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.

Prior ß-blocker treatment decreases leukocyte responsiveness to injury.

Following injury, leukocytes are released from hematopoietic organs and migrate to the site of damage to regulate tissue inflammation and repair, however leukocytes lacking ß2-adrenergic receptor (ß2AR) expression have marked impairments in these processes. ß-blockade is a common strategy for the treatment of many cardiovascular etiologies, therefore the objective of our study was to assess the impact of prior ß-blocker treatment on baseline leukocyte parameters and their responsiveness to acute injury. In a temporal and ßAR isoform-dependent manner, chronic ß-blocker infusion increased splenic vascular cell adhesion molecule-1 (VCAM-1) expression and leukocyte accumulation (monocytes/macrophages, mast cells and neutrophils) and decreased chemokine receptor 2 (CCR2) expression, migration of bone marrow cells (BMC) and peripheral blood leukocytes (PBL), as well as infiltration into the heart following acute cardiac injury. Further, CCR2 expression and migratory responsiveness was significantly reduced in the PBL of patients receiving ß-blocker therapy compared to ß-blocker-naïve patients. These results highlight the ability of chronic ß-blocker treatment to alter baseline leukocyte characteristics that decrease their responsiveness to acute injury and suggest that prior ß-blockade may act to reduce the severity of innate immune responses.

A novel adjuvant, mixture of alum and the beta-adrenergic receptor antagonist propranolol, elicits both humoral and cellular immune responses for heat-killed Salmonella typhimurium vaccine.

OBJECTIVE: To determine the efficacy of the mixture of propranolol (PRP), a beta-adrenergic receptor antagonist, and alum, as a new adjuvant, in the induction of humoral and cellular immunity in response to heat-killed Salmonella typhimurium (S. typhimurium) (HKST) as a model vaccine. METHODS: BALB/c mice were divided into five groups. Mice in the experimental groups received either the HKST vaccine alone or in combination with the adjuvant alum, PRP or the alum-PRP mixture. Mice in the negative control group received phosphate-buffered saline. All mice were immunized two times on days 0 and 14. Two weeks after the last immunization, immune responses to S. typhimurium were assessed. RESULTS: Administration of the alum-PRP mixture as an adjuvant increased the ability of the HKST vaccine to enhance lymphocyte proliferation, shifted the immune response towards a T-helper (Th) 1 pattern and increased S. typhimurium specific IgG, IgG2a and IgG1. This resulted in improved protective immunity against S. typhimurium. CONCLUSION: Administration of the alum-PRP mixture as an adjuvant in combination with the HKST vaccine, can enhance both humoral and cellular immunity and shift the immune responses to a Th1 pattern.

Management of multiple valve disease.

Multivalvular heart disease is not an uncommon situation, but the paucity of data for each specific situation does not allow the proposal of a standardised, evidence-based management strategy. This paper aims at reviewing the available evidence on the management of multivalvular disease, taking into account the interactions between different valve lesions, the diagnostic pitfalls and the strategies that should be considered in the presence of multiple valvular disease.

Bench-to-bedside review: Beta-adrenergic modulation in sepsis.

Sepsis, despite recent therapeutic progress, still carries unacceptably high mortality rates. The adrenergic system, a key modulator of organ function and cardiovascular homeostasis, could be an interesting new therapeutic target for septic shock. Beta-adrenergic regulation of the immune function in sepsis is complex and is time dependent. However, beta2 activation as well as beta1 blockade seems to downregulate proinflammatory response by modulating the cytokine production profile. beta1 blockade improves cardiovascular homeostasis in septic animals, by lowering myocardial oxygen consumption without altering organ perfusion, and perhaps by restoring normal cardiovascular variability. Beta-blockers could also be of interest in the systemic catabolic response to sepsis, as they oppose epinephrine which is known to promote hyperglycemia, lipid and protein catabolism. The role of beta-blockers in coagulation is less clear cut. They could have a favorable role in the septic pro-coagulant state, as beta1 blockade may reduce platelet aggregation and normalize the depressed fibrinolytic status induced by adrenergic stimulation. Therefore, beta1 blockade as well as beta2 activation improves sepsis-induced immune, cardiovascular and coagulation dysfunctions. Beta2 blocking, however, seems beneficial in the metabolic field. Enough evidence has been accumulated in the literature to propose beta-adrenergic modulation, beta1 blockade and beta2 activation in particular, as new promising therapeutic targets for septic dyshomeostasis, modulating favorably immune, cardiovascular, metabolic and coagulation systems.

