scholarly journals Blockade of the JNK Signalling as a Rational Therapeutic Approach to Modulate the Early and Late Steps of the Inflammatory Cascade in Polymicrobial Sepsis

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Gabriele Pizzino ◽  
Alessandra Bitto ◽  
Giovanni Pallio ◽  
Natasha Irrera ◽  
Federica Galfo ◽  
...  
Keyword(s):  
Therapeutic Approach ◽  
Caspase 3 ◽  
Cecal Ligation ◽  
Polymicrobial Sepsis ◽  
Sham Operation ◽  
Cecal Ligation And Puncture ◽  
Inflammatory Cascade ◽  
Human Sepsis ◽  
Histopathologic Analysis ◽  
To Receive

Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.

scholarly journals Hypertonic Saline Solution Drives Neutrophil from Bystander Organ to Infectious Site in Polymicrobial Sepsis: A Cecal Ligation and Puncture Model

PLoS ONE ◽  
2013 ◽  
Vol 8 (9) ◽  
pp. e74369 ◽  
Author(s):  
Mariana Cardillo Theobaldo ◽  
Flavia Llimona ◽  
Ricardo Costa Petroni ◽  
Ester Correia Sarmento Rios ◽  
Irineu Tadeu Velasco ◽  
...  
Keyword(s):  
Hypertonic Saline ◽  
Saline Solution ◽  
Cecal Ligation ◽  
Polymicrobial Sepsis ◽  
Cecal Ligation And Puncture ◽  
Hypertonic Saline Solution ◽  
Puncture Model

scholarly journals Necrostatin-1 accelerates time to death in a rat model of cecal ligation and puncture and massively increases hepatocyte caspase-3 cleavage

2019 ◽  
Vol 316 (4) ◽  
pp. G551-G561 ◽  
Author(s):  
Qin Zhang ◽  
Siwei Wei ◽  
Jiayin Lu ◽  
Weijun Fu ◽  
Hui Chen ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Liver Injury ◽  
Survival Time ◽  
Caspase 3 ◽  
Cecal Ligation ◽  
B Cell Lymphoma ◽  
Cecal Ligation And Puncture ◽  
Interacting Protein ◽  
Regulated Necrosis ◽  
Related Proteins

Necroptosis, a form of regulated necrosis, has been reported to be involved in numerous pathologies, including sepsis. However, a protective effect of the selective inhibitor of necroptosis, necrostatin-1 (Nec-1), against sepsis remains to be confirmed. Animals (rats and mice) were subjected to cecal ligation and puncture (CLP) to mimic clinical sepsis. Nec-1 or its vehicle (control) was administered 20 min before CLP. Survival time was observed up to 72 h after CLP. Specimens of liver tissue and serum were obtained at 6 h, 12 h, and 18 h. Expression of necroptosis-related proteins [receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like (MLKL)] was determined by Western blot analysis. The RIP1/RIP3 interaction and the recruitment of MLKL to RIP3 were also analyzed. Liver function, histopathological changes, serum inflammation cytokines, TUNEL staining, and the expression of apoptosis-related protein, including caspase-3, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X (Bax), was determined. As expected, Nec-1 administration reduced the expression of necroptosis-related proteins and the RIP1/RIP3 interaction, indicating inhibited necroptosis. Surprisingly, Nec-1 treatment exacerbated the liver injury and shortened survival time of septic rats with increased TUNEL-positive cells, cleaved caspase-3 protein content, and Bax/Bcl-2 ratio. Collectively, these findings show that Nec-1 administration inhibited the hepatocyte necroptosis pathway but accelerated apoptosis via the apoptotic pathway in CLP-induced sepsis rat. NEW & NOTEWORTHY The present study demonstrated that a chemical inhibitor necrostatin-1 (Nec-1) or receptor-interacting protein kinase(RIP1) knock down targeted at necroptosis inhibition accelerated liver injury of following sepsis. For fundamental research, these results warrant further investigation of the potential link between Nec-1 administration and the cellular apoptosis following sepsis induced liver injury. For applied research, these results suggest the potential harmful effect of Nec-1 on future sepsis treatment.

scholarly journals Ramipril pretreatment worsened renal injury and survival despite a reduction in renal inflammation in experimentally induced sepsis in mice

2020 ◽  
Vol 21 (2) ◽  
pp. 147032032092397
Author(s):  
Tzvetanka Bondeva ◽  
Katrin Schindler ◽  
Claudia Schindler ◽  
Gunter Wolf
Keyword(s):  
Renal Function ◽  
Enzyme Inhibitor ◽  
Clinical Status ◽  
Cecal Ligation ◽  
Clinical Severity ◽  
Sham Operation ◽  
Cecal Ligation And Puncture ◽  
Renal Inflammation ◽  
Gene And Protein Expression ◽  
Experimentally Induced

