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.

Hydrogen sulfide acts as an inflammatory mediator in cecal ligation and puncture-induced sepsis in mice by upregulating the production of cytokines and chemokines via NF-κB

2007 ◽  
Vol 292 (4) ◽  
pp. L960-L971 ◽  
Author(s):  
Huili Zhang ◽  
Liang Zhi ◽  
Shabbir Moochhala ◽  
Philip K. Moore ◽  
Madhav Bhatia
Keyword(s):  
Hydrogen Sulfide ◽  
Systemic Inflammation ◽  
Lung Inflammation ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Protein Levels ◽  
Proinflammatory Mediators ◽  
Inflammatory Conditions ◽  
Cytokines And Chemokines ◽  
Inflammatory Protein

Recent studies have implied that hydrogen sulfide (H2S) plays a crucial role in several inflammatory conditions. However, so far little is known about the mechanism by which H2S provokes the inflammatory response in sepsis. Thus the aim of this study was to investigate if H2S regulates sepsis-associated systemic inflammation and production of proinflammatory mediators via the activation of NF-κB. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with dl-propargylglycine (PAG; 50 mg/kg ip), NaHS (10 mg/kg ip), or saline. PAG, an inhibitor of H2S formation, was administered either 1 h before or 1 h after CLP, whereas NaHS, an H2S donor, was given at the time of CLP. Some normal mice were given NaHS (10 mg/kg ip) to induce lung inflammation with or without pretreatment with the NF-κB inhibitor BAY 11-7082. Eight hours after CLP, both prophylactic and therapeutic administration of PAG significantly reduced the mRNA and protein levels of IL-1β, IL-6, TNF-α, monocyte chemotactic protein-1, and macrophage inflammatory protein-2 in lung and liver coupled with decreased activation and translocation of NF-κB in lung and liver. Inhibition of H2S formation also significantly reduced lung permeability and plasma alanine aminotransferase activity. In contrast, injection of NaHS significantly aggravated sepsis-associated systemic inflammation and increased NF-κB activation. In addition, H2S-induced lung inflammation was blocked by BAY 11-7082. Therefore, H2S upregulates the production of proinflammatory mediators and exacerbates the systemic inflammation in sepsis through a mechanism involving NF-κB activation.

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.

Hydrogen sulfide ameliorates cardiovascular dysfunction induced by cecal ligation and puncture in rats

2015 ◽  
Vol 34 (10) ◽  
pp. 953-964 ◽  
Author(s):  
RS Abdelrahman ◽  
MS El-Awady ◽  
MA Nader ◽  
EM Ammar
Keyword(s):  
Hydrogen Sulfide ◽  
Vascular Reactivity ◽  
Troponin I ◽  
Histopathological Examination ◽  
Vascular Dysfunction ◽  
Cecal Ligation ◽  
Cecal Ligation And Puncture ◽  
Cardiovascular Dysfunction ◽  
Sodium Hydrosulfide ◽  
Creatine Kinase Mb

Hydrogen sulfide (H2S) is an endogenously produced gaseous messenger that participates in regulation of cardiovascular functions. This study evaluates the possible protective effect of H2S in cardiovascular dysfunction induced by cecal ligation and puncture (CLP) in rats. After 24 h of induction of CLP, heart rate (HR), mortality, cardiac and inflammation biomarkers (creatine kinase-MB (CK-MB) isozyme, cardiac troponin I (cTnI), C-reactive protein (CRP), and lactate dehydrogenase (LDH)), in vitro vascular reactivity, histopathological examination, and oxidative biomarkers (malondialdehyde (MDA), reduced glutathione (GSH), and superoxide dismutase (SOD)) were determined. CLP induced elevations in HR, mortality, serum CK-MB, cTnI, CRP, and LDH, in addition to impaired aortic contraction to potassium chloride and phenylephrine and relaxation to acetylcholine without affecting sodium nitroprusside responses. Moreover, CLP increased cardiac and aortic MDA and decreased SOD, without affecting GSH and caused a marked subserosal and interstitial inflammation in endocardium. Sodium hydrosulfide, but not the irreversible inhibitor of H2S synthesis dl-propargyl glycine, protected against CLP-induced changes in HR, mortality, cardiac and inflammatory biomarkers, oxidative stress, and myocardium histopathological changes without affecting vascular dysfunction. Our results confirm that H2S can attenuate CLP-induced cardiac, but not vascular, dysfunction possibly through its anti-inflammatory and antioxidant effects.

scholarly journals Double-Stranded RNA Dependent Kinase R Regulates Antibacterial Immunity in Sepsis

2020 ◽  
pp. 1-12
Author(s):  
Yanliang Yang ◽  
Lingli Xie ◽  
Yanjun Zhong ◽  
Xiaoli Zhong ◽  
Ran Meng ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Critical Role ◽  
Cecal Ligation ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Bacterial Sepsis ◽  
Double Stranded Rna ◽  
Important Regulator ◽  
Genetic Deletion

