Protection from Lethal Cell Death in Cecal Ligation and Puncture-Induced Sepsis Mouse Model by In Vivo Delivery of FADD siRNA

10.5772/19885 ◽  
2011 ◽  
Author(s):  
Yuichi Hattori ◽  
Naoyuki Matsu
Keyword(s):  
Cell Death ◽  
Mouse Model ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
In Vivo Delivery

scholarly journals Experimentally Approaching the ICU: Monitoring Outcome-Based Responses in the Two-Hit Mouse Model of Posttraumatic Sepsis

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Susanne Drechsler ◽  
Katrin M. Weixelbaumer ◽  
Heinz Redl ◽  
Martijn van Griensven ◽  
Soheyl Bahrami ◽  
...  
Keyword(s):  
Mouse Model ◽  
Femur Fracture ◽  
Cecal Ligation ◽  
Blood Sampling ◽  
Cecal Ligation And Puncture ◽  
Organ Function ◽  
Daily Monitoring ◽  
Circulating Cells ◽  
Facial Vein ◽  
Insight Into

To simulate and monitor the evolution of posttraumatic sepsis in mice, we combined a two-hit model of trauma/hemorrhage (TH) followed by polymicrobial sepsis with repetitive blood sampling. Anesthetized mice underwent femur fracture/sublethal hemorrhage and cecal ligation and puncture (CLP) 48 h later. To monitor outcome-dependent changes in circulating cells/biomarkers, mice were sampled daily (facial vein) for 7 days and retrospectively divided into either dead (DIE) or surviving (SUR) by post-CLP day 7. Prior to CLP, AST was 3-fold higher in DIE, while all other post-TH changes were similar between groups. There was a significant post-CLP intergroup separation. In SUR, RBC and Hb were lower, platelets and neutrophils higher, and lymphocytes mixed compared to DIE. In DIE, all organ function markers except glucose (decrease) were few folds higher compared to SUR. In summary, the combination of daily monitoring with an adequate two-hit model simulates the ICU setting, allows insight into outcome-based responses, and can identify biomarkers indicative of death in the acute posttraumatic sepsis in mice.

scholarly journals Protective Role of Coenzyme Q10 in Acute Sepsis-Induced Liver Injury in BALB/c Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Qian-wei Li ◽  
Qin Yang ◽  
Hong-Yang Liu ◽  
Yu-ling Wu ◽  
Yu-Hua Hao ◽  
...  
Keyword(s):  
Liver Injury ◽  
Coenzyme Q10 ◽  
Cecal Ligation ◽  
Protective Role ◽  
Hepatic Tissue ◽  
Control Group ◽  
Cecal Ligation And Puncture ◽  
Sequestosome 1

Sepsis increases the risk of the liver injury development. According to the research works, coenzyme Q10 exhibits hepatoprotective properties in vivo as well as in vitro. Current work aimed at investigating the protective impacts of coenzyme Q10 against liver injury in septic BALB/c mice. The male BALB/c mice were randomly segregated into 4 groups: the control group, the coenzyme Q10 treatment group, the puncture and cecal ligation group, and the coenzyme Q10+cecal ligation and puncture group. Cecal ligation and puncture was conducted after gavagaging the mice with coenzyme Q10 during two weeks. Following 48 h postcecal ligation and puncture, we estimated hepatic biochemical parameters and histopathological changes in hepatic tissue. We evaluated the expression of factors associated with autophagy, pyroptosis, and inflammation. Findings indicated that coenzyme Q10 decreased the plasma levels in alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase in the cecal ligation and puncture group. Coenzyme Q10 significantly inhibited the elevation of sequestosome-1, interleukin-1β, oligomerization domain-like receptor 3 and nucleotide-binding, interleukin-6, and tumor necrosis factor-α expression levels; coenzyme Q10 also increased beclin 1 levels. Coenzyme Q10 might be a significant agent in the treatment of liver injury induced by sepsis.

