Prolonged alpha-adrenergic stimulation causes changes in leukocyte distribution and lymphocyte apoptosis in the rat

Stevenson, John R.; Westermann, Jürgen; Liebmann, Peter M.; Hörtner, Michael; Rinner, I.; Felsner, P.; Wölfler, Albert; Schauenstein, Konrad

doi:10.1016/s0165-5728(01)00417-9

Cited by 62 publications

(32 citation statements)

References 28 publications

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“…Studies in rats have revealed that increased ␣-adrenergic stimulation, as is seen in CHF, results in lymphocyte apoptosis of both B and T cells, including both CD4 ϩ cells and CD8 ϩ cells, and this process may play a role in the decrease in CD4 ϩ and CD8 ϩ cells observed in this population of dogs with CHF. 34 The impact of the alterations in PBMC subpopulations on the immunologic function of CHF patients remains unclear and merits consideration in future CHF research.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte Subpopulations and Hematologic Variables in Dogs with Congestive Heart Failure

Farabaugh

Freeman

George

2004

Veterinary Internal Medicne

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Alterations in lymphocyte subpopulations and in other hematologic variables have been documented in people with heart failure. The purpose of the current study was to compare flow cytometric and hematologic variables in dogs with congestive heart failure (CHF) to healthy controls. CD4+ peripheral blood mononuclear cells (PBMC) and CD8+ lymphocytes were analyzed by flow cytometry, and white blood cell count, platelet count, hematocrit, and hemoglobin were determined by a complete blood count. Twenty‐five dogs with CHF (International Small Animal Cardiac Health Council [ISACHC] class 2 [n = 12] and ISACHC class 3a [n = 13]) and 13 healthy controls were enrolled in the study. Compared with the controls, dogs with CHF had markedly lower percentages of CD4+ PBMC, CD8+ lymphocytes, hematocrit, and hemoglobin, but markedly higher leukocytes, neutrophils, and platelets. There were no differences in these variables between dogs with dilated cardiomyopathy (n = 6) and those with chronic valvular disease (n = 19). Dogs in ISACHC class 3a had a markedly lower total lymphocyte number, CD4+ and CD8+ cells, and hematocrit, but markedly higher leukocyte and neutrophil numbers relative to the control group. CD4+ and CD8+ subpopulations and other blood cell variables are altered in dogs with CHF. Future studies to determine possible clinical implications of these changes are warranted.

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Section: Discussionmentioning

confidence: 99%

Lymphocyte Subpopulations and Hematologic Variables in Dogs with Congestive Heart Failure

Farabaugh

Freeman

George

2004

Veterinary Internal Medicne

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“…4A,B). Since elevated concentrations of catecholamines can trigger lymphocyte cell death (Harris et al, 1995;Gu et al, 2000;Stevenson et al, 2001;Wahle et al, 2002;del Rey et al, 2003), we tested whether the reduction in spleen size and splenocyte number after T3 SCI was a result of increased immune cell apoptosis. Western blot analyses of homogenized spleen showed elevated levels of activated caspase-3 (a primary effecter of apoptosis) only after T3 SCI; thereby confirming our initial hypothesis (p<0.05; Fig.…”