Introduction: The angiotensin converting enzyme inhibitor ramipril is a standard antihypertensive therapy for many patients. Because angiotensin II may promote inflammation, we were interested in whether basal pretreatment with ramipril may modify renal function and inflammation as well as systemic outcome in experimentally induced sepsis in mice. Material and methods: Ramipril (10 mg/kg/day) pretreatment or placebo (NaCl) was given intraperitoneally for 5 days to C57BL6/J mice, followed by either sham operation or cecal ligation and puncture sepsis induction. Real-time polymerase chain reaction and immunological stains were used to evaluate renal gene and protein expression, respectively. Plasma creatinine, neutrophil-gelatinase associated lipocalin, and blood urea nitrogen were used as markers for renal function. A clinical severity score was determined. Results: Administration of ramipril before cecal ligation and puncture surgery was associated with reduced renal inflammation but did not improved renal function and structure and even worsened the clinical status of septic mice. Conclusions: The data suggest that the effects of ramipril pretreatment are complex. Additional studies including monitoring of hemodynamic parameters are necessary to elucidate the exact mechanism(s) of this observation. In addition, the timing of the ramipril administration could be of importance.

scholarly journals Cecal ligation and puncture accelerates development of ventilator-induced lung injury

2015 ◽  
Vol 308 (5) ◽  
pp. L443-L451 ◽  
Author(s):  
Nadir Yehya ◽  
Yi Xin ◽  
Yousi Oquendo ◽  
Maurizio Cereda ◽  
Rahim R. Rizi ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Mechanical Ventilation ◽  
Lung Injury ◽  
Pulmonary Inflammation ◽  
Cecal Ligation ◽  
Interleukin 1Β ◽  
Sham Operation ◽  
Cecal Ligation And Puncture ◽  
Sprague Dawley ◽  
Ventilator Induced Lung Injury

Sepsis is a leading cause of respiratory failure requiring mechanical ventilation, but the interaction between sepsis and ventilation is unclear. While prior studies demonstrated a priming role with endotoxin, actual septic animal models have yielded conflicting results regarding the role of preceding sepsis on development of subsequent ventilator-induced lung injury (VILI). Using a rat cecal ligation and puncture (CLP) model of sepsis and subsequent injurious ventilation, we sought to determine if sepsis affects development of VILI. Adult male Sprague-Dawley rats were subject to CLP or sham operation and, after 12 h, underwent injurious mechanical ventilation (tidal volume 30 ml/kg, positive end-expiratory pressure 0 cmH2O) for either 0, 60, or 120 min. Biochemical and physiological measurements, as well as computed tomography, were used to assess injury at 0, 60, and 120 min of ventilation. Before ventilation, CLP rats had higher levels of alveolar neutrophils and interleukin-1β. After 60 min of ventilation, CLP rats had worse injury as evidenced by increased alveolar inflammation, permeability, respiratory static compliance, edema, oxygenation, and computed tomography. By 120 min, CLP and sham rats had comparable levels of lung injury as assessed by many, but not all, of these metrics. CLP rats had an accelerated and worse loss of end-expiratory lung volume relative to sham, and consistently higher levels of alveolar interleukin-1β. Loss of aeration and progression of edema was more pronounced in dependent lung regions. We conclude that CLP initiated pulmonary inflammation in rats, and accelerated the development of subsequent VILI.

Transient Receptor Potential Melastatin 2 Protects Mice against Polymicrobial Sepsis by Enhancing Bacterial Clearance

2014 ◽  
Vol 121 (2) ◽  
pp. 336-351 ◽  
Author(s):  
XiaoWei Qian ◽  
Tomohiro Numata ◽  
Kai Zhang ◽  
CaiXia Li ◽  
JinChao Hou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Transient Receptor Potential ◽  
Cecal Ligation ◽  
Polymicrobial Sepsis ◽  
Bacterial Clearance ◽  
Cecal Ligation And Puncture ◽  
Bacterial Burden ◽  
Wild Type ◽  
Transient Receptor Potential Melastatin

Abstract Background: Recent studies suggest that the transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remain unclear. Methods: The authors explored the effects of genetic disruption of TRPM2 on mortality (n = 15), bacterial clearance (n = 6), organ injury, and systemic inflammation during cecal ligation and puncture–induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. Results: After cecal ligation and puncture, Trpm2-knockout mice had increased mortality compared with wild-type mice (73.3 vs. 40%, P = 0.0289). The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. TRPM2-mediated Ca2+ influx plays an important role in lipopolysaccharide or cecal ligation and puncture–induced heme oxygenase-1 (HO-1) expression in macrophage. HO-1 up-regulation decreased bacterial burden both in wild-type bone marrow–derived macrophages and in cecal ligation and puncture–induced septic wild-type mice. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow–derived macrophages. Pretreatment of Trpm2-knockout bone marrow–derived macrophages with HO-1 inducer markedly increased HO-1 expression and decreased bacterial burden. Pretreatment of Trpm2-knockout mice with HO-1 inducer reversed the susceptibility of Trpm2-knockout mice to sepsis by enhancing the bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 messenger RNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 messenger RNA levels. TRPM2 levels correlated with HO-1 levels in septic patients (r = 0.675, P = 0.001). Conclusion: The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression.

