Etiologic role of root canal infection in apical periodontitis and its relationship with clinical symptomatology

Abstract: Evidence shows the polymicrobial etiology of endodontic infections, in which bacteria and their products are the main agents for the development, progression, and dissemination of apical periodontitis. Microbial factors in necrotic root canals (e.g., endotoxin) may spread into apical tissue, evoking and supporting a chronic inflammatory load. Thus, apical periodontitis is the result of the complex interplay between microbial factors and host defense against invasion of periradicular tissues. This review of the literature aims to discuss the complex network between endodontic infectious content and host immune response in apical periodontitis. A better understanding of the relationship of microbial factors with clinical symptomatology is important to establish appropriate therapeutic procedures for a more predictable outcome of endodontic treatment.

Nitric oxide participates in the toxicity of Bacillus thuringiensis Cry1Ab toxin to kill Manduca sexta larvae.

Nitric oxide (NO) produced by the nitric oxide synthase (NOS) enzyme is a reactive oxygen molecule widely considered as important participant in the immune system of different organisms to confront microbial infections. In insects the NO molecule has also been implicated in immune response against microbial pathogens. Bacillus thuringiensis (Bt) is an insect-pathogenic bacterium that produces insecticidal proteins such as Cry toxins. These proteins kill insects because they form pores in the larval-midgut cells. Here we show that intoxication of Manduca sexta larvae with Cry1Ab activates expression of NOS with a corresponding increase in NO. This effect is not observed with a non-toxic mutant toxin Cry1Ab-E129K that is affected in pore formation. The increased production of NO triggered by intoxication with LC50 dose of Cry1Ab toxin is not associated with higher expression of antimicrobial peptides. NO participates in Cry1Ab toxicity since inhibition of NOS by selective l-NAME inhibitor prevented NO production and resulted in reduced mortality of the larvae. The fact that mortality was not completely abolished by L-NAME indicates that other processes participate in toxin action and induction of NO production upon Cry1Ab toxin administration accounts only for a part of the toxicity of this protein to M. sexta larvae.

Mesenteric lymph reperfusion after superior mesenteric artery occlusion shock exacerbates endotoxin translocation in brain.

PURPOSE: To determine the role of mesenteric lymph reperfusion (MLR) on endotoxin translocation in brain to discuss the mechanism of brain injury subjected to superior mesenteric artery occlusion (SMAO) shock. METHODS: Twenty-four rats were randomly assigned to MLR, SMAO, MLR+SMAO and sham groups. MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h and then allowing reperfusion for 2 h in the MLR group; SMAO involved clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h in the SMAO group; occlusion of both the SMA and MLD for 1 h was followed by reperfusion for 2 h in the MLR+SMAO group rats. RESULTS: SMAO shock induced severe increased levels of the endotoxin, lipopolysaccharide receptor, lipopolysaccharide-binding protein, intercellular adhesion molecule-1 and tumor necrosis factor-α. Concurrently, MLR after SMAO shock further aggravates these deleterious effects. CONCLUSION: Mesenteric lymph reperfusion exacerbated the endotoxin translocation in brain; thereby increased inflammatory response occurred, suggesting that the intestinal lymph pathway plays an important role in the brain injury after superior mesenteric artery occlusion shock.

Mesenteric lymph reperfusion after superior mesenteric artery occlusion shock exacerbates endotoxin translocation in brain

PURPOSE: To determine the role of mesenteric lymph reperfusion (MLR) on endotoxin translocation in brain to discuss the mechanism of brain injury subjected to superior mesenteric artery occlusion (SMAO) shock. METHODS: Twenty-four rats were randomly assigned to MLR, SMAO, MLR+SMAO and sham groups. MLR was performed by clamping the mesenteric lymph duct (MLD) for 1 h and then allowing reperfusion for 2 h in the MLR group; SMAO involved clamping the superior mesenteric artery (SMA) for 1 h, followed by reperfusion for 2 h in the SMAO group; occlusion of both the SMA and MLD for 1 h was followed by reperfusion for 2 h in the MLR+SMAO group rats. RESULTS: SMAO shock induced severe increased levels of the endotoxin, lipopolysaccharide receptor, lipopolysaccharide-binding protein, intercellular adhesion molecule-1 and tumor necrosis factor-α. Concurrently, MLR after SMAO shock further aggravates these deleterious effects. CONCLUSION: Mesenteric lymph reperfusion exacerbated the endotoxin translocation in brain; thereby increased inflammatory response occurred, suggesting that the intestinal lymph pathway plays an important role in the brain injury after superior mesenteric artery occlusion shock. .