Combination of recombinant human growth hormone and propranolol decreases hypermetabolism and inflammation in severely burned children.

OBJECTIVE: Recombinant human growth hormone (rhGH) is a salutary modulator of posttraumatic metabolic responses. However, rhGH administration is associated with deleterious side effects, such as hyperglycemia, increased free fatty acids, and triglycerides, which limit its use. Administration of beta-blocker attenuates cardiac work and resting energy expenditure after severe thermal injury and improves fat metabolism and insulin sensitivity. Therefore, the combination of rhGH plus propranolol appears ideal. The aim of the present study was to determine whether rhGH plus propranolol improves hypermetabolism and the inflammatory and acute phase response after severe burn without causing adverse side effects. DESIGN: Prospective randomized control trial. SETTING: Shriners Hospitals for Children. PATIENTS: Fifteen pediatric patients with burns > 40% total body surface area, 0.1-16 yrs of age, admitted within 7 days after burn. Fifteen children were matched for burn size, age, gender, inhalation injury, and infection and served as controls. INTERVENTIONS: Patients in the experimental group received rhGH (0.2 mg/kg/day) and propranolol (to decrease heart rate by 15%) for > or = 15 days. MEASUREMENTS AND MAIN RESULTS: Outcome measurements included resting energy expenditure, body composition, acute phase proteins, and cytokines. Both cohorts were similar in age, burn size, gender, and accompanying injuries. Percent predicted resting energy expenditure significantly decreased in patients receiving rhGH/propranolol (Delta -5% +/- 8%) compared with controls (Delta +35% +/- 20%) (p < .05). rhGH/propranolol administration significantly decreased serum C-reactive protein, cortisone, aspartate aminotransferase, alanine aminotransferase, free fatty acids, interleukin-6, interleukin-8, and macrophage inflammatory protein-1beta when compared with controls, while growth hormone/propranolol increased serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, growth hormone, prealbumin, and interleukin-7 when compared with placebo (p < .05). CONCLUSIONS: rhGH in combination with propranolol attenuates hypermetabolism and inflammation without the adverse side effects found with rhGH therapy alone.

Adrenergic modulation of dendritic cell cancer vaccine in a mouse model: role of dendritic cell maturation.

The aim of the present study was to evaluate the role of beta2-adrenergic receptors (beta2-ARs) in the outcome of a dendritic cell (DC)-based cancer vaccine in the murine E.G7-ovalbumin (OVA) model. We found that unlike the beta2-AR expressed on antigen loaded DCs, beta2-ARs expressed in the site of DCs inoculation may influence the efficacy of the antitumor response. Intradermal injection of Staphylococcus aureus peptidoglycan along with the beta2-AR-specific antagonist ICI 118,551 increased the local innate cytokine response in tumor-bearing mice. When the adoptive transfer of immature DCs loaded with OVA followed this skin preconditioning, the antitumor response was increased and tumor growth was significantly reduced. Surprisingly, when OVA-loaded mature DCs were used, the effect of the skin preconditioning was the opposite and tumor growth was similar to that observed in control, nonimmunized mice. The extent of the antitumor response on transfer of immature or mature DCs was mediated by a different migration in the draining lymph nodes and by a distinct recruitment of endogenous DCs that resulted in a modulation of the OVA-specific cytotoxic T lymphocyte response. The unexpected tolerogenic effect exerted by mature DCs on skin preconditioning was apparently mediated by the expression of a distinctive pattern of cytokines and of the suppressive enzyme indoleamine 2, 3-dioxygenase in draining lymph nodes. In conclusion, we found that beta2-ARs inhibition along with toll-like receptor2 activation at the site of cancer vaccination may either enhance the resulting antitumor response or be tolerogenic in dependence of the maturation state of the transferred DCs.

Antiviral therapy with non-selective beta-blockers: preliminary experimental and clinical corroboration.

