losartan-potassium and Endotoxemia

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Acute kidney injury (AKI) is a frequent complication of sepsis, with a high mortality. Hallmarks of septic-AKI include inflammation, endothelial injury, and tissue hypoxia. Therefore, it would be of interest to develop therapeutic approaches for improving the microvascular damage in septic-AKI. Erythropoietin (EPO) is a well-known cytoprotective multifunctional hormone. Thus, the aim of this study was to evaluate the protective effects of EPO on microvascular injury in a murine model of endotoxemic AKI. Male Balb/c mice were divided into four groups: control, LPS (8 mg/kg, ip.), EPO (3000 IU / kg, sc.) and LPS + EPO. A time course study (0-48 h) was designed. Experiments include, among others, immunohistochemistry and Western blottings of hypoxia-inducible transcription factor (HIF-1α), erythropoietin receptor (EPO-R), vascular endothelial growth factor system (VEGF/VEGFR-2), platelet and endothelial adhesion molecule-1 (PeCAM-1), inducible nitric oxide synthase (iNOS) and phosphorylated nuclear factor kappa B p65 (NF-κB). Data showed that EPO attenuates renal microvascular damage during septic-AKI progression through a) the decrease of HIF-1 alpha, iNOS, and NF-κB and b) the enhancement of EPO-R, PeCAM-1, VEGF, and VEGFR-2 expression. In summary, EPO renoprotection involves the attenuation of septic-induced renal hypoxia and inflammation as well as ameliorates the endotoxemic microvascular injury.

Topics: Acute Kidney Injury; Animals; Blotting, Western; Disease Models, Animal; Disease Progression; Endotoxemia; Erythropoietin; Immunohistochemistry; Inflammation; Lipopolysaccharides; Male; Mice; Mice, Inbred BALB C; Microvessels; Sepsis; Time Factors

Topics: Animals; Brain Diseases; Endotoxemia; Erythropoietin; Humans; Janus Kinase 2; Male; STAT3 Transcription Factor

There is limited evidence that the tissue-protective effects of erythropoietin are mediated by a heterocomplex of the erythropoietin receptor and the β-common receptor ('tissue-protective receptor'), which is pharmacologically distinct from the 'classical' erythropoietin receptor homodimer that is responsible for erythropoiesis. However, the role of the β-common receptor and/or erythropoietin in sepsis-induced cardiac dysfunction (a well known, serious complication of sepsis) is unknown. Here we report for the first time that the β-common receptor is essential for the improvements in the impaired systolic contractility afforded by erythropoietin in experimental sepsis. Cardiac function was assessed in vivo (echocardiography) and ex vivo (Langendorff-perfused heart) in wild-type and β-common receptor knockout mice, that were subjected to lipopolysaccharide (9 mg/kg body weight; young mice) for 16-18 hours or cecal ligation and puncture (aged mice) for 24 hours. Mice received erythropoietin (1000 IU/kg body weight) 1 hour after lipopolysaccharide or cecal ligation and puncture. Erythropoietin reduced the impaired systolic contractility (in vivo and ex vivo) caused by endotoxemia or sepsis in young as well as old wild-type mice in a β-common-receptor-dependent fashion. Activation by erythropoietin of the β-common receptor also resulted in the activation of well-known survival pathways (Akt and endothelial nitric oxide synthase) and inhibition of pro-inflammatory pathways (glycogen synthase kinase-3β, nuclear factor-κB and interleukin-1β). All the above pleiotropic effects of erythropoietin were lost in β-common receptor knockout mice. Erythropoietin attenuates the impaired systolic contractility associated with sepsis by activation of the β-common receptor, which, in turn, results in activation of survival pathways and inhibition of inflammation.