Correlation between clinical/radiographic features and inflammatory cytokine networks produced by macrophages stimulated with endodontic content.

INTRODUCTION: Macrophages are highly activated by endodontic contents. This study investigated the correlation between different clinical signs/symptoms and radiographic features according to the levels of interleukin (IL)-1ß, tumor necrosis factor α (TNF-α), IL-6, IL-10, prostaglandin E(2) (PGE(2)), and their networks produced by endodontic content-stimulated macrophages collected from primary endodontic infection with apical periodontitis (PEIAP). METHODS: Samples were taken from 21 root canals with PEIAP by using paper points. The presence of exudate (EX), pain on palpation (POP), tenderness to percussion (TTP), and the size of the radiographic lesion (SRL) were recorded. Polymerase chain reaction (16S rDNA) was used for bacterial detection and limulus amebocyte lysate (LAL) assay for endotoxin measurement. Raw 264.7 macrophages were stimulated with bacterial contents during 24 hs. The amounts of IL-1ß, TNF-α, IL-6, IL-10 and PGE(2) were measured by enzyme-linked immunosorbent assay. Log-based data were correlated by multiple logistic regression (P < .05). RESULTS: Bacteria and endotoxin were detected in 100% of the samples. IL-6 and TNF-α were positively correlated with SRL and EX, respectively (P < .05). Clinical signs/symptoms and radiographic findings were set as dependent variables for EX-positive correlations between PGE(2), IL-1ß, and TNF-α (P < .05), whereas IL-6 and PGE(2) were positively correlated to each other in POP but negatively correlated in SRL (P < .05). When POP and TTP-POP were set as dependent variables, different cytokine networks were found. CONCLUSIONS: Our findings suggest different roles for each cytokine in the development of apical periodontitis, whose effects of overlapping networks depend on the signs/symptoms and radiographic features found in endodontic infection.

Overexpression of pulmonary extracellular superoxide dismutase attenuates endotoxin-induced acute lung injury.

PURPOSE: Superoxide is produced by activated neutrophils during the inflammatory response to stimuli such as endotoxin, can directly or indirectly injure host cells, and has been implicated in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). We wished to determine the potential for pulmonary overexpression of the extracellular isoform of superoxide dismutase (EC-SOD) to reduce the severity of endotoxin-induced lung injury. METHODS: Animals were randomly allocated to undergo intratracheal instillation of (1) surfactant alone (vehicle); (2) adeno-associated virus (AAV) vectors containing a null transgene (AAV-null); and (3) adeno-associated virus vectors containing the EC-SOD transgene (AAV-EC-SOD) and endotoxin was subsequently administered intratracheally. Two additional groups were randomized to receive (1) vehicle or (2) AAV-EC-SOD, and to undergo sham (vehicle) injury. The severity of the lung injury was assessed in all animals 24 h later. RESULTS: Endotoxin produced a severe lung injury compared to sham injury. The AAV vector encoding EC-SOD increased lung EC-SOD concentrations, and enhanced the antioxidant capacity of the lung. EC-SOD overexpression decreased the severity of endotoxin-induced ALI, reducing the decrement in systemic oxygenation and lung compliance, decreasing lung permeability and decreasing histologic injury. EC-SOD attenuated pulmonary inflammation, decreased bronchoalveolar lavage neutrophil counts, and reduced interleukin-6 and CINC-1 concentrations. The AAV vector itself did not contribute to inflammation or to lung injury. CONCLUSIONS: Pulmonary overexpression of EC-SOD protects the lung against endotoxin-induced ALI.

