The possible cardioprotective effect of ghrelin during experimental endotoxemia in mice.

This study aimed to evaluate the cardioprotective effects of ghrelin in septic mice, focusing on its anti-inflammatory and antioxidant properties. Thirty-five male Swiss mice (8-12 weeks old, 23-33g) were randomly assigned to five groups (n = 7 each): (1) Normal, fed usual diets, (2) Sham, subjected to anesthesia and laparotomy, (3) Sepsis, subjected to cecal ligation and puncture, (4) Vehicle, given an equivalent volume of intraperitoneal saline injections immediately after cecal ligation and puncture, and (5) Ghrelin-treated, administered 80 µg/kg ghrelin intraperitoneal injections immediately following cecal ligation and puncture. Serum levels of tumor necrosis factor-alpha (TNF-α), macrophage migration inhibitory factor (MIF), toll-like receptor 4 (TLR4), and 8-epi-prostaglandin F2 alpha (8-epi-PGF2α) were measured. The extent of cardiac damage was also evaluated histologically. The mean serum levels of TNF-α, MIF, TLR4, and 8-epi-PGF2α levels were significantly higher in the sepsis and vehicle groups than in the normal and sham groups. The levels were significantly lower in the ghrelin-treated group than in the vehicle and sepsis groups. Histological analysis revealed normal myocardial architecture in the normal and sham groups, whereas the sepsis and vehicle groups had severe myocardial injury. The ghrelin-treated group displayed histological features similar to the sham group, indicating reduced myocardial damage. Ghrelin ameliorated sepsis-induced cardiotoxicity in mice by exhibiting strong anti-inflammatory and antioxidant effects. These findings suggest that ghrelin may be a promising therapeutic candidate for the prevention of sepsis-induced cardiotoxicity.

Ghrelin attenuates the inflammatory response induced by experimental endotoxemia in mice.

OBJECTIVE: Aim: The aim of this research is to assess the anti-inflammatory effect of ghrelin in mice models of polymicrobial sepsis. PATIENTS AND METHODS: Materials and Methods: 35 male albino Swiss mice, ages 8-12 weeks, weighing 23-33g, were randomly separated into five groups n = 7; normal group was fed their usual diets until time of sampling, the sham group subjected to Anaesthesia and laparotomy, sepsis group subjected to cecal ligation and puncture, vehicle group was given an equivalent volume of intraperitoneal saline injections immediately after cecal ligation and puncture, and the ghrelin group was treated with 80 µg/kg of ghrelin intraperitoneal injections immediately following cecal ligation and puncture. Twenty hours after cecal ligation and puncture, mice were sacrificed; myocardial tissue and serum samples were collected. Serum IL-1ß, NF-κB, and TLR4 levels were measured, and inflammatory response's effects on cardiac tissue were evaluated. RESULTS: Results: The mean serum IL-1ß, NF-κB, and TLR4 levels were markedly elevated in the sepsis and vehicle groups than in the normal and sham groups. The mean serum levels of IL-1ß, NF-κB, and TLR4 were considerably lower in the ghrelin-treated group than in the vehicle and sepsis groups. Myocardium tissue of the normal and sham groups showed normal architecture. The sepsis and vehicle groups had a severe myocardial injury. The histological characteristics of ghrelin-treated mice differed slightly from those of the normal and sham groups. CONCLUSION: Conclusions: Our study concluded that ghrelin exerts anti-inflammatory effects in polymicrobial sepsis, as indicated by a considerable decrease in the IL-1ß, NF-κB and TLR4 serum levels.

Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study.

Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6-40) and 31 cm/s (14-79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = - 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.

Papel protector de las lipoproteínas de alta densidad en sepsis: aspectos básicos e implicancias clínicas / Protective role of high density lipoproteins in sepsis: basic issues and clinical implications

High density lipoproteins (HDL) are responsible of reverse cholesterol transport and play an important antiatherogenic role. In recent years, several studies suggest that HDL have additional functions, including a possible anti-inflammatory activity in infectious conditions. Furthermore, available evidence indicates that the presence of lipopolysaccharide (LPS) within the circulation during infectious states induced by gram-negative bacteria may be involved in the decrease in HDL cholesterol levels and changes in lipoprotein composition, which have been associated with a higher mortality due to sepsis in animal models and in humans. In this article, we review this subject and also discuss possible mechanisms that explain the positive impact achieved by native HDL, reconstituted HDL, or HDL apolipoprotein peptides on the inflammatory response and mortality in models of endotoxemia. In this regard, it has been proposed that one of the mechanisms by which HDL protect against sepsis may be mediated by its binding ability and/or neutralizing capacity on LPS, avoiding an excessive response of the immune system. Thus, increasing blood levels of HDL and/or parenteral HDL administration may represent a new anti-inflammatory tool for managing septic states in humans.