Topics: Animals; Cecum; Cell Nucleus; Cytokine Receptor Common beta Subunit; Endotoxemia; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Heart; Heart Function Tests; In Vitro Techniques; Interleukin-1beta; Ligation; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Perfusion; Phosphorylation; Protein Transport; Proto-Oncogene Proteins c-akt; Punctures; Sepsis; Signal Transduction; Transcription Factor RelA; Ultrasonography

Septic encephalopathy is characterized by changes in mental status and an increase in neuronal apoptosis. Accumulating evidence has shown that recombinant human erythropoietin (rhEPO) protects brain against ischemia and hypoxia injury. However, whether rhEPO exerts neuroprotective effects on septic encephalopathy remains unclear. We designed the current study to evaluate possible neuroprotection of rhEPO in a model of sepsis.. For this in vitro study, we determined hippocampal neuronal apoptosis by lactate dehydrogenase release, cell counting kit-8 assay, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling staining after treatment with lipopolysaccharide. We transfected the signal transducer and activator of transcription 3 (STAT3) short hairpin RNA at 14 d in vitro for 48 h. For the in vivo study, we performed cecal ligation and peroration surgery. We detected the expression of phospho-Janus-activated kinase 2 (JAK2), total JAK2, phospho-STAT3, total STAT3, Bax and Bcl-XL by Western blot, and examined behavior using the Morris water maze.. Treatment with rhEPO reduces apoptosis and increases cell viability in lipopolysaccharide-treated neuronal cultures. In cecal ligation and peroration rats, rhEPO attenuated the inhibition of phospho-JAK2 and phospho-STAT3. In addition, rhEPO enhanced the expression of Bcl-XL, but depressed Bax, which was abolished by additional administration of inhibitor of JAK2/STAT3 signaling 2-cyano-3-(3,4-dihydroxyphenyl)-N-(benzyl)-2-propenamide,2-cyano-3-(3,4-dihydroxyphenyl)-N-(phenylmethyl)-2-propenamide or (E)-3(6-bromopyridin-2-yl)-2-cyano-N-([S0-1-phenylethyl]acrylamide)in vivo, and was ameliorated by STAT3 short hairpin RNA transfection in vitro. Alternatively, we confirmed the neuronal protective effect of rhEPO by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelingstaining. For the Morris water maze study, rhEPO improved learning and memory disorders without an alternation in locomotor activity.. These results indicated that rhEPO improves brain dysfunction by reducing neuronal apoptosis, and JAK2/STAT3 signaling is likely to be involved. Application of rhEPO may serve as a potential therapy for the treatment of septic encephalopathy.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Brain Diseases; Cecum; Cell Survival; Cognition Disorders; Disease Models, Animal; Endotoxemia; Erythropoietin; Humans; Janus Kinase 2; Learning Disabilities; Ligation; Lipopolysaccharides; Male; Memory Disorders; Neurons; Rats; Rats, Sprague-Dawley; Recombinant Proteins; STAT3 Transcription Factor

Translocated endotoxin derived from intestinal bacteria is a driver of systemic inflammation and oxidative stress. Severe endotoxaemia is an underappreciated, but characteristic finding in haemodialysis (HD) patients, and appears to be driven by acute repetitive dialysis induced circulatory stress. Resistance to erythropoietin (EPO) has been identified as a predictor of mortality risk, and associated with inflammation and malnutrition. This study aims to explore the potential link between previously unrecognised endotoxaemia and EPO Resistance Index (ERI) in HD patients.. 50 established HD patients were studied at a routine dialysis session. Data collection included weight, BMI, ultrafiltration volume, weekly EPO dose, and blood sampling pre and post HD. ERI was calculated as ratio of total weekly EPO dose to body weight (U/kg) to haemoglobin level (g/dL). Mean haemoglobin (Hb) was 11.3±1.3 g/dL with a median EPO dose of 10,000 [IQR 7,500-20,000] u/wk and ERI of 13.7 [IQR 6.9-23.3] ((U/Kg)/(g/dL)). Mean pre-HD serum ET levels were significantly elevated at 0.69±0.30 EU/ml. Natural logarithm (Ln) of ERI correlated to predialysis ET levels (r = 0.324, p = 0.03) with a trend towards association with hsCRP (r = 0.280, p = 0.07). Ln ERI correlated with ultrafiltration volume, a driver of circulatory stress (r = 0.295, p = 0.046), previously identified to be associated with increased intradialytic endotoxin translocation. Both serum ET and ultrafiltration volume corrected for body weight were independently associated with Ln ERI in multivariable analysis.. This study suggests that endotoxaemia is a significant factor in setting levels of EPO requirement. It raises the possibility that elevated EPO doses may in part merely be identifying patients subjected to significant circulatory stress and suffering the myriad of negative biological consequences arising from sustained systemic exposure to endotoxin.

