beta blocks sepsis

Tumor necrosis factor-alpha (TNF-α) is a pivotal mediator that triggers inflammatory process, oxidative stress, and multiple organ injury in sepsis. We investigated the effects of infliximab on survival, mesenteric artery blood flow (MBF), vascular reactivity, and oxidative and inflammatory injuries in cecal ligation and puncture (CLP)-induced sepsis. Wistar rats were divided into Sham, CLP, Sham+infliximab, and CLP+infliximab subgroups. Twenty-four hours before the operations, rats were injected intraperitoneally with infliximab (7 mg/kg) or vehicle (saline; 1 mL/kg)...

BACKGROUND: The cyclooxygenase (COX)-2 overexpression is associated with vascular injury and multiple organ failure in sepsis. However, constitutive COX-1 and basal COX-2 expressions have physiological effects. We aimed to investigate the effects of partial and selective COX-2 inhibition without affecting constitutive COX-1 and basal COX-2 activities by celecoxib on mesenteric artery blood flow (MABF), vascular reactivity, oxidative and inflammatory injuries, and survival in septic rats accomplished by cecal ligation and puncture (CLP)...

Beta blockers are some of the most studied drugs in the pharmacopoeia. They are already widely used in medicine for treating hypertension, chronic heart failure, tachyarrhythmias, and tremor. Whilst their use in the immediate perioperative patient has been questioned, the use of esmolol in the patients with established septic shock has been recently reported to have favourable outcomes. In this paper, we review the role of the adrenergic system in sepsis and the evidence for the use of beta stimulation and beta blockers from animal models to critically ill patients...

The fast-acting β-1 blocker esmolol has been the center of attention since the landmark article by Morrelli and colleagues suggesting that, in patients with sepsis, reducing heart rate by administering esmolol can result in a survival benefit. However, the use of esmolol for the treatment of sepsis and the underlying mechanism responsible for this benefit remain controversial. This commentary discusses the study by Jacquet-Lagrèze and colleagues, who in a pig model of sepsis tested the hypothesis that administration of esmolol to reduce heart rate may correct sepsis-induced sublingual and gut microcirculatory alterations which are known to be associated with adverse outcome...

Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles of human monocytes trained with the Candida albicans cell wall constituent β-glucan, together with a genome-wide transcriptome, we identified the induced expression of genes involved in glucose metabolism. Trained monocytes display high glucose consumption, high lactate production, and a high ratio of nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting a shift in metabolism with an increase in glycolysis dependent on the activation of mammalian target of rapamycin (mTOR) through a dectin-1-Akt-HIF-1α (hypoxia-inducible factor-1α) pathway...

β-blockers are widely used to treat cardiovascular diseases and in the peri-operative period in selected patients. The main benefit in terms of morbidity and/or mortality of their use is believed to be linked to specific effects on myocardial oxygen supply/demand balance, to anti-arrhythmic effects and anti-inflammatory effects. Use of β-blockers in severe sepsis is still under debate and if any, their appropriate indications remain unclear. In this article, we analyze the recent literature addressing the metabolic, immuno-modulatory and hemodynamic effects of non cardio-selective and of cardio-selective β-blockers in experimental and human sepsis in order to help clarifying the potential place of these drugs in patients with severe sepsis...

The type I interferon (IFN) signaling response limits infection of many RNA and DNA viruses. To define key cell types that require type I IFN signaling to orchestrate immunity against West Nile virus (WNV), we infected mice with conditional deletions of the type I IFN receptor (IFNAR) gene. Deletion of the Ifnar gene in subsets of myeloid cells resulted in uncontrolled WNV replication, vasoactive cytokine production, sepsis, organ damage, and death that were remarkably similar to infection of Ifnar-/- mice completely lacking type I IFN signaling...

Lipopolysaccharide (LPS), an endotoxin derived from gram-negative bacteria, promotes the secretion of proinflammatory cytokines and mediates endotoxemia through activation of mitogen activated protein kinases, NF-κB, and interferon regulatory factor-3. Silent information regulator transcript-1 (SIRT1), an NAD-dependent deacetylase, mediates NF-κB deacetylation, and inhibits its function. SIRT1 may affect LPS-mediated signaling pathways and endotoxemia. Here we demonstrate that SIRT1 blocks LPS-induced secretion of interleukin 6 and tumor necrosis factor α in murine macrophages, and protects against lethal endotoxic and septic shock in mice...

BACKGROUND: Leukocytes containing opioid peptides locally control inflammatory pain. In the early phase of complete Freund's adjuvant (CFA)-induced hind paw inflammation, formyl peptides (derived e.g. from Mycobacterium butyricum) trigger the release of opioid peptides from neutrophils contributing to tonic basal antinociception. In the later phase we hypothesized that toll-like-receptor-(TLR)-4 activation of monocytes/macrophages triggers opioid peptide release and thereby stimulates peripheral opioid-dependent antinociception...

