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Β-Adrenergic Modulation in Sepsis Etienne De Montmollin, Jerome Aboab, Arnaud Mansart and Djillali Annane

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Β-Adrenergic Modulation in Sepsis Etienne De Montmollin, Jerome Aboab, Arnaud Mansart and Djillali Annane Available online http://ccforum.com/content/13/5/230 Review Bench-to-bedside review: β-Adrenergic modulation in sepsis Etienne de Montmollin, Jerome Aboab, Arnaud Mansart and Djillali Annane Service de Réanimation Polyvalente de l’hôpital Raymond Poincaré, 104 bd Raymond Poincaré, 92380 Garches, France Corresponding author: Professeur Djillali Annane, [email protected] Published: 23 October 2009 Critical Care 2009, 13:230 (doi:10.1186/cc8026) This article is online at http://ccforum.com/content/13/5/230 © 2009 BioMed Central Ltd Abstract in the intensive care setting [4] – addressing the issue of its Sepsis, despite recent therapeutic progress, still carries unaccep- consequences in sepsis. tably high mortality rates. The adrenergic system, a key modulator of organ function and cardiovascular homeostasis, could be an The present review summarizes current knowledge on the interesting new therapeutic target for septic shock. β-Adrenergic effects of β-adrenergic agonists and antagonists on immune, regulation of the immune function in sepsis is complex and is time cardiac, metabolic and hemostasis functions during sepsis. A dependent. However, β activation as well as β blockade seems 2 1 comprehensive understanding of this complex regulation to downregulate proinflammatory response by modulating the β system will enable the clinician to better apprehend the cytokine production profile. 1 blockade improves cardiovascular homeostasis in septic animals, by lowering myocardial oxygen impact of β-stimulants and β-blockers in septic patients. consumption without altering organ perfusion, and perhaps by restoring normal cardiovascular variability. β-Blockers could also β-Adrenergic receptor and signaling cascade be of interest in the systemic catabolic response to sepsis, as they The β-adrenergic receptor is a G-protein-coupled seven- oppose epinephrine which is known to promote hyperglycemia, transmembrane domain receptor. There are three receptor lipid and protein catabolism. The role of β-blockers in coagulation β β β β β is less clear cut. They could have a favorable role in the septic pro- subtypes: 1, 2 and 3. 1-receptors and 2-receptors are β β coagulant state, as 1 blockade may reduce platelet aggregation widely distributed, but 1-receptors predominate in the heart β and normalize the depressed fibrinolytic status induced by adre- and 2-receptors are mainly found in smooth muscles such as β β nergic stimulation. Therefore, 1 blockade as well as 2 activation vessels and bronchus. Table 1 presents details of the improves sepsis-induced immune, cardiovascular and coagulation β β β β -adrenergic system. Mixed 1 2-agonists include dysfunctions. 2 blocking, however, seems beneficial in the β metabolic field. Enough evidence has been accumulated in the epinephrine and isoproterenol, selective 1-agonists include β β β dobutamine, norepinephrine and dopamine, and selective β - literature to propose -adrenergic modulation, 1 blockade and 2 2 activation in particular, as new promising therapeutic targets for agonists include salbutamol, terbutaline and dopexamine. septic dyshomeostasis, modulating favorably immune, cardio- vascular, metabolic and coagulation systems. Upon activation by specific agonists, activated Gs proteins increase intracystosolic cAMP via an adenylate cyclase- Introduction dependent pathway [5]. cAMP activates protein kinase A, Sepsis still places a burden on the healthcare system, with an which in turn phosphorylates numerous targets in the cell annual increase in incidence of about 9% and a mortality of such as transmembrane channels, and modulates nucleus about 25% and up to 60% when shock is present [1,2]. transcription via the Ras, Raf, MEK and ERK pathways [6]. Uncontrolled systemic inflammatory response is the hallmark The β-receptor itself can be phosphorylated by protein kinase of sepsis and contributes to the development of organ A, inducing its uncoupling from the G protein (acute dysfunction and shock [3]. The exact mechanisms of cardio- response) and its internalization (chronic response) – the vascular failure following severe infection, however, remain whole process leading to a downregulation of β-adrenergic poorly elucidated. The adrenergic system is a key modulator signaling. of organ function and cardiovascular homeostasis. These receptors are widely distributed in the body, including in β-Adrenergic-mediated immune modulation circulating immune cells, vessels, the heart, airways, lungs, Immune response to sepsis adipose tissues, skeletal muscles, and brain. Furthermore, By definition, sepsis corresponds to a syndrome of systemic β-adrenergic modulation