Sepsis-induced Damage Research Articles

GPX4 Shields Organs from Sepsis-induced Damage by Regulating Programmed Cell Death

GPX4 Shields Organs from Sepsis-induced Damage by Regulating Programmed Cell Death

1-Piperidine Propionic Acid Protects from Septic Shock Through Protease Receptor 2 Inhibition.

Sepsis is a complex disorder caused by a dysregulated host response to infection, with high levels of morbidity and mortality. Treatment aimed to modulate immune response and maintain vascular function is still one of the major clinical challenges. This study was designed to test the effect of the small molecule 1-Piperidine Propionic Acid (1-PPA) as molecular targeted agent to block protease-activated receptor 2 (PAR2), one of the major modulators of inflammatory response in LPS-induced experimental endotoxemia. In the THP-1 cell line, LPS-induced cytokine expression was inhibited by 1-PPA in a dose-dependent manner. In LPS-injected mice, treatment with 1-PPA was effective in reducing mortality and sepsis-related symptoms and improved cardiac function parameters. After 6 h from LPS injection, a significant decrease in IL-6, IL-1β, and IL-10 was observed in the lung tissue of 1-PPA-treated mice, compared to controls. In these mice, a significant decrease in vasoactive molecules, especially kininogen-1, was also observed, mainly in the liver. Histopathological analysis confirmed typical features of sepsis in different organs and these findings were markedly reduced in mice treated with 1-PPA. These data demonstrate the effectiveness of 1-PPA in protecting the whole organism from sepsis-induced damage.

Melittin alleviates sepsis-induced acute kidney injury by promoting GPX4 expression to inhibit ferroptosis.

Melittin, the main component of bee venom, is a natural anti-inflammatory substance, in addition to its ability to fight cancer, antiviral, and useful in diabetes treatment. This study seeks to determine whether melittin can protect renal tissue from sepsis-induced damage by preventing ferroptosis and explore the protective mechanism. In this study, we investigated the specific protective mechanism of melittin against sepsis-induced renal injury by screening renal injury indicators and ferroptosis -related molecules and markers in animal and cellular models of sepsis. Our results showed that treatment with melittin attenuated the pathological changes in mice with lipopolysaccharide-induced acute kidney injury. Additionally, we found that melittin attenuated ferroptosis in kidney tissue by enhancing GPX4 expression, which ultimately led to the reduction of kidney tissue injury. Furthermore, we observed that melittin enhanced NRF2 nuclear translocation, which consequently upregulated GPX4 expression. our findings suggest that melittin may be a potential therapeutic agent for the treatment of sepsis-associated acute kidney injury by inhibiting ferroptosis through the GPX4/NRF2 pathway. Our study reveals the protective mechanism of melittin in septic kidney injury and provides a new therapeutic direction for Sepsis-AKI.

Effects of Saffron Yellow A as an Extract of Saffron on the Recovery Treatment and Organ Function of Patients with Sepsis

This research was aimed to investigate the effects of saffron yellow A (SESYA), an extract of saffron, in combination with continuous blood purification on serum factors, coagulation function, rehabilitation progress, and organ function of intensive care (ICU) patients with sepsis. Seventy ICU patients with sepsis and admitted to hospital were assigned to control group (group C), which received continuous blood purification treatment, and treatment group (group T), which received continuous blood purification combined with SESYA treatment. Serum factors (lactic acid (LAC), procalcitonin (PCT), C-reactive protein (CRP)), coagulation-related indicators (activated partial thromboplastin time (APTT), prothrombin time (PT), platelet count (PLT)), quality of life (QoL), prognosis-related indicators [Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation II (APACHE II)], and changes in major organ function indicators (liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST); renal function: creatinine (Cr), blood urea nitrogen (BUN); cardiac function: lactate dehydrogenase (LDH), creatine kinase (CK)) were compared before and after treatment in both groups. The purity of the prepared SESYA exceeded 90%. The serum factors and coagulation function indicators demonstrated inconsiderable differences between groups before treatment (P < 05). Relative to group C, group T showed a marked decrease in serum functional indicators and major coagulation function indicators (P < 05). After treatment, group T exhibited improved QoL scores and decreased prognosis-related indicator scores versus group C (P < 05). The levels of organ function indicators in two groups greatly decreased after treatment (P < 05), with group T showing notably greater improvement compared to group C (P < 05). These findings demonstrate that SESYA, an extract of saffron, can remarkably reduce serum factor levels, improve coagulation function, enhance QoL, and alleviate sepsis-induced damage to vital organs.