Topics: Demography; Endotoxemia; Erythropoietin; Female; Humans; Male; Middle Aged; Models, Biological; Multivariate Analysis; Renal Dialysis; Risk Factors

Sepsis-induced lymphocyte apoptosis plays an important role in the development of immune suppression in septic patients. Erythropoietin (EPO) is a multifunctional cytokine with antiapoptotic properties. We hypothesized that EPO could mitigate mononuclear cell (MNC) apoptosis and modify the dynamic changes of MNCs during endotoxemia. Twenty-six pigs were randomized into three groups: (i) lipopolysaccharides (LPS), (ii) EPO (epoetin-α, 5000 IU/kg) administered 60 min prior to LPS, and (iii) sham. At 120 min of endotoxemia, the animals were fluid resuscitated and the LPS infusion was reduced. MNCs were isolated at 0, 60, 240, and 540 min of endotoxemia, and apoptosis was assessed by flow cytometry. Apoptosis in splenic biopsies was quantified by immunohistochemistry. Endotoxemia increased the number of apoptotic MNCs in the blood (p ≤ 0.01) and the spleen (p = 0.03), and EPO did not modify this increase. The number of T-helper and cytotoxic T cells declined during endotoxemia. The dynamic changes of the MNC subsets were not modified by treatment with EPO. In conclusion, EPO did not modify the LPS-induced changes of MNC subsets or mitigate the levels of apoptosis of MNCs in the blood or in the spleen. This study does not support that EPO confers protection against lymphocyte apoptosis.

Topics: Animals; Apoptosis; Caspase 3; Endotoxemia; Erythropoietin; Female; Leukocyte Count; Lymphocytes; Recombinant Proteins; Swine

Erythropoietin (EPO) is a multifunctional cytokine with anti-apoptotic, anti-inflammatory, and organ protective effects. EPO protects against ischemia-reperfusion injuries, and recent reports suggest that EPO also prevents organ dysfunction in experimental sepsis. The aims of this study were to determine whether EPO prevents endotoxemia-induced organ dysfunction in a porcine model and to characterize the immunomodulatory and anti-apoptotic effects of EPO.. Twenty-eight pigs were randomly assigned to three groups: (1) endotoxemia treated with EPO 5000 IU/kg, (2) endotoxemia treated with placebo, and (3) a sham group anesthetized and submitted to sham operation without treatment. A laparotomy was performed, and a flow probe was placed around the left renal artery, which allowed renal blood flow (RBF) measurements. Endotoxemia was induced by an infusion of lipopolysaccharide. After 2 h, the infusion was reduced to a maintenance dose and the animals were fluid resuscitated. The glomerular filtration rate (GFR), RBF, renal oxygen consumption, and plasma cytokines [interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha] were analyzed. Renal biopsies were analyzed for cytokine content and apoptosis.. Endotoxemia elicited impaired renal function, estimated as GFR, and increased the levels of renal apoptotic cells, with no modifying effect of EPO. Furthermore, EPO had no effect on RBF, renal oxygen consumption, or the systemic hemodynamic response to endotoxemia. EPO did not modify the inflammatory response, measured as changes in cytokine levels in plasma and organs.. EPO did not confer renal protection in this fluid-resuscitated porcine model of endotoxemia, and EPO did not modify the inflammatory response.

Topics: Animals; Apoptosis; Caspase 3; Cytokines; Endotoxemia; Erythropoietin; Female; Glomerular Filtration Rate; Hemodynamics; Immunohistochemistry; Inflammation; Kidney; Kidney Diseases; Kidney Function Tests; Lipopolysaccharides; Oxygen Consumption; Recombinant Proteins; Renal Circulation; Resuscitation; Swine; Tumor Necrosis Factor-alpha

Erythropoietin elicits protective effects in lung tissue injury induced by ischaemic reperfusion and hyperoxia. We investigated the protective roles of erythropoietin in pulmonary inflammation and lung injury during acute endotoxaemia.. A total of 32 male Sprague-Dawley rats were randomly assigned to four groups: saline group, erythropoietin + saline group, saline + lipopolysaccharide group and erythropoietin + lipopolysaccharide group. Rats were treated with erythropoietin (3000 U/kg, i.p.) or saline, 30 minutes prior to lipopolysaccharide administration (6 mg/kg, i.v.). Four hours after lipopolysaccharide injection, samples of pulmonary tissue were collected. Optical microscopy was performed to examine pathological changes in lungs. Wet/dry (W/D) ratios, myeloperoxidase activity, malondialdehyde concentrations and tumour necrosis factor-alpha (TNF-alpha) as well as interleukin 1 beta (IL-1beta) levels in lungs were measured. The pulmonary expression of nuclear factor kappaB (NF-kappaB) p65 was evaluated by Western blotting. Differences between the different groups were analysed by one-way analysis of variance (ANOVA).. The lung tissues from the saline + lipopolysaccharide group were significantly damaged, which were less pronounced in the erythropoietin + lipopolysaccharide group. The W/D ratio increased significantly in the saline + lipopolysaccharide group (5.75 +/- 0.22) as compared with the saline group (3.85 +/- 0.20) (P < 0.01), which was significantly reduced in the erythropoietin + lipopolysaccharide group (4.50 +/- 0.35) (P < 0.01). Myeloperoxidase activity and malondialdehyde levels increased significantly in the saline + lipopolysaccharide group compared with the saline group, which was reduced in the erythropoietin + lipopolysaccharide group. The TNF-alpha level of pulmonary tissue increased significantly in the saline + lipopolysaccharide group ((9.80 +/- 0.82) pg/mg protein) compared with the saline group ((4.20 +/- 0.42) pg/mg protein, P < 0.01). However, the increase of TNF-alpha level of pulmonary tissue was significantly reduced in the erythropoietin + lipopolysaccharide group ((6.50 +/- 0.66) pg/mg protein, P < 0.01). Similarly, pulmonary IL-1beta levels were elevated markedly in the saline + lipopolysaccharide group in contrast to the saline group, whereas the elevation was much less in the erythropoietin + lipopolysaccharide group. The nuclear localization of p65 increased markedly in the saline + lipopolysaccharide group and this enhancement of nuclear p65 expression was much less in the erythropoietin + lipopolysaccharide group.. Erythropoietin attenuates pulmonary inflammation and suppresses TNF-alpha and IL-1beta overproduction during acute endotoxaemia, which is partially mediated by inhibition of NF-kappaB.

Topics: Animals; Anti-Inflammatory Agents; Blotting, Western; Endotoxemia; Erythropoietin; Interleukin-1beta; Lung; Lung Injury; Male; Malondialdehyde; NF-kappa B; Organ Size; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Sepsis has a high mortality (50-80%) when associated with acute renal failure (ARF). Oxidant injury and proinflammatory cytokines and chemokines have been shown to increase with endotoxaemia-related ARF. Since erythropoietin (EPO) has been demonstrated to possess anti-oxidant and anti-inflammatory properties, EPO may have therapeutic efficacy for treating ARF associated with endotoxaemia.. Wild-type mice were given 2.5 mg/kg of intraperitoneal (i.p.) endotoxin, lipopolysaccharide (LPS), and studied 16 h later. Thirty minutes prior to LPS, the mice were given either EPO or vehicle.. During endotoxaemia, EPO was found to significantly attenuate the renal dysfunction, as assessed by glomerular filtration rate (48.1 +/- 12.4 microl/min vs 136.7 +/- 30.2, P < 0.05). Renal blood flow and mean arterial pressure were not significantly different between the two groups. The renal dysfunction during endotoxaemia was associated with a decrease in renal superoxide dismutase (SOD). The EPO-related renal protection was associated with reversal of the effects of endotoxin on renal SOD.. This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction.

Topics: Animals; Cytokines; Endotoxemia; Erythropoietin; Glomerular Filtration Rate; Inflammation; Kidney; Kidney Diseases; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Sepsis; Tumor Necrosis Factor-alpha

Erythropoietin protects many organs against the tissue injury and dysfunction caused by ischaemia/reperfusion and excessive inflammation. This editorial comment discusses the effects of erythropoietin in preclinical models of septic shock, endotoxemia, hemorrhagic shock, spinal cord trauma and zymosan-induced multiple organ failure.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Endotoxemia; Erythropoietin; Mice; Multiple Organ Failure; Shock; Shock, Hemorrhagic; Shock, Septic; Spinal Cord Injuries; Treatment Outcome; Zymosan