scholarly journals TREATMENT OF ABDOMINAL SEPSIS WITH LEVAMISOLE AND PERITONEAL LAVAGE IN RATS

2020 ◽  
Vol 11 (2) ◽  
pp. 73-80
Author(s):  
Gabriela Vieira da Silva ◽  
Aldo Medeiros de Cunha ◽  
Ítalo Medeiros de Azevedo ◽  
Lívia Medeiros Soares Celani ◽  
Filipe Fernandes Santos de Oliveira
Keyword(s):  
Peritoneal Lavage ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Clinical Score ◽  
Abdominal Sepsis ◽  
Control Group ◽  
Treatment Needs ◽  
Lower Growth ◽  
Cecal Ligation Puncture ◽  
Difficult Situations

Introduction: Intra-abdominal sepsis is one of the most difficult situations in surgery and usually presents as a peritonitis. It is a systemic inflammatory response to infection that is often associated with hypoperfusion followed by tissue injury and organ failure. Given that its the sequelae reflect the increasing severity of the systemic response to infection, a correct and early treatment needs to be established. In this sense, the study analyzes the effect of peritoneal lavage and the use of the isomers immunomodulator in the treatment of abdominal sepsis in rats. Methods: The animals were randomly assigned to three groups A (control), B (peritoneal lavage), C (levamisole). All groups underwent laparotomy, anesthesia and cecal ligation/puncture. A ten-parameter clinical score was analyzed, which allowed the classification of sepsis degree, peritoneal fluid cultures, and cytokine dosage. Results: Group C had better scores on the clinical score and also lower growth of bacterial colonies in cultures. A lower dosage of TNF-alpha, IL-Ib, IL-6 and PCR in group C was observed, compared to groups A and B. Conclusion: Levamisole positively influenced the treatment in the parameters analyzed compared to the peritoneal lavage group and the control group.

Proinflammatory role of neutrophil extracellular traps in abdominal sepsis

2014 ◽  
Vol 307 (7) ◽  
pp. L586-L596 ◽  
Author(s):  
Lingtao Luo ◽  
Su Zhang ◽  
Yongzhi Wang ◽  
Milladur Rahman ◽  
Ingvar Syk ◽  
...  
Keyword(s):  
Lung Injury ◽  
Peritoneal Cavity ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Neutrophil Extracellular Traps ◽  
Abdominal Sepsis ◽  
Extracellular Dna ◽  
Extracellular Traps ◽  
Proinflammatory Role

Excessive neutrophil activation is a major component in septic lung injury. Neutrophil-derived DNA may form extracellular traps in response to bacterial invasions. The aim of the present study was to investigate the potential role of neutrophil extracellular traps (NETs) in septic lung injury. Male C57BL/6 mice were treated with recombinant human (rh)DNAse (5 mg/kg) after cecal ligation and puncture (CLP). Extracellular DNA was stained by Sytox green, and NET formation was quantified by confocal microscopy and cell-free DNA in plasma, peritoneal cavity, and lung. Blood, peritoneal fluid, and lung tissue were harvested for analysis of neutrophil infiltration, NET levels, tissue injury, as well as CXC chemokine and cytokine formation. We observed that CLP caused increased formation of NETs in plasma, peritoneal cavity, and lung. Administration of rhDNAse not only eliminated NET formation in plasma, peritoneal cavity, and bronchoalveolar space but also reduced lung edema and tissue damage 24 h after CLP induction. Moreover, treatment with rhDNAse decreased CLP-induced formation of CXC chemokines, IL-6, and high-mobility group box 1 (HMGB1) in plasma, as well as CXC chemokines and IL-6 in the lung. In vitro, we found that neutrophil-derived NETs had the capacity to stimulate secretion of CXCL2, TNF-α, and HMGB1 from alveolar macrophages. Taken together, our findings show that NETs regulate pulmonary infiltration of neutrophils and tissue injury via formation of proinflammatory compounds in abdominal sepsis. Thus we conclude that NETs exert a proinflammatory role in septic lung injury.

scholarly journals Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

2020 ◽  
Author(s):  
Marcela Garzón-Tituaña ◽  
José L Sierra-Monzón ◽  
Laura Comas ◽  
Llipsy Santiago ◽  
Tatiana Khaliulina-Ushakova ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Peritoneal Lavage ◽  
Therapeutic Potential ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
Lavage Fluid ◽  
Abdominal Sepsis ◽  
Granzyme A ◽  
Severe Pathology ◽  
Deficient Mice

ABSTRACTSepsis is a serious syndrome characterised by a dysregulated systemic inflammatory response. Here we have analysed the role and the therapeutic potential of Granzyme A (GzmA) in the pathogenesis of peritoneal sepsis using the Cecal Ligation and Puncture (CLP) polymicrobial sepsis model and samples from humans undergoing abdominal sepsis.Elevated GzmA was observed in serum from patients with abdominal sepsis suggesting that GzmA plays an important role in this pathology. In the CLP model GzmA deficient mice, or WT mice treated with an extracellular GzmA inhibitor, showed increased survival, which correlated with a reduction in proinflammatory markers in both serum and peritoneal lavage fluid. GzmA deficiency did not influence bacterial load in blood and spleen indicating that GzmA has no role in bacterial control. Mechanistically, we found that extracellular active GzmA acts as a proinflammatory mediator in macrophages by inducing the TLR4-dependent expression of IL-6 and TNFα.Our findings implicate GzmA as a key regulator of the inflammatory response during abdominal sepsis, and suggest that it could be targeted for treatment of this severe pathology.

scholarly journals Effects of bromopride on the healing of left colonic anastomoses in rats with induced abdominal sepsis

2012 ◽  
Vol 27 (6) ◽  
pp. 370-375 ◽  
Author(s):  
Silvana Marques e Silva ◽  
Fabiana Pirani Carneiro ◽  
Paulo Gonçalves de Oliveira ◽  
Pedro Henrique Alves de Morais ◽  
Naiara Galvão da Silva ◽  
...  
Keyword(s):  
Tensile Strength ◽  
Adhesion Formation ◽  
Cecal Ligation ◽  
Abdominal Sepsis ◽  
Colon Resection ◽  
Saline Control ◽  
Control Group ◽  
Histopathological Analysis ◽  
Colonic Anastomoses ◽  
Hydroxyproline Concentration

PURPOSE: To evaluate the effects of bromopride on the healing of left colonic anastomoses in rats with induced abdominal sepsis. METHODS: Forty rats were divided into two groups to receive either bromopride (experimental group- E) or saline (control group- C). Each group was divided into subgroups of ten animals each to be euthanized on third (E3 and C3) or seventh day (E7 and C7) after surgery. Sepsis was induced by cecal ligation and puncture. The rats underwent segmental left colon resection and end-to-end anastomosis. Adhesion formation, tensile strength and hydroxyproline concentration were assessed. Histomorphometry of collagen and histopathological analysis were also performed. RESULTS: On postoperative third day, anastomoses in bromopride-treated animals showed lower tensile strength (p=0.02) and greater reduction in hydroxyproline concentration (p=0.04) than in control animals. There was no statistical difference in these parameters on seventh day, and the remaining parameters were similar across subgroups. Collagen content was also similar across subgroups. CONCLUSION: In the presence of abdominal sepsis, the administration of bromopride was associated with decreased tensile strength and hydroxyproline concentration in left colonic anastomoses in rats three days after surgery.

scholarly journals Effect of granulocyte-macrophage colony-stimulating factor on sepsis- induced organ injury in rats

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2893-2898 ◽  
Author(s):  
H Toda ◽  
A Murata ◽  
Y Oka ◽  
K Uda ◽  
N Tanaka ◽  
...  
Keyword(s):  
Survival Rate ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Organ Injury ◽  
Control Group ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) to patients with severe active infections has been questioned because activation of neutrophils may cause tissue injury. To identify the effect of GM-CSF administration on severe sepsis, we examined the survival rate and pathologic changes in vital organs using the rat lethal sepsis model. Rats received 20 micrograms of recombinant murine GM-CSF (rmGM-CSF) 3 hours after the onset of peritonitis induced by cecal ligation and puncture. After 48 hours, the survival rate did not improve, and earlier deaths than in the control group were observed. In addition, the inhibition of early leuko-sequestration in the peritoneal cavity was seen in animals treated with GM-CSF. These results suggested that the administration of rmGM-CSF after the onset of sepsis was not beneficial; thus, we concluded that care should be taken in the clinical use of GM-CSF in severe infection.

scholarly journals The Effects of Montelukast on Antioxidant Enzymes and Proinflammatory Cytokines on the Heart, Liver, Lungs, and Kidneys in a Rat Model of Cecal Ligation and Puncture–Induced Sepsis

2011 ◽  
Vol 11 ◽  
pp. 1341-1356 ◽  
Author(s):  
Ali Kagan Coskun ◽  
Murat Yigiter ◽  
Akgun Oral ◽  
Fehmi Odabasoglu ◽  
Zekai Halici ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Cecal Ligation ◽  
Lipid Peroxide ◽  
Multiple Organ ◽  
Control Group ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Cecal Ligation And Puncture ◽  
Necrosis Factor Alpha ◽  
Liver And Kidney

We investigated the potential protective effects of montelukast (MLK) on cecal ligation and puncture (CLP)–induced tissue injury in vital organs — liver, heart, kidneys, and especially lungs — through inhibition of the proinflammatory cytokine response and the generation of reactive oxygen species (ROS) in rats. The rat groups were (1) a 10-mg/kg MLK-treated CLP group; (2) a 20-mg/kg MLK-treated CLP group; (3) a 20-mg/kg MLK-treated, sham-operated group; (4) a CLP control group; and (5) a sham-operated control group. MLK treatment significantly decreased proinflammatory (tumor necrosis factor-alpha, interleukin-6) cytokine levels following CLP. The lipid peroxide level increased in the lung, heart, liver, and kidney tissues after CLP-induced sepsis, and myeloperoxidase activity increased in the lung, heart, and liver tissues. MLK attenuated this elevation in all tissues except the kidney, dose dependently. The glutathione levels and superoxide dismutase activity were significantly increased in the lung, liver, and kidney tissues after MLK treatment. MLK treatment after CLP also potentially reduced mortality. The lung and kidney tissues were the most protected by MLK under sepsis conditions. We can suggest that MLK reverses the systemic inflammatory reaction to polymicrobial sepsis and thereby reduces multiple organ failure.

Attenuation of lung injury using simvastatin in a rat sepsis model

2012 ◽  
Vol 3 (1) ◽  
pp. 1
Author(s):  
Vítor Brasil Medeiros ◽  
Ítalo Medeiros de Azevedo ◽  
Amália Cínthia Meneses Rego ◽  
Irami Araújo-Filho ◽  
Marília Daniela Ferreira Carvalho ◽  
...  
Keyword(s):  
Lung Injury ◽  
Plasma Levels ◽  
Tissue Injury ◽  
Interleukin 1 ◽  
Cecal Ligation ◽  
Abdominal Sepsis ◽  
Saline Group ◽  
Male Wistar Rats ◽  
Group 2 ◽  
Group 1

Purpose: Considering that statins have pleiotrophic effects, we hypothesized that vimvastatin therapy could help in the setting of sepsis and lung injury. The aim of this study was to address the effect of simvastatin pretreatment on lung injury in rats with abdominal sepsis. Methods: Thirty male Wistar rats weighing 235±26g were used and distributed into the three groups: group 1, n=10 (sham), treated with oral injection of saline (10mL/Kg) 24 hs before and again immediately before surgery; group 2, n=10 (abdominal sepsis+saline), cecal ligation and puncture (CLP) and treatment with saline as group 1; group 3, n=10 (abdominal sepsis+simvastatin), CLP and treatment with oral injection (gavage) of 10mg/Kg of simvastatin suspension (10mg/ml) 24 hs before and again immediately before surgery. Commercial ELISA kits were used for measurement of tumor necrosis factor-alfa (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Lung tissue from all animals was studied with light microscopy to determine the distribution and amount of lung injury. Results: TNF-α plasma expression was significantly lower in rats treated with simvastatin (172.8±25 pg/mL) than in rats treated with 0.9% saline (298.5±63 pg/ml). IL-1 plasma levels showed a drastic decrease (53.3±7 pg/mL) in simvastatin treated rats, compared with the sepsis/saline group rats (127.6±28 pg/mL). The plasma levels of IL-6 in the sepsis/simvastatin treated rats (53.3±7 pg/mL) were lower than in sepsis/saline treated rats (134.6±15mL). In control rats the plasma cytokines were significantly less expressive (28.4±6) than in the other groups. Representative lung histology demonstrated marked inflammation characterized by abundant interstitial neutrophils and edema in group sepsis/saline. Induced inflammation was greatly reduced by simvastatin pretreatment. Conclusion: In conclusion, our data suggest that simvastatin protects the lung against tissue injury in abdominal sepsis via inhibition of cytokines expression.

scholarly journals Mitochondria-Targeted Antioxidants SkQ1 and MitoTEMPO Failed to Exert a Long-Term Beneficial Effect in Murine Polymicrobial Sepsis

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Pia Rademann ◽  
Adelheid Weidinger ◽  
Susanne Drechsler ◽  
Andras Meszaros ◽  
Johannes Zipperle ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Peritoneal Lavage ◽  
Cecal Ligation ◽  
Abdominal Sepsis ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Risk Of Death ◽  
Long Term Effect ◽  
Body Compartments

Mitochondrial-derived reactive oxygen species have been deemed an important contributor in sepsis pathogenesis. We investigated whether two mitochondria-targeted antioxidants (mtAOX; SkQ1 and MitoTEMPO) improved long-term outcome, lessened inflammation, and improved organ homeostasis in polymicrobial murine sepsis. 3-month-old female CD-1 mice (n=90) underwent cecal ligation and puncture (CLP) and received SkQ1 (5 nmol/kg), MitoTEMPO (50 nmol/kg), or vehicle 5 times post-CLP. Separately, 52 SkQ1-treated CLP mice were sacrificed at 24 h and 48 h for additional endpoints. Neither MitoTEMPO nor SkQ1 exerted any protracted survival benefit. Conversely, SkQ1 exacerbated 28-day mortality by 29%. CLP induced release of 10 circulating cytokines, increased urea, ALT, and LDH, and decreased glucose but irrespectively of treatment. Similar occurred for CLP-induced lymphopenia/neutrophilia and the NO blood release. At 48 h post-CLP, dying mice had approximately 100-fold more CFUs in the spleen than survivors, but this was not SkQ1 related. At 48 h, macrophage and granulocyte counts increased in the peritoneal lavage but irrespectively of SkQ1. Similarly, hepatic mitophagy was not altered by SkQ1 at 24 h. The absence of survival benefit of mtAOX may be due to the extended treatment and/or a relatively moderate-risk-of-death CLP cohort. Long-term effect of mtAOX in abdominal sepsis appears different to sepsis/inflammation models arising from other body compartments.

scholarly journals Neuropeptide W Attenuates Oxidative Multi-Organ Injury in Rats Induced with Intra-Abdominal Sepsis

2021 ◽  
Author(s):  
Ali Emre Atici ◽  
Sevil Arabacı Tamer ◽  
Hilal Nisva Levent ◽  
İrem Peker Eyuboglu ◽  
Feriha Ercan ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Cecal Ligation ◽  
Serum Levels ◽  
Abdominal Sepsis ◽  
Organ Injury ◽  
Control Group ◽  
Sprague Dawley ◽  
Reactive Protein ◽  
Liver And Kidney ◽  
The Brain

Abstract Sepsis leads to systemic hypotension, disturbed perfusion, inflammation and tissue toxicity in vital organs. Neuropeptide W (NPW) has modulatory effects in the control of blood pressure and inflammatory processes, implicating a potential beneficial effect against sepsis-induced oxidative damage. Under anesthesia, male Sprague Dawley rats underwent cecal ligation and puncture. Immediately after surgery, either saline or TNF-alpha inhibitor (etanercept; 1 mg/kg) antibiotic (ceftriaxon; 100 mg/kg) combination or NPW (0.1, 1 or 3 µg/kg) was given subcutaneously, and injections were repeated at 12th and 24th h. The sham-operated control group was treated with saline at the same time points. All rats were euthanized at the 25th h of surgery. Sepsis resulted in oxidative damage of the brain, heart, lung, liver and kidney. Elevations in blood urea nitrogen and alkaline phosphatase, showing renal and hepatic dysfunction, were not evident when septic rats were treated with NPW. NPW reduced serum levels of C-reactive protein, corticosterone and interleukin-6, while histopathologically verified tissue damage in all the studied tissues was ameliorated. NPW treatment suppressed lipid peroxidation in the heart, lung and brain, and the depleted antioxidant GSH levels of the brain and heart were replenished by NPW. Moreover, sepsis-related neutrophil recruitment to liver and lung was also suppressed by NPW. Although survival rate of the rats was not significantly prolonged by NPW, most of these improvements in systemic and local inflammatory events were comparable with those reached by the etanercept and antibiotic combination, suggesting the therapeutic impact of NPW during the acute period of sepsis.

scholarly journals SAT0018 THE THERAPEUTIC EFFECT OF STIMULATION OF THE SPLENIC NEUROVASCULAR BUNDLE IN MICE WITH COLLAGEN-INDUCED ARTHRITIS IS ENHANCED BY CONCOMITANT ANTI-TNF TREATMENT

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 939.2-939
Author(s):  
T. Simon ◽  
C. Panzolini ◽  
J. Lavergne ◽  
N. Hypolite ◽  
N. Glaichenhaus ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Clinical Symptoms ◽  
Pulse Amplitude ◽  
Clinical Score ◽  
Control Group ◽  
Research Support ◽  
Collagen Induced Arthritis ◽  
Etanercept Treatment ◽  
Clinical Scores ◽  
Research Grant

Background:Vagus nerve (VN) stimulation has shown the potential to improve the disease development in animal models of arthritis and in patients with RA. However, the VN can affect respiratory, cardiovascular, endocrine and gastro-intestinal physiology. The splenic nerve (SpN) has been confirmed to be the principal effector nerve for the VN-mediated immune control. Previous studies have shown that stimulating the splenic nerve resulted in an increase of norephiniphrine in the spleen, as well as a significant reduction in LPS-induced TNF (1).Objectives:To test the therapeutic efficiency of splenic nerve stimulation (SNS) in collagen-induced arthritis (CIA) in mice alone or in combination with anti-TNF treatment.Methods:CIA was induced in DBA1/J mice by immunization with bovine type II collagen at days 0 and 21. At day 11, mice were implanted with micro-cuff electrode (CorTec) onto the SpN or VN. From day 16 to day 45, SNS were applied as rectangular charged-balanced biphasic pulses with 650 μA pulse amplitude, 200 µs pulse width at 10 Hz frequency for 2 min 1 or 6 times a day using a Plexon stimulator. In order to investigatedthe mechanism of action in more detail, propranolol, a beta-adrenergic receptor (β-AR) antagonist, was added to the drinking water of mice receiving SNS. In addition, a control group was treated with anti-TNF (etanercept, 3 times/week; 10mg/kg i.p.). In curative settings, SNS and/or anti-TNF treatment was applied starting when mice scored positive for 3 consecutive days. Clinical arthritis was determined by visual examination of swelling and redness of the paws and measurement of paw thickness. Sham mice were undergoing the same procedure but did not receive stimulation.Results:In CIA in mice all sham animals developed arthritis, compared to only 14% following six times per day SNS (p <0.001) in a prophylactic setting. In contrast, 85% of the animals developed arthritis (p = 0.35) when SNS was applied only once a day. In both stimulated groups a significant decrease in clinical scores and paw thickness was observed compared to unstimulated group (p < 0.01 and p < 0.05, respectively). While etanercept treatment reduced clinical scores (p <0.001) an immediate rebound in clinical score was seen following treatment arrest, while mice with SNS were still partially protected 35 days after treatment discontinuation (p = 0.013, compared to sham). Propranolol inverted the effect of SNS in CIA mice. Finally, when SNS was applied as a curative treatment, clinical scores were significantly reduced (p < 0.001). Importantly, these clinical scores even further decreased when anti-TNF treatment was given to mice receiving SNS.Conclusion:These studies demonstrate that SNS suppresses pro-inflammatory cytokine production, and reduces clinical symptoms in mice with CIA which is at least partially mediated by the β-AR. The additive effect of anti-TNF in reducing the clinical scores demonstrates that that mechanism of action of SNS is not primarilys mediated by reducing TNF levels. Moreover, anti-TNF potentiating the inhibitory effect of SNS is supporting a combined use of these treatments, or even a combination of SNS with other biologicals, to treat RA, potentially getting more patients closer to remission. In conclusion, the data is providing compelling scientific rationale and pre-clinical evidence that splenic neuromodulation might be a new treatment modality for RA.References:[1] Guyot M et al, Brain Behav Immun. 2019;80:238.Disclosure of Interests:Thomas Simon Grant/research support from: research grant from Galvani Bioelectronics, Clara Panzolini Grant/research support from: Working on research grant Galvani bioelectronics, Julien Lavergne Grant/research support from: working on research grant Galvani Bioelectrocnics, Nicolas Hypolite Grant/research support from: Working on research grant Galvani Bioelectronics, Nicolas Glaichenhaus: None declared, Margriet Vervoordeldonk Employee of: I am an employee of Galvani Bioelectronics, Philippe Blancou Grant/research support from: Received research grant from Galvani Bioelectronics

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