Double-stranded RNA dependent kinase R (PKR) is originally identified as an intracellular sensor of viral infection, but its role in bacterial infection remains largely unknown. Here we report that PKR was an important regulator of antibacterial immunity in sepsis. Genetic deletion of PKR or pharmacological inhibition of its kinase activity markedly increased bacterial loads, organ injury, and mortality in polymicrobial infection induced by cecal ligation and puncture (CLP). In contrast, PKR deficiency or inhibition did not affect bacterial loads, organ injury, or mortality when mice were systemically challenged with <i>Escherichia coli</i>, an abundant microbe in the gastrointestinal tract. PKR deficiency or inhibition markedly decreased the release of interleukin (IL)-1β after CLP. Defect in IL-1 signaling phenocopied PKR deficiency or inhibition in CLP-induced bacterial sepsis. Taken together, these findings identified a critical role of the PKR signaling pathway in antibacterial immunity.

scholarly journals A model-specific role of microRNA-223 as a mediator of kidney injury during experimental sepsis

2017 ◽  
Vol 313 (2) ◽  
pp. F553-F559 ◽  
Author(s):  
James F. Colbert ◽  
Joshay A. Ford ◽  
Sarah M. Haeger ◽  
Yimu Yang ◽  
Kyrie L. Dailey ◽  
...  
Keyword(s):  
Cecal Ligation ◽  
Kidney Injury ◽  
Organ Injury ◽  
Multiple Models ◽  
Infection Model ◽  
Experimental Sepsis ◽  
Bacterial Clearance ◽  
Cecal Ligation And Puncture ◽  
Slurry Injection

Sepsis outcomes are heavily dependent on the development of septic organ injury, but no interventions exist to interrupt or reverse this process. microRNA-223 (miR-223) is known to be involved in both inflammatory gene regulation and host-pathogen interactions key to the pathogenesis of sepsis. The goal of this study was to determine the role of miR-223 as a mediator of septic kidney injury. Using miR-223 knockout mice and multiple models of experimental sepsis, we found that miR-223 differentially influences acute kidney injury (AKI) based on the model used. In the absence of miR-223, mice demonstrated exaggerated AKI in sterile models of sepsis (LPS injection) and attenuated AKI in a live-infection model of sepsis (cecal ligation and puncture). We demonstrated that miR-223 expression is induced in kidney homogenate after cecal ligation and puncture, but not after LPS or fecal slurry injection. We investigated additional potential mechanistic explanations including differences in peritoneal bacterial clearance and host stool virulence. Our findings highlight the complex role of miR-223 in the pathogenesis of septic kidney injury, as well as the importance of differences in experimental sepsis models and their consequent translational applicability.

scholarly journals Evaluation the cardiopulmonary markers in cecal ligation and puncture induced sepsis in Wistar rats

2020 ◽  
Vol 6 (5) ◽  
Author(s):  
Tina Didari ◽  
Shokoufeh Hassani ◽  
Maryam Baeeri ◽  
Vida Kazemi ◽  
Mohammad Abdollahi ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Cecal Ligation ◽  
Myocardial Necrosis ◽  
Control Group ◽  
Sham Operation ◽  
Myeloperoxidase Activity ◽  
Cecal Ligation And Puncture ◽  
Necrosis Factor Alpha ◽  
Needle Size ◽  
Pathological Assessment

Objective: Sepsis is a clinical problem caused by host immune disability against pathogens. Rodent Cecal Ligation and Puncture (CLP) models mimic sepsis in humans. Gauges needle size in CLP is related to cytokine storm, inflammation, and organ failure. This study focus, for the first time, on precise and inexpensive biochemical markers to evaluate the difference of sepsis severity in the heart and lung tissues, one day after cecal ligation and puncture-induced sepsis with needle gauge 18 (G-18). Methods: Twelve adult male Wistar rats were randomly allocated into two groups of 6 animals. These groups include; sham operation as the control group and underwent CLP procedure with G-18. All rats were sacrificed 24 hours after CLP then lungs and heart samples were collected for biochemical and histological assessment. Following the procedure, reactive oxygen species (ROS), Myeloperoxidase Activity (MPO), Tumor Necrosis Factor-Alpha (TNF-α), High Mobility Group Box 1 (HMGB1), lactate generation, caspases (-3 and -9), gene expression of autophagy and cellular hypoxia and pathological assessment of both tissues were measured. Results: Increased level of ROS, MPO, pro-inflammatory cytokines, hyperlactatemia, caspases production, overexpression of hypoxia (PRKAA1 gene), and autophagy (MAP1LC3B gene) in the lungs were higher compared to heart 24 hours after the procedure. Moreover, hyperplasia of pneumocyte and inflammatory cells, and myocardial necrosis were found in the pathological assessment. Conclusion: The purpose of  study was to determine the severity of sepsis by means of cost effective and precise inflammatory markers. Our findings demonstrated that injury-related indicators in lungs meaningfully increased compared to heart 24 hours after CLP.