Low-dose endotoxin induces inflammation by selectively removing nuclear receptors and activating CCAAT/enhancer-binding protein δ.

Subclinical levels of circulating endotoxin are associated with the pathogenesis of diverse human inflammatory diseases, by mildly inducing the expression of proinflammatory mediators. In this study, we examined the molecular mechanism responsible for the effect of low-dose LPS in macrophages. In contrast to high-dose LPS, which activates NF-κB and induces the robust expression of proinflammatory mediators, we observed that low-dose LPS failed to activate NF-κB. Instead, it selectively activated C/EBPδ and removed nuclear repressors, including peroxisome proliferator-activated receptor α and retinoic acid receptor α, enabling a mild and leaky expression of proinflammatory mediators. The effect of low-dose LPS required IRAK-1, which interacts with and acts upstream of IκB kinase ε to contribute to LPS-mediated induction of C/EBPδ and proinflammatory mediators. Additionally, mice fed a high-fat diet acquired elevated levels of endotoxin and proinflammatory mediators in an IRAK-1-dependent fashion. Taken together, these data reveal a distinct pathway preferentially used by low-dose endotoxin in initiating low-grade inflammation.

[Myocardial dysfunction in sepsis--definition and pathogenetic mechanisms]. / Myokardiální dysfunkce v sepsi--charakteristika a patogenetické mechanizmy.

Sepsis is considered to be the major cause of morbidity and mortality of patients hospitalised in intensive care. It's defined as a systemic inflammatory response of organism to infection. Incidence of myocardial dysfunction in studies with severe sepsis patients is up to two thirds of patients. Cardiac dysfunction shows a continuum from isolated and mild diastolic dysfunction to combined severe diastolic and systolic failure of both ventricles mimicking even cardiogenic shock in some patients. Typical features of septic myocardial dysfunction (SMD) are decrease in ejection fraction (EF) with dilatation ofventricles, e.g. increase in end-diastolic volume (EDV). Reversibility of myocardial dysfunction during a period from 7 to 10 days in survivors is other typical manifestation of SMD. Hence, one can speculate that development of such a type ofSMD as a temporary protective compensatory mechanism could be advantageous for of an individual patient. A large body ofevidence about mechanisms ofSMD was described; endothelial dysfunction with consequent microcirculatory and mitochondrial dysfunction and role of circulating factors are considered to be the most important.

Effect of the hydrophobicity to net positive charge ratio on antibacterial and anti-endotoxin activities of structurally similar antimicrobial peptides.

The interaction between host-defense antimicrobial peptides (AMPs) and the bacterial lipopolysaccharide (LPS) governs both the susceptibility of the bacteria to the peptide and the ability of the peptide to inhibit LPS activation of immune cells. Both functions depend on the biophysical properties of the peptides. However, the sequence and structural diversity of AMPs makes it difficult to determine common denominators required for antimicrobial and LPS neutralizing activities. Toward this end, we synthesized and investigated a series of nine 12-amino acid peptides and their fatty acid-conjugated analogues composed of both D- and L-isomers of Leu and Lys at various ratios. The positions of the D-amino acids were preserved. These peptides differ in their net positive charge and hydrophobicity. However, their overall structure in the membrane is similar, as determined by Fourier transform infrared spectroscopy. The peptides and their analogues were functionally tested for their antibacterial and hemolytic activity, their ability to permeate LPS vesicles, their ability to neutralize LPS activation of macrophages, and their effect on LPS morphology, determined by negative staining electron microscopy. The data revealed that increasing the ratio between hydrophobicity and the net positive charge increases both antimicrobial and LPS neutralization activities, but with different modes of contributions. Whereas antimicrobial activity increases linearly with the increase in the peptides' hydrophobicity, peptides with different hydrophobicities are endowed with similar LPS neutralizing activities. Besides adding important information regarding AMP parameters involved in antimicrobial and anti-LPS activities, this study suggests the use of such diastereomers as potential templates for the development of simple molecules that conduct both types of functions.

