scholarly journals Intestinal permeability is reduced and IL-10 levels are increased in septic IL-6 knockout mice

2001 ◽  
Vol 281 (3) ◽  
pp. R1013-R1023 ◽  
Author(s):  
Quan Wang ◽  
Cheng Hui Fang ◽  
Per-Olof Hasselgren
Keyword(s):  
Intestinal Permeability ◽  
Cecal Ligation ◽  
Fluorescein Isothiocyanate ◽  
Sham Operation ◽  
Cecal Ligation And Puncture ◽  
Wild Type ◽  
Mucosal Permeability ◽  
Ussing Chambers ◽  
Intestinal Segments

Sepsis is associated with increased intestinal permeability, but mediators and mechanisms are not fully understood. We examined the role of interleukin (IL)-6 and IL-10 in sepsis-induced increase in intestinal permeability. Intestinal permeability was measured in IL-6 knockout (IL-6 −/−) and wild-type (IL-6 +/+) mice 16 h after induction of sepsis by cecal ligation and puncture or sham operation. In other experiments, mice or intestinal segments incubated in Ussing chambers were treated with IL-6 or IL-10. Intestinal permeability was assessed by determining the transmucosal transport of the 4.4-kDa marker fluorescein isothiocyanate conjugated dextran and the 40-kDa horseradish peroxidase. Intestinal permeability for both markers was increased in septic IL-6 +/+ mice but not in septic IL-6 −/− mice. Treatment of nonseptic mice or of intestinal segments in Ussing chambers with IL-6 did not influence intestinal permeability. Plasma IL-10 levels were increased in septic IL-6 −/− mice, and treatment of septic mice with IL-10 resulted in reduced intestinal permeability. Increased intestinal permeability during sepsis may be regulated by an interaction between IL-6 and IL-10. Treatment with IL-10 may prevent the increase in mucosal permeability during sepsis.

Heat shock response reduces intestinal permeability in septic mice: potential role of interleukin-10

2002 ◽  
Vol 282 (3) ◽  
pp. R669-R676 ◽  
Author(s):  
Quan Wang ◽  
Per-Olof Hasselgren
Keyword(s):  
Heat Shock ◽  
Intestinal Permeability ◽  
Heat Shock Response ◽  
Sodium Arsenite ◽  
Cecal Ligation ◽  
Interleukin 10 ◽  
Sham Operation ◽  
Protective Effects ◽  
Mucosal Permeability ◽  
Shock Response

Sepsis and other critical illnesses are associated with increased permeability of the intestinal mucosa. Loss of mucosal integrity may lead to multiple organ failure in these conditions. We tested the hypothesis that induction of the heat shock response reduces sepsis-induced increase in intestinal permeability. The heat shock response was induced in mice by intraperitoneal injection of 10 mg/kg sodium arsenite. Two hours later, at which time mucosal heat shock protein 72 levels were increased, sepsis was induced by cecal ligation and puncture (CLP) or sham operation was performed. Sixteen hours after sham operation or CLP, intestinal permeability was determined by measuring the appearance in blood of 4.4-kDa fluorescein isothiocyanate-conjugated dextran and 40-kDa horseradish peroxidase administered by gavage. Sepsis resulted in increased mucosal permeability for both markers, and this effect of sepsis was substantially reduced in mice treated with sodium arsenite. Plasma levels of the anti-inflammatory cytokine interleukin (IL)-10 were increased in septic mice pretreated with sodium arsenite, and the protective effect of sodium arsenite on intestinal permeability in septic mice was reversed by treatment with anti-IL-10 antibody. The present results suggest that sepsis-induced increase in mucosal permeability can be reduced by the heat shock response and that increased IL-10 levels may be involved in the protective effects of the heat shock response.

Role of hydrogen sulfide in cecal ligation and puncture-induced sepsis in the mouse

2006 ◽  
Vol 290 (6) ◽  
pp. L1193-L1201 ◽  
Author(s):  
Huili Zhang ◽  
Liang Zhi ◽  
Philip K. Moore ◽  
Madhav Bhatia
Keyword(s):  
Hydrogen Sulfide ◽  
Systemic Inflammation ◽  
Mammalian Cells ◽  
Cecal Ligation ◽  
Organ Injury ◽  
Sham Operation ◽  
Myeloperoxidase Activity ◽  
Cecal Ligation And Puncture ◽  
Sodium Hydrosulfide

Endogenous hydrogen sulfide (H2S) is naturally synthesized in various types of mammalian cells from l-cysteine in a reaction catalyzed by two enzymes, cystathionine-γ-lyase (CSE) and/or cystathionine-β-synthase. The latest studies have implied that H2S functions as a vasodilator and neurotransmitter. However, so far there is little information about the role played by H2S in systemic inflammation such as sepsis. Thus the aim of this study was to investigate the potential role of endogenous H2S in cecal ligation and puncture (CLP)-induced sepsis. Male Swiss mice were subjected to CLP-induced sepsis and treated with saline (ip), dl-propargylglycine (PAG, 50 mg/kg ip), a CSE inhibitor, or sodium hydrosulfide (NaHS; 10 mg/kg ip). PAG was administered either 1 h before or 1 h after the induction of sepsis, whereas NaHS was given at the same time of CLP. CLP-induced sepsis significantly increased the plasma H2S level and the liver H2S synthesis 8 h after CLP compared with sham operation. Induction of sepsis also resulted in a significant upregulation of CSE mRNA in liver. On the other hand, prophylactic as well as therapeutic administration of PAG significantly reduced sepsis-associated systemic inflammation, as evidenced by myeloperoxidase activity and histological changes in lung and liver, and attenuated the mortality of CLP-induced sepsis. Injection of NaHS significantly aggravated sepsis-associated systemic inflammation. Therefore, the effect of inhibition of H2S formation and administration of NaHS suggests that H2S plays a proinflammatory role in regulating the severity of sepsis and associated organ injury.