Suppressive Effects of Ginsenoside Rh1 on HMGB1-Mediated Septic Responses

2019 ◽  
Vol 47 (01) ◽  
pp. 119-133 ◽  
Author(s):  
Wonhwa Lee ◽  
Soo-Hyun Cho ◽  
Ji-Eun Kim ◽  
Changhun Lee ◽  
Jee-Hyun Lee ◽  
...  
Keyword(s):  
Survival Rate ◽  
Mouse Model ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Leukocyte Adhesion ◽  
Biological Activities ◽  
Umbilical Vein ◽  
Cecal Ligation ◽  
Korean Red Ginseng

High mobility group box 1 (HMGB1) is considered as a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses, and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Ginsenoside Rh1, a protopanaxatriol type ginsenoside, is one of the major bioactive components of Korean red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. Ginsenoside Rh1 exhibits potent biological activities such as antistress, anti-oxidant, anti-inflammatory and immunomodulatory effects. We examined the effects of ginsenoside Rh1 on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. Ginsenoside-Rh1 was administered after the HMGB1 challenge. The antiseptic activity of ginsenoside Rh1 was determined by measuring the permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and mice, and the survival rate in a sepsis mouse model. Ginsenoside Rh1 significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated HUVECs. Furthermore, ginsenoside Rh1 suppressed the production of tumor necrosis factor (TNF)-[Formula: see text], interleukin (IL)-6, activation of nuclear factor (NF)-[Formula: see text]B and extracellular signal-regulated kinase (ERK) 1/2 by HMGB1. Ginsenoside Rh1 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ginsenoside Rh1 reduced the cecal ligation and puncture (CLP)-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results indicated that ginsenoside Rh1 might be useful in the treatment of sepsis by targeting HMGB1.

scholarly journals Maresin 1 attenuates mitochondrial dysfunction through the ALX/cAMP/ROS pathway in the cecal ligation and puncture mouse model and sepsis patients

2018 ◽  
Vol 98 (6) ◽  
pp. 715-733 ◽  
Author(s):  
Jiaqi Gu ◽  
Lingchun Luo ◽  
Qian Wang ◽  
Songfan Yan ◽  
Jing Lin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mitochondrial Dysfunction ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Maresin 1

scholarly journals BMX Represses Thrombin-PAR1–Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis

2020 ◽  
Vol 126 (4) ◽  
pp. 471-485 ◽  
Author(s):  
Zhao Li ◽  
Mingzhu Yin ◽  
Haifeng Zhang ◽  
Weiming Ni ◽  
Richard W. Pierce ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cecal Ligation ◽  
Endothelial Permeability ◽  
Vascular Leakage ◽  
Lung Epithelial Cells ◽  
Negative Regulator ◽  
Cecal Ligation And Puncture ◽  
Early Sepsis

Rationale: BMX (bone marrow kinase on the X chromosome) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown. Objective: We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture models. Methods and Results: The cecal ligation and puncture model was applied to WT (wild type) and BMX-KO (BMX global knockout) mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect transendothelial electrical resistance in vitro and, the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early cecal ligation and puncture–induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells by 2- to 3-fold. The expression of BMX in macrophages, neutrophils, platelets, and lung epithelial cells was undetectable compared with that in endothelial cells, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-PAR1 (protease-activated receptor-1) signaling in endothelial cells by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pretreatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early cecal ligation and puncture–induced sepsis. Conclusions: Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.

scholarly journals Antimicrobial peptide LL-37 ameliorates a murine sepsis model via the induction of microvesicle release from neutrophils

2020 ◽  
Vol 26 (7) ◽  
pp. 565-579 ◽  
Author(s):  
Yumi Kumagai ◽  
Taisuke Murakami ◽  
Kuwahara-Arai ◽  
Toshiaki Iba ◽  
Johannes Reich ◽  
...  
Keyword(s):  
Antimicrobial Peptide ◽  
Ex Vivo ◽  
Protective Action ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
Mouse Bone Marrow ◽  
Cecal Ligation And Puncture ◽  
Sepsis Survivors ◽  
Antibacterial Potential