NADPH oxidase NOX2 mediates rapid cellular oxidation following ATP stimulation of endotoxin-primed macrophages.

The phagocytic NADPH oxidase (NOX2) plays a fundamental role in host defense and innate immunity. Here we demonstrate that external ATP triggers rapid cellular oxidation inhibited by diphenyleneiodonium in endotoxin-primed J774 macrophages and primary murine bone marrow-derived macrophages. To identify the source of reactive oxygen species (ROS), we compared responses between wild-type and NOX2-deficient macrophages. ATP-mediated ROS production was strongly attenuated in NOX2-deficient macrophages where responses were comparable to inhibition with diphenyleneiodonium. Notably, spatial differences in superoxide anion formation were observed where ROS formation was partially antagonized by extracellular superoxide dismutase in primary bone marrow-derived macrophages but unaffected in J774 macrophages. Loss of NOX2 was not observed to affect ATP-induced cell death. However, ATP-evoked cell death was found to be partially dependent on caspase-1 and cathepsin B activation. In conclusion, NOX2 plays a fundamental role in conferring macrophages with the ability to respond to extracellular ATP stimulation with robust changes in cellular oxidation.

Role of proinflammatory activity contained in gastric juice from intensive care unit patients to induce lung injury in a rabbit aspiration model.

OBJECTIVE: Although aspiration pneumonitis is a severe complication in patients hospitalized in intensive care units, its pathogenesis is poorly understood. The aim of this study was to determine whether the intensity of lung injury and inflammation developing after aspiration during mechanical ventilation differed depending on the inflammatory activity of intensive care unit patients' gastric fluid. DESIGN: In vitro study on human gastric juice and randomized controlled animal study. SETTING: Research laboratories of academic institutions. SUBJECTS: Male New-Zealand white rabbits. INTERVENTIONS: Proinflammatory activity of gastric juice from 17 intensive care unit patients and 12 controls undergoing elective surgery was measured based on a target cell activation assay. Two gastric juices from intensive care unit patients with similar pH but differing for their in vitro proinflammatory activity (high and low) were further instilled into the trachea of ventilated rabbits. Lung function, mechanics, pathology, leukocyte infiltration, and local cytokine levels were measured after 6 hrs. MEASUREMENTS AND MAIN RESULTS: Gastric juice from intensive care unit patients, even buffered at pH 7.4, stimulated human type II-like A549 epithelial cells to up-regulate intercellular adhesion molecule-1 and interleukin-8, significantly more than juice obtained in controls. Gastric juice from an intensive care unit patient supporting high proinflammatory activity in vitro also induced a more severe and persistent drop in PaO2/FIO2 and respiratory system compliance in ventilated rabbits, a worse histologic score, higher lung lavage concentrations of inflammatory cells, interleukin-8 (p < 0.01), and growth-related oncogene-alpha (p < 0.01) than one fluid with low proinflammatory activity. CONCLUSION: Gastric juice from critically ill patients is proinflammatory and stimulates human pulmonary cells in vitro. A human gastric juice with high proinflammatory activity is more "toxic" to the lung than one with low proinflammatory activity in a ventilated rabbit model, an effect that is independent of pH and particulate matter content.

Nematode resistance.

Plant-parasitic nematodes are major pests of both temperate and tropical agriculture. Many of the most damaging species employ an advanced parasitic strategy in which they induce redifferentiation of root cells to form specialized feeding structures able to support nematode growth and reproduction over several weeks. Current control measures, particularly in intensive agriculture systems, rely heavily on nematicides but alternative strategies are required as effective chemicals are withdrawn from use. Here, we review the different approaches that are being developed to provide resistance to a range of nematode species. Natural, R gene-based resistance is currently exploited in traditional breeding programmes and research is ongoing to characterize the molecular basis for the observed resistant phenotypes. A number of transgenic approaches hold promise, the best described being the expression of proteinase inhibitors to disrupt nematode digestion. The application of plant-delivered RNA interference (RNAi) to silence essential nematode genes has recently emerged as a potentially valuable resistance strategy.