ENHANCED EFFICACY OF RESVERATROL-LOADED SILVER NANOPARTICLE IN ATTENUATING SEPSIS-INDUCED ACUTE LIVER INJURY: MODULATION OF INFLAMMATION, OXIDATIVE STRESS, AND SIRT1 ACTIVATION.

Sepsis-induced acute liver injury is a life-threatening condition involving inflammation, oxidative stress, and endothelial dysfunction. In the present study, the preventive effects of resveratrol (RV) alone and RV-loaded silver nanoparticles (AgNPs + RV) against sepsis-induced damage were investigated and compared in a rat model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Rats were divided into four groups: Sham, CLP, RV, and AgNPs + RV. Pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation, presepsin, procalcitonin (PCT), 8-hydroxy-2'-deoxyguanosine (8-OHDG), vascular endothelial growth factor (VEGF), and sirtuin-1 (SIRT1) levels were assessed to determine the treatments' effects. AgNPs + RV treatment significantly reduced pro-inflammatory cytokines, NF-κB activation, presepsin, PCT, 8-OHDG, and VEGF levels compared with the CLP group, indicating attenuation of sepsis-induced liver injury. Both RV and AgNPs + RV treatments increased SIRT1 levels, suggesting a potential role of SIRT1 activation in mediating the protective effects. In conclusion, AgNPs + RV treatment demonstrated extremely enhanced efficacy in alleviating sepsis-induced liver injury by modulating inflammation, oxidative stress, and endothelial dysfunction, potentially mediated through SIRT1 activation. In this study, the effect of AgNPs + RV on sepsis was evaluated for the first time, and these findings highlight AgNPs + RV as a promising therapeutic strategy for managing sepsis-induced liver injury, warranting further investigation.

PLK1 protects intestinal barrier function during sepsis by targeting mitochondrial dynamics through TANK-NF-κB signalling

BackgroundIntestinal barrier integrity in the pathogenesis of sepsis is critical. Despite an abundance of evidence, the molecular mechanism of the intestinal barrier in sepsis pathology remains unclear. Here, we report a protective role of polo-like kinase 1 (PLK1) in intestinal barrier integrity during sepsis.MethodsMice with PLK1 overexpression (CAG-PLK1 mice) or PLK1 inhibition (BI2536-treated mice) underwent caecal ligation and puncture (CLP) to establish a sepsis model. The intestinal barrier function, apoptosis in the intestinal epithelium, mitochondrial function and NF-κB signalling activity were evaluated. To suppress the activation of NF-κB signalling, the NF-κB inhibitor PDTC, was administered. The Caco-2 cell line was chosen to establish an intestinal epithelial injury model in vitro.ResultsSepsis destroyed intestinal barrier function, induced excessive apoptosis in the intestinal epithelium, and disrupted the balance of mitochondrial dynamics in wild-type mice. PLK1 overexpression alleviated sepsis-induced damage to the intestinal epithelium by inhibiting the activation of NF-κB signalling. PLK1 colocalized and interacted with TANK in Caco-2 cells. Transfecting Caco-2 cells with TANK-SiRNA suppressed NF-κB signalling and ameliorated mitochondrial dysfunction, apoptosis and the high permeability of cells induced by lipopolysaccharide (LPS). Furthermore, TANK overexpression impaired the protective effect of PLK1 on LPS-induced injuries in Caco-2 cells.ConclusionOur findings reveal that the PLK1/TANK/NF-κB axis plays a crucial role in sepsis-induced intestinal barrier dysfunction by regulating mitochondrial dynamics and apoptosis in the intestinal epithelium and might be a potential therapeutic target in the clinic.