Sepsis is a life-threatening disease caused by systemic dys-regulated inflammatory response to infection. We previously revealed that LL-37, a human cathelicidin antimicrobial peptide, improves the survival of cecal ligation and puncture septic mice. Ectosomes, microvesicles released from neutrophils, are reported to be elevated in sepsis survivors; however, the functions of ectosomes in sepsis remain largely unknown. Therefore, we herein elucidated the protective action of LL-37 on sepsis, by focusing on LL-37-induced ectosome release in a cecal ligation and puncture model. The results demonstrated the enhancement of ectosome levels by LL-37 administration, accompanied by a reduction of bacterial load. Importantly, ectosomes isolated from LL-37-injected cecal ligation and puncture mice contained higher amounts of antimicrobial proteins/peptides and exhibited higher antibacterial activity, compared with those from PBS-injected cecal ligation and puncture mice, suggesting that LL-37 induces the release of ectosomes with antibacterial potential in vivo. Actually, LL-37 stimulated mouse bone-marrow neutrophils to release ectosomes ex vivo, and the LL-37-induced ectosomes possessed antibacterial potential. Furthermore, administration of LL-37-induced ectosomes reduced the bacterial load and improved the survival of cecal ligation and puncture mice. Together these observations suggest LL-37 induces the release of antimicrobial ectosomes in cecal ligation and puncture mice, thereby reducing the bacterial load and protecting mice from lethal septic conditions.

Efficacy of Panobinostat (LBH589) in Multiple Myeloma Cell Lines and In Vivo Mouse Model: Tumor-Specific Cytotoxicity and Protection of Bone Integrity in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1510-1510 ◽  
Author(s):  
Joseph D. Growney ◽  
Peter Atadja ◽  
Wenlin Shao ◽  
Youzhen Wang ◽  
Minying Pu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Bone Density ◽  
Mouse Model ◽  
Cortical Bone ◽  
Cell Lines ◽  
Single Agent ◽  
Synergistic Cytotoxicity

Abstract Panobinostat (LBH589) is a highly potent oral pan-deacetylase (DAC) inhibitor currently undergoing clinical development in hematologic and solid malignancies. Here we report the effects of panobinostat on multiple myeloma (MM) cells in vitro and in a murine xenograft model in vivo. Panobinostat exhibited potent cytotoxic activity (IC50 <10 nM) against 8 MM cell lines (KMS-12PE, KMS-18, LP-1, NCI H929, KMS-11, RPMI8226, OPM-2, and U266). Panobinostat has been shown to affect signals involved in MM cell-cycle arrest and cell death, and to induce apoptosis via mitochondrial perturbation. In addition, panobinostat has been shown to selectively induce cell death of plasma cells isolated from MM patients without toxicity to normal lymphocytes or granulocytes. To investigate the effect of panobinostat in vivo, a disseminated luciferized MM.1S xenograft mouse model was treated with vehicle or panobinostat 15 mg/kg by intraperitoneal (i.p.) administration qd×5 for 3 weeks. Panobinostat treatment reduced the burden of MM.1S tumor cells to 22% treated over control (T/C) relative to vehicle-treated animals. In addition, MM.1S tumor-bearing mice treated with panobinostat displayed reduced trabecular and cortical bone damage relative to vehicle-treated animals. The mean ± SEM trabecular bone density and cortical bone density (% Bone Volume/Total Volume) of panobinostat-treated animals was 14.5% ± 2.0 and 98.1% ± 0.4, respectively, compared with 2.2% ± 0.3 and 89.1% ± 1.5 in vehicle-treated animals. In combination with the proteosome inhibitor bortezomib (BZ), panobinostat displayed significant synergistic cytotoxicity without additional toxicity to normal bone marrow stromal cells in vitro. In the MM.1S-luciferase tumor mouse model, combined treatment with panobinostat at 10 mg/kg i.p. qd×5 for 4 weeks and BZ at 0.2 mg/kg intravenously 1qw for 4 weeks reduced tumor burden to 7% T/C relative to vehicle, panobinostat alone (31% T/C), or BZ alone (44% T/C). Disease progression, measured as median time to endpoint (TTE) was improved from 37 to 54 days (P<0.05) by panobinostat and to 46 days by BZ (P<0.05). The combination treatment further improved clinical outcome relative to both single-agent treatment groups (P<0.05), extending the TTE to 73 days. In contrast to BZ, the immunomodulatory drug thalidomide (TH) had no significant single-agent activity at 150 mg/kg p.o. qd for 4 weeks. However, combination activity (18% T/C) was observed when TH was combined with a sub-efficacious dose of panobinostat (5 mg/kg, 64% T/C). Combination of panobinostat and TH increased the TTE to 50 days, compared with 37.5, 43, and 39.5 days (P<0.05), respectively, for the vehicle, panobinostat, or TH as single agents. These data demonstrate that panobinostat exhibits significant anti-proliferative and anti-tumor activities on MM cells both in vitro and in vivo. Panobinostat, as a single agent or in combination with BZ or TH, is a promising therapy for MM, and these studies may provide the rationale for clinical evaluation of panobinostat and BZ combination in the treatment of MM.