Lipopolysaccharide-binding protein plasma levels and liver TNF-alpha gene expression in obese patients: evidence for the potential role of endotoxin in the pathogenesis of non-alcoholic steatohepatitis.

BACKGROUND: Some lines of evidence suggest that endotoxin may induce non-alcoholic steatohepatitis (NASH) in a background of fatty liver. However, a clear association between increased endotoxemia and development of steatohepatitis in obese patients has not been confirmed. We aim to assess the endotoxemic state of patients with non-alcoholic fatty liver disease (NAFLD) and its relationship with the liver expression of TNF-alpha and the presence of NASH. METHODS: Prospective study comprising 40 patients with morbid obesity who were diagnosed with NAFLD. Blood samples and liver biopsies were collected. Endotoxemia was assessed by the evaluation of circulating level of LPS-binding protein (LBP). Plasma levels of LBP and TNF-alpha were assessed by ELISA. The expression of TNF-alpha in liver tissue was evaluated by real-time PCR. Histological examination was performed to evaluate the presence of steatosis or NASH. RESULTS: Levels of LBP were increased in obese patients with NAFLD. In addition, plasma level of LBP was increased in patients with steatohepatitis (14.2 +/- 3.9 microg/mL) when compared with patients with simple steatosis (11.5 +/- 3.2 microg/mL), P=0.041. The TNF-alpha mRNA expression in liver tissue was significantly higher in patients with NASH. This increment correlated with the rise in plasma levels of LBP (r=0.412, P=0.036). CONCLUSION: NAFLD patients have elevated plasma levels of LBP and they are further increased in patients with NASH. This increase is related to a rise in TNF-alpha gene expression in the hepatic tissue which supports a role for endotoxemia in the development of steatohepatitis in obese patients.

Ativação imune-inflamatória na insuficiência cardíaca / Immune-inflammatory activation in heart failure

Apesar de relativamente recente, nota-se um acúmulo crescente e robusto de evidências experimentais e clínicas que apontam um estado gradativo de ativação imune-inflamatória em pacientes com insuficiência cardíaca (IC). Níveis elevados de diversas citocinas são encontrados na circulação e no músculo cardíaco de indivíduos com IC, correlacionando-se, invariavelmente, com o grau de gravidade da doença e agindo na disfunção endotelial, no estresse oxidativo, na indução de anemia, na apoptose miocitária e na perda gradativa de massa muscular esquelética - no que se convencionou denominar o paradigma inflamatório da IC. Não só o miocárdio, mas diversos tecidos parecem sintetizar tais citocinas e perpetuar esse contínuo estado de inflamação em baixo grau, inclusive leucócitos, monócitos, células musculares esqueléticas e endoteliais - em resposta a estímulos hemodinâmicos, infecciosos, à hipóxia, ao estresse oxidativo e à ativação neuro-humoral, entre outros. Desse modo, forma-se uma rede de moléculas que interagem entre si, estabelecendo, ainda, conexões com outros eixos que efetivamente contribuem para a deterioração clínica dos pacientes - o que se encaixa no modelo fisiopatológico de acometimento multissistêmico que tem sido cada vez mais atribuído à IC. Ainda que a dosagem periférica desses biomarcadores reúna evidências bastante sólidas de poder prognóstico, os resultados dos ensaios terapêuticos que modularam em fase clínica a alça imune-inflamatória foram, até então, pouco encorajadores. Desse modo, acreditamos que é fundamental compreender melhor a ativação inflamatória e sua multifacetada relação com os eixos de descompensação da doença, para que possamos estabelecer novas perspectivas terapêuticas com impacto de relevância em um futuro próximo.