Protective effects of farnesyltransferase inhibitor on sepsis-induced morphological aberrations of mitochondria in muscle and increased circulating mitochondrial DNA levels in mice

Sepsis remains a leading cause of mortality in critically ill patients and is characterized by multi-organ dysfunction. Mitochondrial damage has been proposed to be involved in the pathophysiology of sepsis. In addition to metabolic impairments resulting from mitochondrial dysfunction, mitochondrial DNA (mtDNA) causes systemic inflammation as a damage-associated molecular pattern when it is released to the circulation. Metabolic derangements in skeletal muscle are a major complication of sepsis and negatively affects clinical outcomes of septic patients. However, limited knowledge is available about sepsis-induced mitochondrial damage in skeletal muscle. Here, we show that sepsis induced profound abnormalities in cristae structure, rupture of the inner and outer membranes and enlargement of the mitochondria in mouse skeletal muscle in a time-dependent manner, which was associated with increased plasma mtDNA levels. Farnesyltransferase inhibitor, FTI-277, prevented sepsis-induced morphological aberrations of the mitochondria, and blocked the increased plasma mtDNA levels along with improved survival. These results indicate that protein farnesylation plays a role in sepsis-induced damage of the mitochondria in mouse skeletal muscle. Our findings suggest that mitochondrial disintegrity in skeletal muscle may contribute to elevated circulating mtDNA levels in sepsis.

Tetramethylpyrazine Ameliorates Lipopolysaccharide-Induced Sepsis in Rats via Protecting Blood-Brain Barrier, Impairing Inflammation and Nitrous Oxide Systems.

The aim of this study was to assess the underlying impact of Tetramethylpyrazine (TMP), which is the main activity compound of Ligusticum chuanxiong Hort, on the blood–brain barrier, inflammatory and nitrous oxide systems in a rat model of lipopolysaccharide (LPS)-induced sepsis. The SD rats were divided into control group, LPS treatment group, and LPS + TMP treatment group. TMP administered by tail vein injection. The mortality of experimental rats was recorded during the experiment. Rats were sacrificed after 14 days. Peripheral blood was collected and the expression levels of inflammatory factors TNF-α, IL-1β, and IL-6 were detected by ELISA. The integrity of blood-brain barrier was detected by sodium fluorescein staining. Lung and brain tissues were taken to detect the infiltration of immune cells. Immunohistochemistry was performed to detect the expression of tight junctions related proteins and oxidative stress-related proteins. The results showed that TMP treatment for 14 days significantly decreased the weight loss and increased the survival rate of the septic rats significantly. TMP decreased the infiltration of inflammatory cells and alleviated the sepsis-induced damage in both the lung and brain tissues. The inflammatory cytokines TNF-α, IL-1β, and IL-6, were significantly decreased post-TMP treatment. Histopathological analysis with sodium fluorescein staining density showed that TMP had a protective effect on the basal lamina and cerebral cortex. Also, TMP significantly increased expression of the tight junction-related proteins claudin-5 and occludin in the brain tissue and increased the expression of the ZO-1, Occludin, and Claudin-5 genes, indicating alleviated the degree of blood–brain barrier destruction. Furthermore, immunohistochemistry (IHC) and immunoblotting confirmed that TMP could inhibit the indicators of the nitrous oxide system, iNOS and eNOS; in addition, TMP significantly decreased the levels of MDA and NO. The findings showed that TMP treatment during sepsis was associated with the protection of the blood–brain barrier and the suppression of inflammatory reactions and the nitrous oxide system. This study reveals a promising protective role of TMP in septic encephalopathy and may suggest a therapeutic approach for fighting the deadly disease of sepsis in the clinic.