scholarly journals The Na+/H+ exchanger isoform 3 is required for active paracellular and transcellular Ca2+ transport across murine cecum

2013 ◽  
Vol 305 (4) ◽  
pp. G303-G313 ◽  
Author(s):  
Juraj Rievaj ◽  
Wanling Pan ◽  
Emmanuelle Cordat ◽  
R. Todd Alexander
Keyword(s):  
Water Movement ◽  
Water Flux ◽  
Wild Type Mouse ◽  
Wild Type ◽  
Rt Pcr ◽  
Ussing Chambers ◽  
Voltage Clamps ◽  
Paracellular Absorption ◽  
Mouse Intestine

Intestinal calcium (Ca2+) absorption occurs via paracellular and transcellular pathways. Although the transcellular route has been extensively studied, mechanisms mediating paracellular absorption are largely unexplored. Unlike passive diffusion, secondarily active paracellular Ca2+ uptake occurs against an electrochemical gradient with water flux providing the driving force. Water movement is dictated by concentration differences that are largely determined by Na+ fluxes. Consequently, we hypothesized that Na+ absorption mediates Ca2+ flux. NHE3 is central to intestinal Na+ absorption. NHE3 knockout mice (NHE3−/−) display impaired intestinal Na+, water, and Ca2+ absorption. However, the mechanism mediating this latter abnormality is not clear. To investigate this, we used Ussing chambers to measure net Ca2+ absorption across different segments of wild-type mouse intestine. The cecum was the only segment with net Ca2+ absorption. Quantitative RT-PCR measurements revealed cecal expression of all genes implicated in intestinal Ca2+ absorption, including NHE3. We therefore employed this segment for further studies. Inhibition of NHE3 with 100 μM 5-( N-ethyl- N-isopropyl) amiloride decreased luminal-to-serosal and increased serosal-to-luminal Ca2+ flux. NHE3−/− mice had a >60% decrease in luminal-to-serosal Ca2+ flux. Ussing chambers experiments under altered voltage clamps (−25, 0, +25 mV) showed decreased transcellular and secondarily active paracellular Ca2+ absorption in NHE3−/− mice relative to wild-type animals. Consistent with this, cecal Trpv6 expression was diminished in NHE3−/− mice. Together these results implicate NHE3 in intestinal Ca2+ absorption and support the theory that this is, at least partially, due to the role of NHE3 in Na+ and water absorption.

scholarly journals A study for a role of inducible NO synthase in septic rats with cecal ligation and puncture (CLP)

1999 ◽  
Vol 79 ◽  
pp. 97
Author(s):  
Masayoshi Abe ◽  
Iku Okamoto ◽  
Kazuhiko Shibata ◽  
Keiichi Tanaka ◽  
Noriyuki Sakata ◽  
...  
Keyword(s):  
Cecal Ligation ◽  
No Synthase ◽  
Cecal Ligation And Puncture ◽  
Inducible No Synthase

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 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.

Differential effect of imipenem treatment on injury caused by cecal ligation and puncture in wild-type and NK cell-deficient β2-microgloblin knockout mice

2006 ◽  
Vol 290 (2) ◽  
pp. G277-G284 ◽  
Author(s):  
Victor T. Enoh ◽  
Cheng Y. Lin ◽  
Tushar K. Varma ◽  
Edward R. Sherwood
Keyword(s):  
Metabolic Acidosis ◽  
Knockout Mice ◽  
Nk Cell ◽  
Plasma Concentrations ◽  
Cecal Ligation ◽  
Systemic Infection ◽  
Cecal Ligation And Puncture ◽  
Wild Type ◽  
Term Survival ◽  
The Impact

Our previous studies showed that β2-microglobulin knockout mice treated with anti-asialoGM1 (β2MKO/αAsGM1 mice) are resistant to injury caused by cecal ligation and puncture (CLP). However, CLP-induced injury is complex. Potential mechanisms of injury include systemic infection, cecal ischemia, and translocation of bacterial toxins such as endotoxin and superantigens. Currently, it is unclear which of these mechanisms of injury contributes to mortality in wild-type mice and whether β2MKO/αAsGM1 mice are resistant to any particular mechanisms of injury. In the present study, we hypothesized that systemic infection is the major cause of injury after CLP in wild-type mice and that β2MKO/αAsGM1 mice are resistant to infection-induced injury. To test this hypothesis, wild-type and β2MKO/αAsGM1 mice were treated with the broad-spectrum antibiotic imipenem immediately after CLP to decrease the impact of systemic infection in our model. Treatment of wild-type and β2MKO/αAsGM1 mice with imipenem decreased bacterial counts by at least two orders of magnitude. However, all wild-type mice, whether treated with saline or imipenem, died by 42 h after CLP and had significant hypothermia, metabolic acidosis, and high plasma concentrations of the cytokines interleukin-6, macrophage inflammatory protein-2, and keratinocyte-derived chemokine. β2MKO/αAsGM1 mice showed 40% long-term survival, which was increased to 90% by imipenem treatment. β2MKO/αAsGM1 mice had less hypothermia, decreased metabolic acidosis, and lower cytokine concentrations at 18 h after CLP compared with wild-type mice. These results suggest that infection is not the major cause of mortality for wild-type mice in our model of CLP. Other mechanisms of injury such as cecal ischemia or translocation of microbial toxins may be more important. β2MKO/αAsGM1 mice appear resistant to these early, non-infection-related causes of CLP-induced injury but showed delayed mortality associated with bacterial dissemination, which was ablated by treatment with imipenem.

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.

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