Despite being relatively recent, a growing and significant accumulation of experimental and clinical evidence has been observed that points to a gradual state of immune-inflammatory activation in patients with heart failure (HF). High levels of several cytokines are found in the circulation and cardiac muscle of individuals with HF, and invariably correlate with the severity of the disease. These cytokines act on endothelial dysfunction, oxidative stress, induction of anemia, myocyte apoptosis, and on the progressive loss of skeletal muscle mass - which is conventionally called the inflammatory paradigm of HF. Not only the myocardium, but also several tissues seem to synthesize these cytokines and perpetuate this continuous inflammatory state at a low degree, including leukocytes, monocytes, skeletal muscle cells and endothelial cells - in response to hemodynamic and infectious stimuli, to hypoxia, to oxidative stress, to neurohumoral activation, and others. Thus, a network of molecules that interact with each other is formed, and connections with other axes that effectively contribute to the clinical deterioration of the patients are also established - which fits into the pathophysiological model of multisystemic involvement that has been increasingly attributed to HF. Although the determination of these biomarkers in peripheral blood provides solid evidence of prognostic power, the results of therapeutic trials that modulated the immune-inflammatory loop in the clinical phase have been, so far, hardly encouraging. Therefore, we believe that a better understanding of the inflammatory activation and its multifaceted relation with the axes of decompensation of the disease is key for new therapeutic perspectives with a relevant impact to be established in the near future.

Endogenous endotoxin participates in causing a panenteric inflammatory ileus after colonic surgery.

OBJECTIVE: To investigate muscularis inflammation and endogenous endotoxin as causes of postoperative ileus. BACKGROUND: Postoperative inflammatory ileus of the colon is associated with a significant delay in gastrointestinal transit. We investigated whether these changes are caused by the downstream obstructive barrier of the surgically altered colon or by small intestinal muscularis inflammation itself. Furthermore, we evaluated the mechanistic role of gut derived endotoxin in the development of postoperative intestinal dysfunction. METHODS: Rats underwent surgical manipulation of the colon. Isolated gastrointestinal transit was analyzed in animals with ileostomy. The perioperative emigration of intracolonic particles was investigated by colonic luminal injection of fluorescently labeled LPS and microspheres. Mediator mRNA induction was quantified by real-time RT-PCR. Muscularis leukocytic infiltrates were characterized. In vitro circular muscle contractility was assessed in a standard organ bath. RESULTS: Ileostomy rats presented with a significant delay in small intestinal transit after colonic manipulation. This was associated with leukocyte recruitment and inflammatory mediator mRNA induction within the small intestinal muscularis. Colonic manipulation caused the transference of intracolonic LPS and microspheres into the intestinal muscularis. Postoperative in vitro small intestinal circular muscle contractility was impaired by 42% compared with controls. Gut decontamination and TLR-4 deletion significantly alleviated the small intestinal muscularis inflammation and prevented intestinal muscle dysfunction. CONCLUSIONS: Selective colonic manipulation initiates a distant inflammatory response in the small intestinal muscularis that contributes to postoperative ileus. The data provide evidence that gut-derived bacterial products are mechanistically involved in the initiation of this remote inflammatory cascade.

Different TNFalpha expression elicited by glucose in monocytes from type 2 diabetes mellitus patients.

Increased plasma concentrations of tumor necrosis factor alpha (TNFalpha) system components appear in type 2 diabetes patients with poor glycemic control. We have analyzed the expression of TNFalpha, TNFR1 and TNFR2 when monocytes and lymphocytes isolated from a group of recent onset type 2 diabetic patients, with fasting glucose levels below 7.0mM and glycated haemoglobin (Hb1Ac) in the normal range, were stimulated with high glucose or LPS endotoxin. We report, that cultured monocytes from these type 2 diabetic patients, in comparison to monocytes from non-diabetic individuals, had an enhanced response to LPS but did not respond to an acute glucose challenge (p<0.05). No differences were observed in the cultured lymphocyte fractions. These results indicate the existence of differences, elicited by LPS or high glucose related stimulus, between monocytes isolated from non-diabetic subjects or from type 2 diabetes patients.

Vitamin E inhibits endotoxin-mediated transport of phosphatases to lipid rafts.