Sepsis-induced damage to endothelial glycocalyx (literature review)

Glycocalyx is a gel-like layer covering the surface of vascular endothelial cells. It consists of membrane-attached proteoglycans, glycosaminoglycan chains, glycoproteins, and plasma adhesive proteins. Glycocalyx plays a key role in maintaining vascular homeostasis, controls vascular permeability and the tone of the microvasculature, prevents microvascular thrombosis and regulates leukocyte adhesion. In sepsis and septic shock, damage and shedding of glycocalyx occurs. The degradation of glycocalyx is activated by reactive oxygen species and pro-inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-1β (IL-1β). The inflammation-mediated degradation of glycocalyx leads to vascular hyperpermeability, unregulated vasodilation, microvascular thrombosis, and enhanced leukocyte adhesion. The inflammation-mediated degradation of glycocalyx leads to vascular hyperpermeability, unregulated vasodilation, microvascular thrombosis, and enhanced leukocyte adhesion. Clinical studies have demonstrated a correlation between the levels of glycocalyx components in the blood and organ dysfunction and mortality in sepsis and septic shock. Inflammation-induced damage to glycocalyx can cause a number of specific clinical effects of sepsis, including acute kidney damage, respiratory failure and liver dysfunction. Infusion therapy is an integral part of the treatment of sepsis, but super-aggressive infusion load methods (leading to hypervolemia) may increase the degradation of glycocalyx. Moreover, some markers of glycocalyx degradation, such as circulating levels of syndecan 1 or heparan sulfate, can be used as markers of endothelial dysfunction and sepsis severity.

Effects of N-acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia.

BackgroundModulation of inflammation and oxidative stress appears to limit sepsis-induced damage in experimental models. The kidney is one of the most sensitive organs to injury during septic shock. In this study, we evaluated the effect of N-acetylcysteine (NAC) administration in conjunction with fluid resuscitation on renal oxygenation and function. We hypothesized that reducing inflammation would improve the microcirculatory oxygenation in the kidney and limit the onset of acute kidney injury (AKI).MethodsRats were randomized into five groups (n = 8 per group): (1) control group, (2) control + NAC, (3) endotoxemic shock with lipopolysaccharide (LPS) without fluids, (4) LPS + fluid resuscitation, and (5) LPS + fluid resuscitation + NAC (150 mg/kg/h). Fluid resuscitation was initiated at 120 min and maintained at fixed volume for 2 h with hydroxyethyl starch (HES 130/0.4) dissolved in acetate-balanced Ringer’s solution (Volulyte) with or without supplementation with NAC (150 mg/kg/h). Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein was measured using phosphorimetry. Biomarkers of renal injury, inflammation, and oxidative stress were assessed in kidney tissues.ResultsFluid resuscitation significantly improved the systemic and renal macrohemodynamic parameters after LPS. However, the addition of NAC further improved cortical renal oxygenation, oxygen delivery, and oxygen consumption (p < 0.05). NAC supplementation dampened the accumulation of NGAL or L-FABP, hyaluronic acid, and nitric oxide in kidney tissue (p < 0.01).ConclusionThe addition of NAC to fluid resuscitation may improve renal oxygenation and attenuate microvascular dysfunction and AKI. Decreases in renal NO and hyaluronic acid levels may be involved in this beneficial effect. A therapeutic strategy combining initial fluid resuscitation with antioxidant therapies may prevent sepsis-induced AKI.

Obesity Exacerbates Sepsis-Induced Oxidative Damage in Organs.