scholarly journals Beneficial effect of STAT3 decoy oligodeoxynucleotide transfection on organ injury and mortality in mice with cecal ligation and puncture-induced sepsis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Samar Imbaby ◽  
Naoyuki Matsuda ◽  
Kengo Tomita ◽  
Kohshi Hattori ◽  
Sailesh Palikhe ◽  
...  
Keyword(s):  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Signal Transducers ◽  
Significant Survival ◽  
Upstream Kinase ◽  
Stat3 Decoy

Abstract Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We investigated whether in vivo introduction of synthetic double-stranded STAT3 decoy oligodeoxynucleotides (ODNs) can provide benefits for reducing organ injury and mortality in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We found that STAT3 was rapidly activated in major end-organ tissues following CLP, which was accompanied by activation of the upstream kinase JAK2. Transfection of STAT3 decoy ODNs downregulated pro-inflammatory cytokine/chemokine overproduction in CLP mice. Moreover, STAT3 decoy ODN transfection significantly reduced the increases in tissue mRNAs and proteins of high mobility group box 1 (HMGB1) and strongly suppressed the excessive elevation in serum HMGB1 levels in CLP mice. Finally, STAT3 decoy ODN administration minimized the development of sepsis-driven major end-organ injury and led to a significant survival advantage in mice after CLP. Our results suggest a critical role of STAT3 in the sepsis pathophysiology and the potential usefulness of STAT3 decoy ODNs for sepsis gene therapy.

scholarly journals Sulforaphane Suppresses Sepsis-Mediated Renal Functions in Cecal Ligation and Puncture Mouse Model

2018 ◽  
Vol 13 (6) ◽  
pp. 1934578X1801300 ◽  
Author(s):  
In-Chul Lee ◽  
Jong-Sup Bae
Keyword(s):  
Lipid Peroxidation ◽  
Superoxide Dismutase ◽  
Glutathione Peroxidase ◽  
Mouse Model ◽  
Plasma Levels ◽  
Renal Damage ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Antioxidant Defense System ◽  
Cecal Ligation And Puncture

Sulforaphane (SFN), a natural isothiocyanate present in cruciferous vegetables such as broccoli and cabbage, is effective in preventing carcinogenesis, diabetes, and inflammatory responses. This study was initiated to determine whether SFN could modulate renal functional damage in a mouse model of sepsis and to elucidate the underlying mechanisms. The potential of SFN treatment to reduce renal damage induced by cecal ligation and puncture (CLP) surgery in mice was measured by assessment of serum creatinine, blood urea nitrogen (BUN), lipid peroxidation, total glutathione, glutathione peroxidase activity, catalase activity, and superoxide dismutase activity. Treatment with SFN resulted in elevated plasma levels of BUN and creatinine, and of protein in urine in mice with CLP-induced renal damage. SFN treatment also reduced the plasma levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α),▢increased lipid peroxidation, and markedly enhanced the antioxidant defense system by restoring the levels of superoxide dismutase, glutathione peroxidase, and catalase in kidney tissues. The present results suggested that SFN protects mice against sepsis-triggered renal injury.

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