The production and release of inflammatory mediators is regulated by the coordinated activity of kinases and phosphatases. These proteins are known to regulate one another through an unknown mechanism. Previously, we have demonstrated that autocrine release of oxidants regulates macrophage activation in a similar fashion. The purpose of this study is to determine if attenuated oxidant activity by antioxidant exposure can regulate endotoxin-mediated kinase and phosphatase activity. Human promonocytic THP-1 cells were stimulated with lipopolysaccharide. Selected cells were pretreated with alpha-tocopherol succinate, LY294002, or an AKT inhibitor (1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate). Lipid raft and cellular protein were analyzed for lipid raft toll-like receptor 4 (TLR4) receptor formation and mitogen-activated protein kinase (MAPK) activation. Harvested supernatants were analyzed for tumor necrosis factor (TNF)-alpha production. Lipopolysaccharide stimulation led to the lipid raft mobilization of TLR4 and heat shock protein 70. This was followed by lipid raft mobilization of SH related complex homology 2 domain-containing inositol-5-phosphate (SHIP), activation of the MAPK, and production of TNF-alpha. Pretreatment with alpha-tocopherol succinate did not affect mobilization of TLR4 or heat shock protein 70, but did result in attenuated mobilization of SHIP, activation of the MAPK, and production of TNF-alpha. In addition, alpha-tocopherol succinate was associated with increased activation of the counter-regulatory kinase protein kinase B. Pretreatment with LY294002 or 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate reversed the effects of alpha-tocopherol succinate. Thus, it seems that endotoxin-mediated activation requires the coordinated activity of kinases and phosphatases. Antioxidant exposure in the form of vitamin E seems to attenuate endotoxin-mediated SHIP activation resulting in increased AKT activity, and attenuated MAPK activation and TNF-alpha production.

Role of intestinal function in cachexia.

PURPOSE OF REVIEW: Cachexia is a prominent feature in many chronic diseases, but its pathogenesis is still not fully understood. This article reviews recent research into the role of the gut barrier in the pathogenesis of inflammation and cachexia with special emphasis on two potentially catabolic diseases: liver cirrhosis and chronic heart failure. RECENT FINDINGS: There is increasing evidence that catabolic diseases such as liver cirrhosis and chronic heart failure are associated with increased gut permeability, endotoxemia and enhanced expression of proinflammatory cytokines. In liver cirrhosis normalization of portal hypertension by insertion of a transjugular intrahepatic portosystemic stent shunt obviously causes improvement not only of gut barrier function, but also of nutritional status. SUMMARY: Although its pathogenesis is not yet completely understood, proinflammatory cytokines have been implicated in the onset and progression of cachexia. Recent data support the hypothesis that impaired gut barrier function and increased permeability further translocation of endotoxins. Increased endotoxemia might be a potent trigger of systemic inflammatory response which is involved in the pathogenesis of the cachexia syndrome. Thus, it is tempting to speculate that therapeutic strategies for the improvement of gut barrier function will concomitantly improve nutritional status.

Systemic inflammation in heart failure--the whys and wherefores.

Patients with chronic heart failure (HF) are characterized by systemic inflammation, as evident by raised circulating levels of several inflammatory cytokines with increasing levels according to the degree of disease severity. In addition to the myocardium itself, several tissues and cells can contribute to this inflammation, including leukocytes, platelets, tissue macrophages and endothelial cells. Although the mechanisms for the systemic inflammation is unknown, both infectious (e.g., endotoxins) and non-infectious (e.g., oxidative stress and hemodynamic overload) events could be operating, also including activation of Toll-like receptors as well as interaction with the neurohormone system. A growing body of evidence suggests that this systemic inflammation in chronic HF may play a role in the development and progression of this disorder, not only by promoting myocardial dysfunction, but also by inducing pathogenic consequences in other organs and tissues, thereby contributing to additional aspects of the HF syndrome such as cachexia, endothelial dysfunction and anemia. Although this inappropriate immune activation and inflammation could represent a new target for therapy in patients with chronic HF, the anti-tumor necrosis factor trials have been disappointing, and future research in this area will have to more precisely identify the most important mechanisms and actors in the immunopathogenesis of chronic HF in order to develop better immunomodulating agents for this disorder.