Sepsis progression is linked to the imbalance between reactive oxygen species and antioxidant enzymes. Sepsis affects multiple organs, but when associated with a chronic inflammatory disease, such as obesity, it may be exacerbated. We hypothesized that obesity could aggravate the oxidative damage to peripheral organs of rats submitted to an animal model of sepsis. Male Wistar rats aged 8weeks received hypercaloric nutrition for 2months to induce obesity. Sepsis was induced by cecal ligation and puncture (CLP) procedure, and sham-operated rats were considered as control group. The experimental groups were divided into sham + eutrophic, sham + obese, CLP + eutrophic, and CLP + obese. Twelve and 24h after surgery, oxidative damage to lipids and proteins and superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in the liver, lung, kidney, and heart. The data indicate that obese rats subjected to sepsis present oxidative stress mainly in the lung and liver. This alteration reflected an oxidative damage to lipids and proteins and an imbalance of SOD and CAT levels, especially 24h after sepsis. It follows that obesity due to its pro-inflammatory phenotype can aggravate sepsis-induced damage in peripheral organs.

Carbon Monoxide-Releasing Molecule-2 Reduces Intestinal Epithelial Tight-Junction Damage and Mortality in Septic Rats.

ObjectiveDamage to intestinal epithelial tight junctions plays an important role in sepsis. Recently we found that Carbon Monoxide-Releasing Molecule-2 (CORM-2) is able to protect LPS-induced intestinal epithelial tight junction damage and in this study we will investigate if CORM-2 could protect intestinal epithelial tight junctions in the rat cecal ligation and puncture (CLP) model.Materials and MethodsThe CLP model was generated using male Sprague-Dawley (SD) rats according to standard procedure and treated with CORM-2 or inactive CORM-2 (iCORM-2), 8 mg/kg, i.v. immediately after CLP induction and euthanized after 24h or 72h (for mortality rate only). Morphological changes were investigated using both transmission electron and confocal microscopy. The levels of important TJ proteins and phosphorylation of myosin light chain (MLC) were examined using Western blotting. Cytokines, IL-1β and TNF-α were measured using ELISA kits. The overall intestinal epithelial permeability was evaluated using FD-4 as a marker.ResultsCORM-2, but not iCORM-2, significantly reduced sepsis-induced damage of intestinal mucosa (including TJ disruption), TJ protein reduction (including zonula occludens-l (ZO-1), claudin-1 and occludin), MLC phosphorylation and proinflammatory cytokine release. The overall outcomes showed that CORM-2 suppressed sepsis-induced intestinal epithelial permeability changes and reduced mortality rate of those septic rats.ConclusionsOur data strongly suggest that CORM-2 could be a potential therapeutic reagent for sepsis by suppressing inflammation, restoring intestinal epithelial barrier and reducing mortality.

Blocking NAD+/CD38/cADPR/Ca2+ pathway in sepsis prevents organ damage

BackgroundAlthough the nicotinamide adenine dinucleotide (NAD+)/CD38/cyclic ADP ribose (cADPR)/Ca2+ signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD+/CD38/cADPR/Ca2+ signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage. Materials and methodsMale Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD+, cADPR, CD38, and intracellular Ca2+ levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin–eosin-stained and assayed for malondialdehyde and superoxide dismutase activities. ResultsNAD+, cADPR, CD38, and intracellular Ca2+ levels increased in the hearts, livers, and kidneys of septic rats as early as 6–24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca2+ mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats. ConclusionsThe NAD+/CD38/cADPR/Ca2+ signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage.

Obesity promotes oxidative stress and exacerbates sepsis-induced brain damage.

Sepsis is a severe clinical syndrome in which a system-wide inflammatory response follows initial attempts to eliminate pathogens. It is not novel that in sepsis the brain is one of the first organs affected which causes an increase in morbidity and mortality and its consequences may be exacerbated when associated with a diagnosis of chronic inflammation, such as in obesity. Thus, the aim of the present study is to evaluate the susceptibility to brain damage after sepsis in obese rats. During two months, Wistar rats, 60 days, 250-300g received hypercaloric nutrition to induce obesity. Sepsis was submitted to the cecal ligation and perforation (CLP) procedure and sham-operated rats was considered control group. The experimental groups were divided into Sham + Eutrophic, Sham + Obesity, CLP + Eutrophic and CLP + Obesity. Twelve and twenty four hours after surgery the blood brain barrier (BBB) permeability, nitrite/nitrate concentration, myeloperoxidase (MPO) activity, oxidative damage to lipids and proteins and superoxide dismutase (SOD) and catalase (CAT) activities were evaluated in the hippocampus, cortex and prefrontal cortex. The data indicate that in obese rats subjected to sepsis occurs an increase of BBB permeability in different brain regions compared to eutrophic septic rats. This alteration reflected an increase of MPO activity, concentration of nitrite/nitrate, oxidative damage to lipids and proteins and an imbalance of SOD and CAT especially 24 hours after sepsis. It follows that obesity due to its pro-inflammatory phenotype can aggravate or accelerate the sepsis-induced damage in rat brain.