The systemic inflammatory reaction in polymicrobial sepsis induced by murine cecal ligation and puncture is equally dependent on C5 and CD14

Immunobiology ◽  
2012 ◽  
Vol 217 (11) ◽  
pp. 1129
Author(s):  
Tom E. Mollnes ◽  
Andreas Barratt-Due ◽  
Søren E. Pischke ◽  
Øystein Sandanger ◽  
Miles A. Nunn ◽  
...  
Keyword(s):  
Inflammatory Reaction ◽  
Cecal Ligation ◽  
Polymicrobial Sepsis ◽  
Cecal Ligation And Puncture ◽  
Systemic Inflammatory Reaction

scholarly journals Study on adhesion formation and the healing of colon anastomosis in rats with induced peritoneal sepsis

2011 ◽  
Vol 26 (suppl 2) ◽  
pp. 100-105 ◽  
Author(s):  
Silvana Marques e Silva ◽  
Marcos Vinícius Melo de Oliveira ◽  
Alexandre Malta Brandão ◽  
Fabiana Pirani Carneiro ◽  
Vânia Maria Moraes Ferreira ◽  
...  
Keyword(s):  
Adhesion Formation ◽  
Cecal Ligation ◽  
Abdominal Sepsis ◽  
Colon Anastomosis ◽  
Cecal Ligation And Puncture ◽  
Strength Assessment ◽  
The Third ◽  
Peritoneal Infection ◽  
Histopathologic Analysis

PURPOSE: To evaluate the effects of abdominal sepsis on adhesion formation and colon anastomosis healing in rats. METHODS: Forty rats were distributed in two groups containing 20 rats each for left colon anastomosis in the presence (Group S) or absence (Group N) of induced sepsis by cecal ligation and puncture. Each group was divided into subgroups for euthanasia on the third (N3 and S3) or seventh (N7 or S7) post-operative day. The amount of adhesions was evaluated and a segment of the colon was removed for histopathologic analysis, bursting strength assessment, hydroxyproline and the determination of tissue collagen. RESULTS: The subjects which underwent cecal ligation and puncture presented a higher amount of intra-abdominal adherences in both third (p=0,00) and seventh (p=0,00) post-operatory days. Smaller bursting strengths were found in the S3 subgroup, and greater bursting strengths were found in the S7 subgroup. There was no difference in the variations on the concentrations of hydroxyproline, tissue collagen and histopathology. CONCLUSIONS: The peritoneal infection which was developed by cecal ligation and puncture raised the amount of intra-cavitary adhesions. There was a decrease in the amount of colonic anastomosis on the third post-operatory day with a following raise on the seventh without any effects on other healing parameters.

scholarly journals Can the Cecal Ligation and Puncture Model Be Repurposed To Better Inform Therapy in Human Sepsis?

2020 ◽  
Vol 88 (9) ◽  
Author(s):  
John C. Alverdy ◽  
Robert Keskey ◽  
Renee Thewissen
Keyword(s):  
Cecal Ligation ◽  
Human Microbiome ◽  
Disease Process ◽  
Underlying Disease ◽  
Human Condition ◽  
National Institutes Of Health ◽  
Cecal Ligation And Puncture ◽  
Human Sepsis ◽  
Compare And Contrast ◽  
Puncture Model

ABSTRACT A recent report by the National Institutes of Health on sepsis research has implied there is a trend to move away from mouse models of sepsis. The most commonly used animal model to study the pathogenesis of human sepsis is cecal ligation and puncture (CLP) in mice. The model has been the mainstay of sepsis research for decades and continues to be considered the gold standard to inform novel pathways of sepsis physiology and its therapeutic direction. As there have been many criticisms of the model, particularly regarding its relevance to human disease, how this model might be repurposed to be more reflective of the human condition begs discussion. In this piece, we compare and contrast the mouse microbiome of the CLP model to the emerging science of the microbiome of human sepsis and discuss the relevance for mice to harbor the specific pathogens present in the human microbiome during sepsis, as well as an underlying disease process to mimic the characteristics of those patients with undesirable outcomes. How to repurpose this model to incorporate these “human factors” is discussed in detail and suggestions offered.

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