Las lipoproteínas de alta densidad (HDL) son responsables del transporte reverso de colesterol y ejercen un importante papel anti-aterogénico. En los últimos años, diversos estudios indican que las HDL también tendrían otras funciones críticas, incluyendo una posible actividad anti-inflamatoria durante estados infecciosos. Además, la evidencia disponible sugiere que la presencia de lipopolisacárido (LPS) en la circulación durante estados infecciosos inducidos por bacterias gramnegativas podría estar involucrado en la disminución del colesterol HDL y los cambios en composición de esta clase lipoproteínas, lo cual se asociaría con una mayor tasa de mortalidad por sepsis en modelos animales y en humanos. En este trabajo, se revisan los antecedentes mencionados y además se discuten posibles mecanismos que explican la disminución de la respuesta inflamatoria y de la mortalidad que se logran en modelos de endotoxemia tratados con HDL o preparaciones similares. En este sentido, se ha propuesto que uno de los mecanismos protectores de las HDL estaría mediado por su capacidad de unión y/o neutralización del LPS, evitando una respuesta exacerbada del sistema inmune. De esta manera, el aumento de los niveles sanguíneos de HDL y/o su administración parenteral podrían constituir nuevas herramientas anti-inflamatorias para el manejo de estados sépticos en humanos.

Efeito da suplementação com L-glutamina livre e na forma de dipeptídeo sobre eixo glutamina-glutationa, sistema imune, sistema inflamatório e vias de sinalização proteica em camundongos submetidos à endotoxemia / Effects of dietary supplementation with L-glutamine in the free and dipeptide forms on glutamine-glutathione axis, immune system, inflammatory system and protein signaling pathwaysin mice submitted to endotoxemia

A sepse é a principal causa de morte em unidades de terapia intensiva (UTIs) no mundo. A reduzida disponibilidade do aminoácido mais abundante do organismo, a glutamina contribui para o complicado estado catabólico da sepse. No presente estudo investigamos os efeitos da suplementação oral com L-glutamina e L-alanina (GLN+ALA), ambos na norma livre e como dipeptídeo, L-alanil-L-glutamina (DIP), sobre o eixo glutamina-glutationa (GSH), sistema imune, inflamação, proteínas de choque térmico (HSPs) e expressão de genes envolvidos com vias de sinalização proteica em animais endotoxêmicos. Camundongos C57/B6 foram submetidos à endotoxemia (Escherichia coli LPS, 5 mg.kg-1, grupo LPS) e suplementados por 48 horas com L-glutamina (1 g.kg-1) e L-alanina (0,61 g.kg-1, grupo GLN+ALA-LPS) ou 1,49 g.kg-1 de DIP (grupo DIP-LPS). A endotoxemia promoveu depleção da concentração de glutamina no plasma (71%), músculo esquelético (50%) e fígado (49%), quando comparado ao grupo CTRL, sendo restauradas nos grupos DIP-LPS e GLN+ALA-LPS (P<0,05), fato que atenuou a redução da GSH e o estado redox (taxa GSSG/GSH) em eritrócitos circulantes, musculo e fígado (P<0,05). A suplementação em animais endotoxêmicos resultou em uma upregulation dos genes GSR, GPX1 e GCLC no músculo e fígado. A concentração das citocinas plasmáticasTNF-α, IL-6, IL-1ß e IL-10 foi atenuada pelas suplementações, bem como a expressão de mRNAs envolvidos com a resposta inflamatória, ativadas pela via do NF-κB(P<0,05). Concomitantemente, verificou-se aumento da capacidade proliferativa de linfócitos T e B circulantes nos grupos GLN+ALA-LPS e DIP-LPS. A expressão de mRNAs e a concentração de HSPs no tecido muscular foi restabelecida pelas suplementações, contudo, a expressão mRNAs relacionados às vias de síntese e degradação proteica foi somente estimulada no tecido hepático(P<0,05). Os resultados do presente estudo demonstram que a suplementação por via oral com GLN+ALA ou DIP podem ser utilizados clinicamente como métodos nutricionais em reverter o quadro de depressão da disponibilidade de glutamina corporal da sepse induzida por LPS, tendo impacto no eixo glutamina-glutationa, sistema imune e inflamatório