Section: T3 Sci Induces Splenocyte Cell Death and B Cell Apoptosismentioning

confidence: 99%

Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation

Lucin

Sanders

Jones

et al. 2007

Experimental Neurology

171

217

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Individuals with spinal cord injury (SCI) are highly susceptible to infection. This post-traumatic immune suppression is thought to occur via alterations in sympathetic nervous system (SNS) or hypothalamic-pituitary-adrenal (HPA) axis function. Normally, the HPA axis and SNS help coordinate proper immune function. After SCI, the HPA axis becomes activated and descending input to sympathetic preganglionic neurons (SPNs) is impaired. Because lymphoid organs are innervated by SPNs distributed throughout the thoracolumbar spinal cord, we predicted leveldependent immune suppression after SCI due to activation of the HPA axis and loss of descending input to SPNs. We tested this hypothesis by measuring indices of HPA (circulating corticosterone; CORT) and SNS function (norepinephrine (NE) in spleen) as well as antigen-specific antibody synthesis against an exogenous non-self protein following high or low level SCI. Using a midthoracic (T9) spinal contusion injury model, we found that CORT was elevated after SCI with aberrant patterns of diurnal CORT synthesis evident through at least the first 24 hours post-injury. However, splenic NE and antibody synthesis were similar to uninjured controls. Injury severity did not change these parameters. Indeed, CORT, NE and antibody synthesis were similar after T9 contusion or transection SCI. In contrast, high level SCI (T3) caused sustained increases in CORT and splenic NE along with impaired antibody synthesis and elevated splenocyte apoptosis. The immunosuppressive effects of T3 SCI were caused by NE acting at β2-adrenergic receptors (β2AR) and could be reversed using β2AR blockers. Interestingly, impaired antibody after T3 SCI could be Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript mimicked after T9 SCI with a β2AR agonist. These data illustrate the immunosuppressive effects of the SNS after high-level SCI and indicate that immune deficits may be overcome using β-blockers.

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“…The proinflammatory cytokines that were increased after zymosan injection in control animals (IL-1, IL-6, TNF␣) attract immune cells, and their reduced expression by clonidine would thereby prevent leukocytosis. ␣2-Adrenoceptor stimulation induces apoptosis in lymphocytes (Stevenson et al, 2001), providing an alternative explanation for reduced leukocytosis in clonidine-treated animals. This mechanism seems unlikely, however, because clonidine did not alter leukocyte number in gelfoam in the absence of zymosan or the number of leukocytes that failed to exclude trypan blue.…”

Section: ␣2-adrenoceptors Transform the Immune Response To Acute Neurmentioning

confidence: 99%

α2-Adrenoceptor Stimulation Transforms Immune Responses in Neuritis and Blocks Neuritis-Induced Pain

Romero‐Sandoval

McCall²,

Eisenach³

2005

J. Neurosci.

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Neuropathic pain may be primarily driven by immune responses in peripheral nerves. Peripherally released catecholamines may exacerbate neuropathic pain and also modulate immune responses in a complex and sometimes opposing manner by actions on multiple adrenoceptor subtypes. We showed previously that injection of the ␣2-adrenoceptor agonist clonidine at the site of peripheral nerve injury reduces pain behavior and local tissue pro-inflammatory cytokine content in rats. The current study used a model of acute inflammatory neuritis to test the efficacy and mechanisms of action of ␣2-adrenoceptor stimulation to reduce pain. Zymosan, injected on the sciatic nerve, caused hypersensitivity to mechanical stimuli ipsilateral to injection and contralaterally, so-called mirror image pain. Ipsilateral hypersensitivity was inhibited dose-dependently by perineural injection of clonidine. Zymosan increased leukocyte number at the site of injection 3 d later as well as their content of interleukin 1␣ (IL-1␣), IL-1␤, and IL-6. Perineural clonidine prevented both the increase in leukocyte number and cytokine expression induced by zymosan. Additionally, clonidine reduced the capacity of leukocytes to express pro-inflammatory cytokines as assessed by treatment of cells ex vivo with lipopolysaccharide, whereas no repression of IL-10 production occurred. Clonidine reduced the number of macrophages and lymphocytes as well as their expression of tumor necrosis factor ␣. All of the effects of clonidine were prevented by coadministration of an ␣2A-adrenoceptor-preferring antagonist. These results suggest that ␣2-adrenoceptor stimulation transforms cytokine gene expression, especially in macrophages and lymphocytes from a pro-to an anti-inflammatory profile in the setting of neuritis, likely relieving neuritis-induced pain by this mechanism.

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Prolonged alpha-adrenergic stimulation causes changes in leukocyte distribution and lymphocyte apoptosis in the rat

Cited by 62 publications

References 28 publications

Lymphocyte Subpopulations and Hematologic Variables in Dogs with Congestive Heart Failure

Lymphocyte Subpopulations and Hematologic Variables in Dogs with Congestive Heart Failure

Impaired antibody synthesis after spinal cord injury is level dependent and is due to sympathetic nervous system dysregulation

α2-Adrenoceptor Stimulation Transforms Immune Responses in Neuritis and Blocks Neuritis-Induced Pain

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