderate exercise, increases in leukocyte numbers are related mainly to plasma norepinephrine concentrations, but with more intense exercise epinephrine concentrations assume a major importance. As exercise continues, plasma cortisol levels also rise, inducing an influx of neutrophils from bone marrow and an efflux of other leukocyte subsets. A combination of exercise and heat stress augments both hormonal and leukocyte responses. But these changes seem to be reversed if temperatures are clamped by exercising in cold water. If a second bout of exercise is performed with an inter-test interval of 30-45 min, neither hormone concentrations nor immune responses show any great cumulative effect under temperate conditions. However, in a hot environment the second exercise bout induces a larger and more persistent neutrophilia. Training influences these various responses mainly by decreasing the stress imposed when exercising at a given absolute work-rate.