Cecal Ligation and Puncture Peritonitis Model Shows Decreased Nicotinic Acetylcholine Receptor Numbers in Rat Muscle 

1999 ◽  
Vol 91 (2) ◽  
pp. 448-460 ◽  
Author(s):  
Hiroshi Tsukagoshi ◽  
Toshihiro Morita ◽  
Kenichiro Takahashi ◽  
Fumio Kunimoto ◽  
Fumio Goto
Keyword(s):  
Systemic Inflammation ◽  
Nicotinic Acetylcholine Receptors ◽  
Cecal Ligation ◽  
Sham Operation ◽  
Cecal Ligation And Puncture ◽  
Nicotinic Acetylcholine ◽  
Anterior Tibial Muscle ◽  
Anterior Tibial ◽  
Alpha Bungarotoxin ◽  
Peritonitis Model

Background Although systemic inflammation is believed to cause upregulation of nicotinic acetylcholine receptors (nAchRs) in muscle, chronic infections such as Chagas' disease occasionally are complicated by myasthenia gravis. The authors investigated how a nonlethal cecal ligation and puncture (CLP) peritonitis model in rats could affect muscle nAchR. Methods On day 1, 4, 7, 14, or 21 after CLP or sham operation, nAchR binding was assayed in the anterior tibial muscle and diaphragm using [125I]alpha-bungarotoxin. The presence or absence of weakness, in vivo dose-response relationships for d-tubocurarine, and serum anti-nAchR antibody titers were assayed in separate experiments. Results Systemic inflammation was most severe during the first 4 to 5 days. Numbers of nAchRs were decreased in anterior tibial muscle on days 7, 14, and 21 after CLP, and in the diaphragm on days 7 and 14 (P &lt; 0.01). Both 50% and 90% blocking doses of d-tubocurarine) were lower in CLP rats than in sham-operated rats on days 7, 14, and 21 (P &lt; .05). Weakness was overt in approximately half of CLP rats at these times. Serum anti-nAchR antibody (0.7-1.4 nM) was detectable beginning on day 4 and continuing throughout the 21-day observation period in 58-67% of CLP rats. Conclusions During the recovery phase of injury, nonlethal CLP peritonitis resulted in downregulation of nAchR. However, further study is needed to determine the role of anti-nAchR antibodies in the development of decreased receptor numbers and impaired neuromuscular function.

Local Anesthetics Reduce Mortality and Protect against Renal and Hepatic Dysfunction in Murine Septic Peritonitis

2004 ◽  
Vol 101 (4) ◽  
pp. 902-911 ◽  
Author(s):  
George Gallos ◽  
Dean R. Jones ◽  
Samih H. Nasr ◽  
Charles W. Emala ◽  
H Thomas Lee
Keyword(s):  
Local Anesthetic ◽  
Local Anesthetics ◽  
Hepatic Dysfunction ◽  
Inflammatory Responses ◽  
Cecal Ligation ◽  
Organ Injury ◽  
Myeloperoxidase Activity ◽  
Cecal Ligation And Puncture ◽  
Markers Of Inflammation ◽  
Septic Peritonitis

Background Mortality from sepsis frequently results from multiple organ injury and dysfunction. Cecal ligation and puncture is an established murine model of septic peritonitis that produces septic shock characterized by an initial hyperinflammatory response. In addition to their anesthetic properties, local anesthetics have been shown to attenuate inflammatory responses both in vivo and in vitro. In the current study, the ability of local anesthetic infusions to protect against sepsis-induced mortality, as well as renal and hepatic dysfunction after cecal ligation and puncture, was investigated. Methods C57BL/6 mice received mini-osmotic pumps containing saline (vehicle), 10% lidocaine, or 1% bupivacaine and were subjected to cecal ligation and puncture. Twenty-four hours after cecal ligation and puncture, renal and hepatic functions were assessed as well as markers of inflammation (proinflammatory cytokine protein and mRNA concentrations and myeloperoxidase activity). Renal apoptosis and 7-day survival was also assessed. Results Mice treated with lidocaine or bupivacaine infusion showed improved survival and had significantly lower plasma creatinine, aspartate aminotransferase, and alanine aminotransferase concentrations compared with mice receiving vehicle alone. Significant reduction in plasma tumor necrosis factor-alpha and keratinocyte-derived chemokine, as well as reductions in myeloperoxidase activity, intracellular adhesion molecule-1 protein expression, mRNA concentrations of proinflammatory markers, and apoptosis were observed in renal cortices from both local anesthetic groups. Conclusions The current data demonstrate that local anesthetic infusions confer a protective effect in mice from septic peritonitis by attenuating the hyperacute inflammatory response. This suppression resulted in improved mortality and less progression to acute kidney and liver injury and dysfunction.

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.

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