is a frequent therapeutic intervention inflammatory response triggered by invading pathogens [7]. IFN = interferon; IL = interleukin; NF = nuclear factor; Th1 = T-helper type 1; Th2 = T-helper type 2; TNF = tumor necrosis factor. Page 1 of 8 (page number not for citation purposes) Critical Care Vol 13 No 5 de Montmollin et al. Table 1 The β-adrenergic system Target Sympathetic receptor β β Heart Cardiac muscle 1 2 increases β β Heart rate 1 2 increases β Blood vessels Vascular smooth muscle 2 relaxes β Smaller coronary arteries 2 dilates β Hepatic artery 2 dilates β Arteries to skeletal muscle 2 dilates β Veins 2 dilates β Respiratory system Smooth muscles of bronchioles 2 relaxes β Digestive system Smooth muscle of gastrointestinal tract 2 relaxes β Sphincters of gastrointestinal tract 2 contracts β Kidney 1 enhances renin secretion β Liver 2 increases glycogenolysis, gluconeogenesis β β Adipose cells 1 3 stimulates lipolysis β Urinary system Detrusor 2 relaxes β Sphincter 2 relaxes β Reproductive system Uterus 2 relaxes β Nervous system Ciliary muscles 2 relaxes In bone marrow tissues, sepsis is associated with a shift in ambivalence of immune response in sepsis reflects the the myelopoietic production towards the monocyte lineage, at difficulty of finding therapeutic targets for immunomodulation. the expense of the granulocytic lineage [8]. Activated mononuclear cells release a broad variety of proinflammatory β-Adrenergic system and immune modulation cytokines, including IL-1, IL-6, TNFα, IL-12, IL-15 and IL-18, The β-adrenergic system is a well-known powerful modulator as well as the so-called late mediators, high mobility group of the immune system [11]. Lymphoid organs such as the box 1 and macrophage migration inhibitory factor [3]. Generally, spleen, thymus, lymph nodes and bone marrow are predomi- the synthesis of proinflammatory cytokines is mediated by nantly innervated by the sympathetic system. The majority of NFκB. In parallel, a physiologic counter-inflammatory lymphoid cells express β-adrenergic receptors on their response is initiated with the release of IL-10, IL-1-receptor surface, with the exception of T-helper type 2 (Th2) cells. The antagonist and soluble TNFα-receptor among various anti- density of cell surface receptors varies with cell type, natural inflammatory mediators. Mononuclear cells are subsequently killer cells having the highest density. The efficiency of reprogrammed, allowing the inflammation to be turned off. In receptor coupling with adenylate cyclase also differs among addition, following the initial hyperinflammatory response, immune cells, with natural killer cells and monocytes being immune cell apoptosis occurs, taking part in the secondary the most responsive cells. impairment of immune function. Apoptosis concerns mainly B lymphocytes and CD4+ cells, as well as dendritic cells and In bone marrow, monocytic production appears to be under β epithelial cells. It appears that, apart from direct immune cell the influence of sympathetic activation via 2-receptors. Indeed, stock depletion, apoptotic bodies induce macrophage anergy monocytes have an increased sensitivity to epinephrine. Upon and favor anti-inflammatory cytokine secretion [9]. adrenergic stimulation, monocytes differentiate into mature macrophages [12] that are functionally different in their cyto- Sepsis is therefore characterized by a balance between pro- kine response [13]. inflammatory signals and anti-inflammatory signals to immuno- effector cells [10]. Excessive systemic inflammation may favor Immune cell apoptosis is at least partly mediated by the development of organ failure, and excess anti- catecholamines, via α-adrenergic and β-adrenergic pathways. β inflammatory mediators may compromise the local response Nonspecific and specific 2 blockade induce splenocyte to infection. This issue has not yet been elucidated, and the apoptosis [14]. Epinephrine also exerts apoptosis, however, Page 2 of 8 (page number not for citation purposes) Available online http://ccforum.com/content/13/5/230 Figure 1 activation of natural killer cells [23]. Two studies in septic mice showed that propranolol upregulated Th1-mediated IFNγ production and downregulated the Th2-mediated IL-6 synthesis [15,24]. In these experiments, however, propranolol- treated animals had a greater mortality rate. In another study on severely burnt children, propranolol administration significantly decreased serum TNF and IL-1β concentrations, and did not increase mortality [25]. Interestingly, in septic β rats, selective 1 blocking by esmolol decreased circulating TNFα and IL-1β concentrations [26]. Similarly, landiolol, β another selective 1-blocker, also decreased circulating levels of TNFα, IL-6, and high mobility group box 1 [27]. While IL-10 production was not altered by β blockade [28], it was increased by β-agonists [18,19]. The mechanisms by which β 1-adrenoceptor
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