Current research on new therapeutic strategies for sepsis uses different animal models, such as the lipopolysaccharide-induced endotoxemia model and the cecal ligation and puncture (CLP) peritonitis model. By using genetic and pharmacologic inhibition of the type I interferon (IFN) receptor (IFNAR1), we show that type I IFN signaling plays a detrimental role in these sepsis models. Mortality after CLP was reduced even when type I IFN responses were blocked after the onset of sepsis. Our findings reveal that type I IFNs play an important detrimental role during sepsis by negatively regulating neutrophil recruitment...

Toll/IL-1R resistance (TIR) domain-containing adapter-inducing IFN-β (TRIF) is a Toll-like receptor (TLR) adapter that mediates MyD88-independent induction of type I interferons through activation of IFN regulatory factor 3 and NFκB. We have examined peptides derived from the TRIF TIR domain for ability to inhibit TLR4. In addition to a previously identified BB loop peptide (TF4), a peptide derived from putative helix B of TRIF TIR (TF5) strongly inhibits LPS-induced cytokine and MAPK activation in wild-type cells...

INTRODUCTION: Pharmacological agents that block beta-adrenergic receptors have been associated with improved outcome in burn injury. It has been hypothesized that injuries leading to a hypermetabolic state, such as septic shock, may also benefit from beta-blockade; however, outcome data in experimental models have been contradictory. Thus, we investigated the effect of beta-blockade with propranolol on survival, hemodynamics, lung heat shock protein (HSP) expression, metabolism and inflammatory markers in a rat cecal ligation and puncture (CLP) model of sepsis...

OBJECTIVES: Cardiac depression is a well-described manifestation of the sepsis syndrome. An important underlying mechanism is the attenuation of the adrenergic response at the cardiomyocyte level. By reducing their cell-specific function (contractility), the cardiomyocytes reduce their energy expenditure. Consequently, the cardiac myocytes survive in a hibernation-like state as long as intracellular energy generation is limited. The objective of this study was to review β-blocker therapy for the treatment of septic patients...

Neutrophil adhesion to the vasculature and chemotaxis within tissues play critical roles in the inflammatory response to injury and pathogens. Unregulated neutrophil activity has been implicated in the progression of numerous chronic and acute diseases such as rheumatoid arthritis, asthma, and sepsis. Cell migration of anchorage-dependent cells is known to depend on both chemical and mechanical interactions. Although neutrophil responses to chemical cues have been well characterized, little is known about the effect of underlying tissue mechanics on neutrophil adhesion and migration...

BACKGROUND: Toll-like receptors (TLRs) are among the first-line sentinels for immune detection and responsiveness to pathogens. The TLR2 subfamily of TLRs (TLR1, TLR2, TLR6) form heterodimers with each other and are thus able to recognize a broad range of components from several microbes such as yeast, Gram-positive bacteria and protozoa. Until now, TLR2 activation by bacterial ligands has long been associated with pro-inflammatory cytokines but not type I interferon responses. METHODOLOGY/PRINCIPAL FINDINGS: Using a variety of transgenic mice, here we provide in vivo and in vitro data showing that TLR2 activation does in fact induce interferon-beta and that this occurs via MyD88-IRF1 and -IRF7 pathways...

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...

We examined our hypothesis that heme-oxygenase-1 (HO-1)-derived carbon monoxide (CO) inhibits the release of high-mobility group box 1 (HMGB1) in RAW264.7 cells activated with lipopolysaccharide (LPS) in vitro and in LPS- or cecal ligation and puncture (CLP)-induced septic mice in vivo, so that HO-1 induction or CO improves survival of sepsis in rodents. We found that pretreatment with HO-1 inducers (hemin, cobalt protoporphyrin IX) or transfection of HO-1 significantly inhibited HMGB1 release, which was blocked by HO-1 small interfering RNA, in cells activated by LPS...

Etomidate blocks the cortisol synthesis by specifically inhibiting the activity of 11 beta-hydroxylase, resulting in a primary adrenal insufficiency. Therefore, a serum accumulation of 11 beta-deoxycortisol and a low secretion of serum cortisol must be required as diagnostic criteria to assign that adrenal impairment to the drug. These requirements have been rarely fulfilled in studies exploring the contribution of etomidate to the adrenal insufficiency despite numerous causes of adrenal derangement. In critically ill patients without sepsis, a single dose of etomidate results in a wide adrenal inhibition, reversible in 48 h after etomidate administration...

Previous studies suggest that the blockade of beta-adrenoceptors augments the release of inflammatory regulators in response to proinflammatory stimuli. High-mobility group box 1 (HMGB-1) is a key mediator in the development of sepsis. We investigated whether landiolol, a short-acting selective beta1-adrenoceptor-blocking agent, can attenuate acute lung injury and cardiac dysfunction in a rat model of endotoxin-induced sepsis. We administered LPS i.v. to rats, with or without simultaneous treatment with landiolol (0...

Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus...