scholarly journals Inhibition of iNOS protects against the deleterious effects of sub-lethal sepsis and ethanol in the cardiorenal system

2021 ◽  
Author(s):  
Arthur H. Sousa ◽  
Gabriel T. Do Vale ◽  
Jose A Nascimento ◽  
Wanessa Mayumi Carvalho Awata ◽  
Carla Brigagão Pacheco da Silva ◽  
...  
Keyword(s):  
Biochemical Analysis ◽  
Molecular Mechanisms ◽  
Renal Cortex ◽  
Cecal Ligation ◽  
Selective Inhibitor ◽  
Oxygen Species ◽  
Cecal Ligation And Puncture ◽  
Post Surgery ◽  
Lethal Sepsis ◽  
Pro Inflammatory Cytokines

We tested the hypothesis that ethanol would aggravate the deleterious effects of sub-lethal cecal ligation and puncture (SL-CLP) sepsis in the cardiorenal system and that inhibition of iNOS would prevent such response. Male C57BL/6 mice were treated with ethanol for 12 weeks. One hour before SL-CLP surgery, mice were treated with N6-(1-Iminoethyl)-lysine (L-NIL, 5 mg/kg, i.p), a selective inhibitor of iNOS. A second dose of L-NIL was administered 24 h after SL-CLP surgery. Mice were killed 48 h post-surgery and blood, the renal cortex and left ventricle (LV) were collected for biochemical analysis. L-NIL attenuated the increase in serum creatinine levels induced by ethanol, but not by SL-CLP. Ethanol, but not SL-CLP increased creatine kinase (CK)-MB activity and L-NIL did not prevent this response. In the renal cortex, L-NIL prevented the redox imbalance induced by ethanol and SL-CLP. Inhibition of iNOS also decreased lipoperoxidation induced by ethanol and SL-CLP in the LV. L-NIL prevented the increase of pro-inflammatory cytokines and reactive oxygen species (ROS) induced by ethanol and/or SL-CLP in the cardiorenal system, suggesting that iNOS modulated some of the molecular mechanisms that underlie the deleterious effects of both conditions in the cardiorenal system.

Intrahepatic STAT-3 activation and acute phase gene expression predict outcome after CLP sepsis in the rat

1998 ◽  
Vol 275 (6) ◽  
pp. G1423-G1429 ◽  
Author(s):  
Kenneth M. Andrejko ◽  
Jodi Chen ◽  
Clifford S. Deutschman
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Signal Transducer ◽  
Lethal Sepsis

Interleukin-6 (IL-6) regulates hepatic acute phase responses by activating the transcription factor signal transducer and activator of transcription (STAT)-3. IL-6 also may modulate septic pathophysiology. We hypothesize that 1) STAT-3 activation and transcription of α2-macroglobulin (A2M) correlate with recovery from sepsis and 2) STAT-3 activation and A2M transcription reflect intrahepatic and not serum IL-6. Nonlethal sepsis was induced in rats by single puncture cecal ligation and puncture (CLP) and lethal sepsis via double-puncture CLP. STAT-3 activation and A2M transcription were detected at 3–72 h and intrahepatic IL-6 at 24–72 h following single-puncture CLP. All were detected only at 3–16 h following double-puncture CLP and at lower levels than following single-puncture CLP. Loss of serum and intrahepatic IL-6 activity after double-puncture CLP correlated with mortality. Neither intrahepatic nor serum IL-6 levels correlated with intrahepatic IL-6 activity. STAT-3 activation following single-puncture CLP inversely correlated with altered transcription of gluconeogenic, ketogenic, and ureagenic genes. IL-6 may have both beneficial and detrimental effects in sepsis. Fulminant sepsis may decrease the ability of hepatocytes to respond to IL-6.

scholarly journals Parenteral Succinate Reduces Systemic ROS Production in Septic Rats, but It Does Not Reduce Creatinine Levels

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Sebastián P. Chapela ◽  
Isabel Burgos ◽  
Christian Congost ◽  
Romina Canzonieri ◽  
Alexis Muryan ◽  
...  
Keyword(s):  
Complex I ◽  
Electron Transport Chain ◽  
Cecal Ligation ◽  
Multiple Organ ◽  
Sepsis Group ◽  
Control Group ◽  
Ros Production ◽  
Oxygen Species ◽  
Cecal Ligation And Puncture ◽  
Transport Chain

In sepsis, reactive oxygen species (ROS) production is increased. This process takes place mainly within the electron transport chain. ROS production is part of the pathophysiology of multiple organ failure in sepsis. Succinate yields Dihydroflavine-Adenine Dinucleotide (FADH2), which enters the chain through complex II, avoiding complex I, through which electrons are lost. The aim of this work is to determine if parenteral succinate reduces systemic ROS production and improves kidney function. Rats with cecal ligation and puncture were used as model of sepsis, and 4 groups were made: Control group; Succinate group, which only received parenteral succinate; Sepsis group; and Sepsis which received parenteral succinate. Systemic ROS are measured 24 hours after the procedure. Rats subjected to cecal puncture treated with succinate had less systemic ROS than Septic untreated rats (p=0.007), while there were no differences in creatinine levels (p=0.07). There was no correlation between creatinine and systemic ROS levels (p=0.3). We concluded that parenteral succinate reduces ROS levels, but it does not reduce creatinine levels. Since there is no correlation between both levels, the processes would not be related.

scholarly journals Inhibition of Leukocyte Rolling by Nitric Oxide during Sepsis Leads to Reduced Migration of Active Microbicidal Neutrophils

2002 ◽  
Vol 70 (7) ◽  
pp. 3602-3610 ◽  
Author(s):  
Claudia Farias Benjamim ◽  
João Santana Silva ◽  
Zuleica Bruno Fortes ◽  
Maria Aparecida Oliveira ◽  
Sérgio Henrique Ferreira ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Mortality ◽  
Neutrophil Migration ◽  
Cecal Ligation ◽  
No Synthase ◽  
Leukocyte Rolling ◽  
Cecal Ligation And Puncture ◽  
Infection Site ◽  
Microbicidal Activity ◽  
Lethal Sepsis

ABSTRACT We developed two models of sepsis with different degrees of severity, sublethal and lethal sepsis, induced by cecal ligation and puncture. Lethal sepsis induced by cecal ligation and puncture (L-CLP) resulted in failure of neutrophil migration to the infection site and high mortality. Treatment of septic animals with aminoguanidine (AG), a nitric oxide (NO) synthase inhibitor, precluded the failure of neutrophil migration and protected the animals from death. However, cytokine-induced NO synthase (iNOS)-deficient (iNOS−/−) mice subjected to L-CLP did not present neutrophil migration failure, but 100% lethality occurred. iNOS−/− mice subjected to sublethal sepsis induced by cecal ligation and puncture (SL-CLP) also suffered high mortality despite the occurrence of neutrophil migration. This apparent paradox could be explained by the lack of microbicidal activity in neutrophils of iNOS−/− mice present at the infection site due to their inability to produce NO. Notably, SL- and L-CLP iNOS−/− mice showed high bacterial numbers in exudates. The inhibition of neutrophil migration by NO is due to inhibition of a neutrophil/endothelium adhesion mechanism, since a reduction in leukocyte rolling, adhesion, and emigration was observed in L-CLP wild-type mice. These responses were prevented by AG treatment and were not observed in the iNOS−/− L-CLP group. There was no significant change in L-selectin expression in neutrophils from L-CLP mice. Thus, it seems that the decrease in leukocyte rolling is due to a defect in the expression of adhesion molecules on endothelial surfaces mediated by iNOS-derived NO. In conclusion, the results indicate that despite the importance of NO in neutrophil microbicidal activity, its generation in severe sepsis reduces neutrophil migration by inhibiting leukocyte rolling and their firm adhesion to the endothelium, in effect impairing the migration of leukocytes and consequently their fundamental role in host cell defense mechanisms.

Glatiramer acetate treatment inhibits inflammatory responses and improves survival in a mice model of cecal ligation and puncture-induced sepsis

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Elahe Maleki ◽  
Mohammad Sheibani ◽  
Sadaf Nezamoleslami ◽  
Ahmad Reza Dehpour ◽  
Nasrin Takzaree ◽  
...  
Keyword(s):  
Survival Rate ◽  
Glatiramer Acetate ◽  
Inflammatory Cytokines ◽  
Cecal Ligation ◽  
Protective Effects ◽  
Cecal Ligation And Puncture ◽  
Mice Model ◽  
Term Survival ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Abstract Objectives Sepsis is a clinical crisis which has been considered as one of the important causes of mortality across the world. We hypothesized that modulation of hyper-inflammatory phase of sepsis pathophysiology can lead to protective effects on survival outcome. Glatiramer acetate (GA) is a neuroprotective drug commonly used in multiple sclerosis (MS). GA is characterized by immunom activity via regulation of innate and adaptive immunity. This study was designed to evaluate the acute treatment with GA on initial inflammatory response-induced mortality in septic mice. Methods Cecal ligation and puncture (CLP) model was operated on male mice as a model of Polymicrobial sepsis. GA was administrated intraperitoneally after the sepsis induction at doses of 0.5, 1, and 2 mg/kg in three treatment groups. To investigate the effect of GA on short-term survival, septic mice were observed during 72 h after CLP. Serum levels of TNF-α, IL-1β, and IL-6 as pro-inflammatory cytokines and also IL-10 as a critical anti-inflammatory cytokine were analysed. To consider sepsis-induced acute kidney injury, renal functional biomarkers and histopathological changes was assessed. Results GA treatment significantly improved survival rate at doses of 1, and 2 mg/kg. Survival improvement was accompanied by remarkable reduction in the pro-inflammatory cytokines and enhanced production of IL-10. GA showed to have protective effects on renal function as well. Conclusions Immunomodulatory and anti-inflammatory properties of GA resulted in increase in survival rate and decrease in inflammatory markers in mice model of cecal ligation and puncture–induced sepsis.

scholarly journals Tripterygium glycoside improves regulatory T cells and attenuates acute organ dysfunction in septic mice

2021 ◽  
Vol 19 ◽  
pp. 205873922110008
Author(s):  
Xiaoming Zhang ◽  
Xiaojie Zhou
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cecal Ligation ◽  
Multiple Organ ◽  
Protective Effects ◽  
Cecal Ligation And Puncture ◽  
Mice Model ◽  
Tnf Α ◽  
Lung And Kidney ◽  
Pro Inflammatory Cytokines

Sepsis is a fatal infectious disease accompanied by multiple organ failure. Immune dysfunction and inflammatory response play an important role in the progression of the disease. Tripterygium glycoside (TG) has immune suppression and anti-inflammatory effects. Here, we investigated the effects of TG on cecal ligation and puncture (CLP)-induced sepsis. Septic mice model was induced by cecal ligation and puncture(CLP), after administration of TG, specimens are collected at designated time points. Histopathology changes of lung tissues and Kidney tissues were observed under light microscope, magnetic microbeads were used to isolate splenic CD4+CD25+ regulatory T cells (Tregs), and phenotypes were then analyzed by flow cytometry. ELISA method was employed to detect the concentrations of plasma TNF-α, IL-6, and IL-10. Nuclear p-NF-κB and Cytoplasmic IkB-a was detected by western blot. TG administration significantly alleviated lung and kidney inflammatory injury and improved the survival of septic mice. Furthermore, the suppressive function of regulatory T cells was enhanced and plasma expression of IL-10 was increased following TG treatment. The NF-B signaling pathway and secretion of plasma TNF-α and IL-6 was notably inhibited in septic mice treated with TG. TG exerts protective effects through improving regulatory T cells and attenuating pro-inflammatory cytokines in septic mice.

Assessment of Sumatriptan on Sepsis-Induced Kidney injury in the Cecal Ligation and Puncture Mice Model

Drug Research ◽  
2021 ◽  
Author(s):  
Hasan Yousefi-Manesh ◽  
Samira Shirooie ◽  
Tayebeh Noori ◽  
Seyed Mohammad Tavangar ◽  
Mohammad Sheibani ◽  
...  
Keyword(s):  
Immune Response ◽  
Mortality Rate ◽  
Inflammatory Cytokines ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Effects ◽  
Cecal Ligation And Puncture ◽  
Term Survival ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

AbstractSepsis is a severe systemic inflammatory response with high mortality rate resulting from different microorganisms. Cytokines activation is essential for the immune response, but in painful conditions like sepsis, cytokines act as a double-edged sword and dysregulate immune response which is life-threatening owing to multiple organ dysfunction. The abnormality in 5-HT function is involved in pathological conditions like irritable bowel syndrome, inflammation, myocardial ischemia, itch and renal injury. Sumatriptan, a 5-HT1B/1D agonist, has anti-inflammatory and anti-oxidative stress effects on animal models. This study was aimed to assess the effects of sumatriptan on kidney injury, the levels of pro-inflammatory cytokines and the percentage of survival in (CLP)-induced sepsis were examined.Cecal ligation and puncture (CLP) model was done on adult C57BL/6 male mice to induce Polymicrobial sepsis. Sumatriptan was injected intraperitoneally 1 h after the sepsis induction by CLP at doses of 0.1, 0.3, and 1 mg/kg in 3 treatment groups. To study the effect of sumatriptan on short-term survival, septic animals were detected 72 h after CLP. Serum levels of TNF-α, IL-1β, IL-6 and IL-10 were evaluated. To study sepsis-induced acute renal failure, kidney functional biomarkers and histopathological alterations were evaluated.Sumatriptan (0.3 mg/kg) administration significantly enhanced survival rate (P<0.01) compared to the CLP group. The beneficial effects of sumatriptan were related to a significant decrease in the pro-inflammatory cytokines and elevated level of IL-10. Sumatriptan presented protective effects on kidney biomarkers and histopathology assay.Anti-inflammatory effects of sumatriptan lead to decrease mortality rate and inflammatory cytokines in CLP induction sepsis in C57BL/6 mice.

scholarly journals Induced sepsis by cecal ligation and puncture in a rat model: hepatic and renal histological features

2019 ◽  
Vol 76 (2) ◽  
pp. 232
Author(s):  
Adrian Florin GAL ◽  
Sidonia BOGDAN ◽  
Flavia RUXANDA ◽  
Vasile RUS
Keyword(s):  
Rat Model ◽  
Cecal Ligation ◽  
Control Group ◽  
Cecal Ligation And Puncture ◽  
Histological Features ◽  
Post Surgery ◽  
Male Wistar Rats ◽  
Group 2 ◽  
Urinary Space ◽  
Glomerular Tuft

Animal models have been developed in an attempt to test potential therapeutic agents. The study aims to determine the hepatic and renal histological features induced by sepsis following cecal ligation and puncture (CLP) in a rat model. Regarding the material, we used 20 adult-male Wistar rats (control group 1, n=10, and group 2, n=10, that underwent CLP protocol). The experimental protocol was approved by the National Sanitary Veterinary and Food Authority, Cluj (Romania), project number 116/11.05.2018. The endpoint of the experiment was pre-set to 10 hours post-surgery. A complete necropsy survey was performed. The main renal lesions detected histologically were: glomerular congestion and edema, hyalinization of glomerular mesangium, presence of hyaline in the urinary space with associated compression atrophy of vascular glomerular tuft, granules of hyaline in the lumen of cortical tubules, and reduction of the urinary space. The hepatic lesion identified histologically was represented by isolated miliary necrotic foci.

Trilobatin Protects Cardiomyocytes from Hypoxia/ Reperfusion Injury by Regulating the Nuclear Factor Erythroid 2-Related Factor 2/Heme Oxygenase-1 Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 133-138
Author(s):  
Wenyu Chen ◽  
Hui He
Keyword(s):  
Heme Oxygenase ◽  
Molecular Mechanisms ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Cellular Injury ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
H9c2 Cells ◽  
Natural Plant ◽  
Induced Changes

Trilobatin is a natural plant-derived glycosylated flavonoid that has been shown to exhibit multiple beneficial pharmacologic activities including protection of heart against H/R-induced cardiomyocyte injury. However, the molecular mechanisms underlying protection from H/R-induced cardiomyocyte injury remain unknown. Using H9C2 cells as a model, we examined the effect of trilobatin on H/R-induced cellular injury, apoptosis, and generation of reactive oxygen species. The results showed that trilobatin protected H9C2 cells not only from cell death and apoptosis, but also counteracted H/R-induced changes in malondialdehyde, superoxide dismutase, glutathione, and glutathione peroxidase. The evaluation of the mechanism underlying the effect of trilobatin on protection from H/R-induced cellular injury suggested changes in the regulation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway.

Juglone Attenuates Sepsis-Induced Acute Lung Injury via Suppression of the TLR4/Nf-κb Pathway

2020 ◽  
Vol 18 (2) ◽  
pp. 201-206
Author(s):  
Qiu Nan ◽  
Xu Xinmei ◽  
He Yingying ◽  
Fan Chengfen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Nuclear Factor Kappa B ◽  
Cecal Ligation ◽  
Myeloperoxidase Activity ◽  
Nuclear Factor ◽  
Cecal Ligation And Puncture ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Nuclear Factor Kappa

Sepsis, with high mortality, induces deleterious organ dysfunction and acute lung injury. Natural compounds show protective effect against sepsis-induced acute lung injury. Juglone, a natural naphthoquinone, demonstrates pharmacological actions as a pro-apoptotic substrate in tumor treatment and anti-inflammation substrate in organ injury. In this study, the influence of juglone on sepsis-induced acute lung injury was investigated. First, a septic mice model was established via cecal ligation and puncture, and then verified via histopathological analysis of lung tissues, the wet/dry mass ratio and myeloperoxidase activity was determined. Cecal ligation and puncture could induce acute lung injury in septic mice, as demonstrated by alveolar damage and increase of wet/dry mass ratio and myeloperoxidase activity. However, intragastric administration juglone attenuated cecal ligation and puncture-induced acute lung injury. Secondly, cecal ligation and puncture-induced increase of inflammatory cells in bronchoalveolar lavage fluid was also alleviated by the administration of juglone. Similarly, the protective effect of juglone against cecal ligation and puncture-induced acute lung injury was accompanied by a reduction of pro-inflammatory factor secretion in bronchoalveolar lavage fluid and lung tissues. Cecal ligation and puncture could activate toll-like receptor 4/nuclear factor-kappa B signaling pathway, and administration of juglone suppressed toll-like receptor 4/nuclear factor-kappa B activation. In conclusion, juglone attenuated cecal ligation and puncture-induced lung damage and inflammatory response through inactivation of toll-like receptor 4/nuclear factor-kappa B, suggesting a potential therapeutic strategy in the treatment of sepsis-induced acute lung injury.

Inactivation of Nf-κb Pathway by Taxifolin Attenuates Sepsis-Induced Acute Lung Injury

2019 ◽  
Vol 18 (2) ◽  
pp. 176-182
Author(s):  
Chen Weiyan ◽  
Deng Wujian ◽  
Chen Songwei
Keyword(s):  
Acute Lung Injury ◽  
B Cells ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Light Chain ◽  
Cecal Ligation ◽  
Nuclear Factor ◽  
Kappa Light Chain ◽  
Cecal Ligation And Puncture ◽  
Light Chain Enhancer

Acute lung injury is a clinical syndrome consisting of a wide range of acute hypoxemic respiratory failure disorders. Sepsis is a serious complication caused by an excessive immune response to pathogen-induced infections, which has become a major predisposing factor for acute lung injury. Taxifolin is a natural flavonoid that shows diverse therapeutic benefits in inflammation- and oxidative stress-related diseases. In this study, we investigated the role of taxifolin in a mouse model of cecal ligation and puncture-induced sepsis. Cecal ligation and puncture-operated mice presented damaged alveolar structures, thickened alveolar walls, edematous septa, and hemorrhage compared to sham-treated controls. Cecal ligation and puncture mice also showed increased wet-to-dry (W/D) lung weight ratio and elevated total protein concentration and lactate dehydrogenase level in bronchoalveolar lavage fluid. Taxifolin treatment protected animals against sepsis-induced pulmonary damage and edema. Septic mice presented compromised antioxidant capacity, whereas the administration of taxifolin prior to cecal ligation and puncture surgery decreased malondialdehyde concentration and enhanced the levels of reduced glutathione and superoxide dismutase in mice with sepsis-induced acute lung injury. Moreover, cecal ligation and puncture-operated mice showed markedly higher levels of proinflammatory cytokines relative to sham-operated group, while taxifolin treatment effectively mitigated sepsis-induced inflammation in mouse lungs. Further investigation revealed that taxifolin suppressed the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in cecal ligation and puncture-challenged mice by regulating the phosphorylation of p65 and IκBα. In conclusion, our study showed that taxifolin alleviated sepsis-induced acute lung injury via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, suggesting the therapeutic potential of taxifolin in the treatment sepsis-induced acute lung injury.

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