Treatment with non-selective beta-blockers has been proposed to have an indirect antiviral activity acting via an enhanced performance of the immune system, and the mechanism of this activity has been laid out earlier. Experimental and clinical findings are presented that corroborate the hypothesis that inhibiting the immunosuppressive and stress-related cAMP-PKA pathway will enhance the immune system's ability to recognize foreign antigen and to access its vast repertory in an improved way, resulting in an indirect antiviral activity. Other drugs having an inhibitory effect on the cAMP-PKA pathway in cells of the immune system and therefore expected to have a comparable activity spectrum with different specific side-effects are presented, for example aspirin. Additionally the so far unexplained anticancer activity of aspirin is related to the same mechanism of an enhanced performance of the immune system.

Enantioselective immunoaffinity extraction for simultaneous determination of optically active bufuralol and its metabolites in human plasma by HPLC.

A combined method of immunoaffinity extraction with high-performance liquid chromatography has been developed for the enantioselective determination of bufuralol and its metabolites in human plasma. The antibodies having high affinity toward the asymmetric center at the C-1 position of bufuralol and its 1'-oxidized metabolites and low affinity to their antipodes were elicited by immunization of rabbits with immunogens, (1R)- and (1S)-1'-oxobufuralol O-carboxymethyloxime-bovine serum albumin conjugates, respectively. 0.5 ml Of the immunoaffinity adsorbent (7.6 mg.ml-1 for anti-(1S)-antibody and 28.8 mg.ml-1 for anti-(1R)-antibody) prepared by immobilization of an antibody was capable of retaining up to 1 microgram of (R)- and (S)-bufuralol and up to 500 ng of other metabolites. The adsorbates were recovered quantitatively by elution with methanol-10 mM ammonium acetate buffer (pH 5) (95:5, v/v) without any interfering peaks on the high-performance liquid chromatogram. The proposed method was evaluated to be useful for the simultaneous determination of optically active bufuralol and its metabolite in plasma with acceptable recovery and precision.

Beta-blocking autoantibodies in pediatric bronchial asthma.

We have used the inhibition of binding of a potent beta antagonist, iodohydroxybenzylpindolol, to canine lung-plasma membrane beta-adrenergic receptors as a test for beta-blocking autoantibodies in the sera of 376 mildly and severely asthmatic children. This binding inhibition assay, coupled with a variant test in which the binding assay was performed on selected sera (binding values below 2 SD from the mean) before and after immunodepletion of the sera (removal of IgG and IgA), permitted the conclusion that about 5% of the juvenile asthmatic population studied produce beta-blocking autoantibodies.

Influence of prazosin on the development of antinuclear antibodies in hypertensive patients.

A recent publication suggested that antinuclear antibodies (ANA) occur in up to one third of patients treated with the hypotensive drug prazosin (Minipress). We have examined a large group of hypertensive patients and found ANA in 9.7% of 145 patients taking prazosin and in 12.2% of hypertensive patients on any treatment regimen. Excluding patients taking methyldopa (a drug associated with a high ANA incidence), the ANA incidence fell to 6.9% in the prazosin-treated group and to 7.2% of all treated hypertensives. Of over 350 untreated hypertensive patients, 6.0% had ANA. Prazosin did not increase the ANA incidence in patients on or off various drug combinations including beta blockers and diuretics. Analysis of the data by age and sex confirmed our conclusion that prazosin therapy is not accompanied by an increase in ANA.

[Effect of beta-adrenergic drugs on humoral immune response factors]. / Vliianie na beta-adrenergichni lekarstveni serdstva vurkhu niakoi faktori na khumoralmiia imunen otgovor.

The authors examined the influence of beta-adrenergic stimulators Isoprenaline and Salbutamol as well as beta-adrenergic blockers Propranolol, Practolol and Pindolol on the proliferation of cells, forming plaques, 7S-immunoglobulins, hemagglutination titres and hemolytic activity of the complement. Primary stimulation with subsequent inhibition was induced by beta-adrenergic agonists and inhibition--by beta blocker Propronanol in a base of 10 mg/kg on the proliferation of cells, forming antibodies. The results were in correlation with hemagglutination titres. Salbutamol and beta-blockers inhibited immune hemolysis. The mechanisms of the observed effect are discussed in respect to the specific and nonspecific effect of the drugs used.