Anti-inflammatory activity of curcumin-loaded solid lipid nanoparticles in IL-1β transgenic mice subjected to the lipopolysaccharide-induced sepsis

Sepsis is a significant public healthcare problem, affecting millions of people worldwide each year, killing one in four, and increasing in incidence. Thus, advanced therapeutic strategies are required to treat sepsis patients. Curcumin (Cur) is a promising anti-inflammatory agent for various inflammatory disorders. However, the therapeutic efficacy of Cur is limited due to poor aqueous solubility, rapid degradation, and low bioavailability. The aims of this study were to evaluate the therapeutic potential of Cur-loaded solid lipid nanoparticles (Cur-SLNs) for sepsis treatment. A firefly luciferase transgenic mouse was used to monitor real time interleukin 1β (IL-1β) expression in lipopolysaccharide (LPS)-induced sepsis model to examine the protective effect of Cur-SLNs, and to elucidate its underlying molecular mechanisms. Mice (female or male) were intraperitoneally administered with free Cur or Cur-SLNs (30 mg/kg) before the intraperitoneal delivery of LPS (3 mg/kg). Our results indicated that Cur-SLNs can effectively reduced levels of IL-1β expression compared to free Cur, especially at 3 h after LPS injection. Also, Cur-SLNs significantly decreased the expression of serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β as compared with free Cur, but augmented anti-inflammatory cytokine IL-10 by ELISA assay. Further, marked alleviation of the sepsis-induced damage to organs, including kidney, liver, and heart was observed with Cur-SLNs treatment as determined by hematoxylin/eosin-staining. Western blot analyses revealed that Cur-SLNs can significantly lower the expression levels of TLR4, TLR2, and TNF-α in lymph node tissues. Meanwhile, it showed suppressions of NF-κB activation and IκBα degradation levels. In conclusion, we suggested that Cur-SLNs may be used as an effective and safe therapeutic agent in treating sepsis in high-risk patient groups.

Loss of caveolin-1 promotes endothelial-mesenchymal transition during sepsis: A membrane proteomic study

Sepsis is a clinical syndrome that reflects an uncontrolled systemic inflammatory response to microbial infections. Endothelial cells, which are highly responsive to their extracellular environment, are the primary targets of sepsis-induced damage. Endothelial-mesenchymal transition (EndMT), characterized by loss of endothelial cell markers and gain of mesenchymal cell markers, contributes to embryonic cardiac formation as well as development of various diseases. We showed that incubation with septic serum induced a rapid loss of endothelial barrier integrity in a human umbilical vein endothelial cell (HUVEC) monolayer. Notably, exposure to septic serum triggered EndMT in HUVECs, companied by increased cell motility and invasion. Furthermore, membrane proteomic analysis was applied to analyze the key mediators in septic serum-induced EndMT. A total of 29 proteins with altered expression level were positively identified. Expression of four proteins with the most significant alteration, including caveolin-1, S100A4, α-enolase and galectin-1, were validated by western blotting. Finally, we showed that restoration of caveolin-1 expression markedly attenuated septic serum-induced EndMT in HUVEC cells. This is the first report showing that endothelial cells undergo EndMT during sepsis. The present study may lead to a better understanding of the biological role of endothelial cells and caveolin-1 during sepsis.

Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment

The development of cognitive impairment in sepsis is associated with neurotoxic effects caused by oxidative stress. We have assessed the effects of acute and extended administration of guanosine (GUA) on brain oxidative stress parameters and cognitive impairment in rats submitted to sepsis by cecal ligation and perforation (CLP). To achieve this goal, male Wistar rats underwent either sham operation or CLP with GUA. Rats subjected to CLP were treated with intraperitoneal injection of GUA (8 mg/kg after CLP) or vehicle. Twelve and 24 h after CLP, the rats were sacrificed, and samples from brain (hippocampus, striatum, cerebellum, prefrontal cortex and cortex) were obtained and assayed for thiobarbituric acid reactive species (TBARS) formation and protein carbonyls. On the 10th day, another group of rats was submitted to the behavioral tasks. GUA administration reduced TBARS and carbonyl levels in some brain regions between 12 and 24 h after CLP, and ameliorated cognitive impairment evaluated 10 days after CLP. Our data provide the first experimental demonstration that GUA was able to reduce the consequences of CLP-induced sepsis in rats, by decreasing oxidative stress parameters in the brain and recovering the memory impairment.

Blockade of tissue factor-factor X binding attenuates sepsis-induced respiratory and renal failure

Tissue factor expression in sepsis activates coagulation in the lung, which potentiates inflammation and leads to fibrin deposition. We hypothesized that blockade of factor X binding to the tissue factor-factor VIIa complex would prevent sepsis-induced damage to the lungs and other organs. Acute lung injury was produced in 15 adult baboons primed with killed Escherichia coli [1 x 10(9) colony-forming units (CFU)/kg], and then 12 h later, they were given 1 x 10(10) CFU/kg live E. coli by infusion. Two hours after live E. coli, animals received antibiotics with or without monoclonal antibody to tissue factor intravenously to block tissue factor-factor X binding. The animals were monitored physiologically for 34 h before being killed and their tissue harvested. The antibody treatment attenuated abnormalities in gas exchange and lung compliance, preserved renal function, and prevented tissue neutrophil influx and bowel edema relative to antibiotics alone (all P < 0.05). It also attenuated fibrinogen depletion (P < 0.01) and decreased proinflammatory cytokines, e.g., IL-6 and -8 (P < 0.01), in systemic and alveolar compartments. Similar protective effects of the antibody on IL-6 and -8 expression and permeability were found in lipopolysaccharide-stimulated endothelial cells. Blockade of factor X binding to the tissue factor-factor VIIa complex attenuates lung and organ injuries in established E. coli sepsis by attenuating the neutrophilic response and inflammatory pathways.

Protective effect of β-glucan against oxidative organ injury in a rat model of sepsis

Sepsis leads to various organ damage and dysfunction. One of the underlying mechanisms is thought to be the oxidative damage due to the generation of free radicals. In this study, we investigated the putative protective role of β-glucan against sepsis-induced oxidative organ damage. Sepsis was induced by caecal ligation and puncture (CLP) in Wistar albino rats. Sham operated (control) and sepsis groups received saline or β-glucan (50 mg/kg, po) once daily for 10 days and 30 min prior to and 6 h after the CLP. Sixteen hours after the surgery, rats were decapitated and the biochemical changes were determined in the brain, diaphragm, kidney, heart, liver and lung tissues using malondialdehyde (MDA) content – an index of lipid peroxidation – glutathione (GSH) levels – a key antioxidant – and myeloperoxidase (MPO) activity – an index of neutrophil infiltration. Serum TNF-α levels were assessed by RIA method. Tissues were also examined under light microscope to evaluate the degree of sepsis-induced damage. The results demonstrate that sepsis significantly decreased GSH levels and increased the MDA levels and MPO activity ( p < 0.05– p < 0.001) causing oxidative damage. Elevated plasma TNF-α levels in septic rats significantly reduced to control levels in β-glucan treated rats. Since β-glucan administration reversed these oxidant responses, it seems likely that β-glucan protects against sepsis-induced oxidative organ injury.