Sepsis is the leading cause of death inintensive care units (ICUs) in the world.The availability ofthe most abundant amino acid in the body, glutamine, is reduced in this situation, fact that contribute to the complicated catabolic state of sepsis. In the present study, we investigated the effects of oral supplementation with L-glutamine and L-alanine (GLN+ALA), both in their free form and as a dipeptide, L-alanyl-L-glutamine (DIP) on glutamine-glutathione axis (GSH), immune and inflammatory system, heat shock proteins (HSPs) expression and gene expressions involved in protein signaling pathways during endotoxemia. C57/B6 mice were subjected to endotoxemia (Escherichia coli LPS, 5 mg.kg-1, LPS group) and supplemented for 48 hours with L-glutamine (1 g.kg-1) plus L-alanine(0.61 g.kg-1, GLN+ALA-LPS group) or 1.49 g.kg-1of DIP (DIP-LPS group). Endotoxemia promoted depletion glutamine concentration in plasma (71%), skeletal muscle (50%) and liver (49%), when compared to the CTRL group, and was restored in the DIP-LPS e GLN+ALA-LPS (P<0.05), fact that attenuate the reduction of GSH and the redox state (GSSG/GSH rate) in circulating erythrocytes, liver and muscle (P<0.05). Supplementations in endotoxemic mice resulted in upregulation of GSR, GCLC and GPX1 genes in muscle and liver. Plasma concentration of TNF-α, IL-6, IL-1ß and IL-10 were attenuated by supplementation as well as the expression of mRNAs involved in the inflammatory response, activated by NFκ-B pathway (P <0.05). At the same time, high proliferative capacity of circulating T and B lymphocytes GLN+ALA-LPS e DIP-LPS were observed. HSPs (protein and mRNAs) and in muscle were restored by the supplements, however, the mRNAs expression related to the synthesis and degradation of protein pathways was only stimulated in the liver (P <0.05). Our results demonstrate that oral supplementation with GLN+ALA or DIP can be used as clinically nutritional methods to reverse the depression of body glutamine availability during sepsis induced by LPS, impacting on the glutamine-glutathione axis, immune and inflammatory system

Propolis derivatives inhibit the systemic inflammatory response and protect hepatic and neuronal cells in acute septic shock

BACKGROUND: Severe pathogenic infection triggers excessive release of cytokines as part of the massive inflammatory response associated with septic shock. OBJECTIVES: To investigate the protective effect of caffeic acid phenethye ester (CAPE) against lipopolysaccharide (LPS) induced endotoxemia, hepatic and neuronal damage and the associated systemic inflammatory response (SIR). METHODS: Fifty male Wister rats were divided into: control, LPS, and CAPE+LPS groups. Plasma concentrations of various cytokines, including TNF-α, IL-1α, IL-1β, IL-6, IL-4, IL-10, and sICAM-1 were evaluated. In addition, the histopathological changes in the hepatic and neural cells were assessed. RESULTS: The LPS group showed high inflammatory cytokines and sICAM-1 levels reflecting the presence of SIR. Hepatocyte necrosis, apoptosis, extensive hemorrhage and inflammatory cellular infiltration together with brain astrocytes swelling, early neuron injury and presence of inflammatory foci confirmed the toxic tissue damage. Use of CAPE decreased the inflammatory cytokines and increased the anti-inflammatory cytokines levels. This biochemical evidence of decreased SIR was confirmed histologically by decreased cellular infiltration in the liver and brain tissue which coincides with preserved structure and protection of the liver and brain cells from the toxic effects of LPS. CONCLUSION: The ability of CAPE to alleviate the SIR, hepatic and neuronal cell damage induced by LPS and galactosamine could be attributed to its ability to reverse the imbalance of the pro- and anti-inflammatory cytokines which may lead to the inhibition of adhesion molecules' expression. CAPE is a promising agent that could help in the prophylaxis and treatment of septic shock.