H2S Increases Survival during Sepsis: Protective Effect of CHOP Inhibition

Ferlito, Marcella; Wang, Qihong; Fulton, William B.; Colombani, Paul; Marchionni, Luigi; Fox-Talbot, Karen; Paolocci, Nazareno; Steenbergen, Charles

doi:10.4049/jimmunol.1300835

Cited by 67 publications

(63 citation statements)

References 63 publications

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“…Previous studies have documented that elevated H 2 S suppress inflammatory response on macrophages or mouse to maintain immune homeostasis [24][25][26]. In this study, we identified Nox4-ROS as a key signaling pathway that exaggerated inflammatory response in macrophages or septic mouse.…”

Section: Discussionmentioning

confidence: 68%

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Wang

Pan

Long

et al. 2018

Cell Physiol Biochem

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Background/Aims: Sepsis is a severe and complicated syndrome that is characterized by dysregulation of host inflammatory responses and organ failure. Cystathionine-γ-lyase (CSE)/ hydrogen sulfide (H₂S) has potential anti-inflammatory activities in a variety of inflammatory diseases. NADPH oxidase 4 (Nox4), a member of the NADPH oxidases, is the major source of reactive oxygen species (ROS) and its expression is increased in sepsis, but its function in CSE-mediated anti-inflammatory activities remains unknown. Methods: Macrophages were either transfected with CSE, Nox4 siRNA or transduced with lentiviral vector encoding CSE or Nox4, and then stimulated with lipopolysaccharide (LPS). The expression of inflammatory mediators and signaling pathway activation were measured by quantitative PCR (qPCR), ELISA, and immunoblotting. LPS-induced shock severity in WT, Nox4 knockdown and CSE knockout (CSE^-/-) mice was assessed. Results: Here we showed that CSE and Nox4 were upregulated in macrophage and mouse in response to LPS. After LPS stimulation, the inflammatory responses were significantly ameliorated by lentiviral Nox4 shRNA knockdown, but were exacerbated by lentiviral overexpressing Nox4. Furthermore, Nox4 mediated inflammation through PI3K/Akt and p-p38 mitogen-activated protein kinase signal pathway. Notably, CSE knockout served to amplify the inflammatory cascade by increasing Nox4-ROS signaling activation in septic mice and macrophage. Similarly, the enhanced production of inflammatory mediators by macrophages was reduced by CSE overexpression. Conclusion: Thus, we demonstrated that CSE/H₂S attenuated LPS-induced sepsis against oxidative stress and inflammation damage probably largely through mediated Nox4 pathway.

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Section: Discussionmentioning

confidence: 68%

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Wang

Pan

Long

et al. 2018

Cell Physiol Biochem

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“…New researches on ER stress signaling have recently revealed a new and fascinating interaction between ER stress and sepsis associated cell death [80-83]. Recently, a number of investigators have reported that the suppression of ER stress stabilizes protein conformation, facilitates the trafficking of mutant proteins, and improves ER folding capacity and suggested that ER stress is a potential therapeutic target for various diseases including diabetes, cystic fibrosis, sepsis, trauma and hemorrhage and ischemic injuries of brain, kidney spinal cords and liver [84-87].…”

Section: Introductionmentioning

confidence: 99%

“…Transcription factor CHOP is a major inducer of apoptosis in response to ER stress, however, recent evidences suggested an inflammatory role of CHOP as a mediator of the inflammatory response in sepsis. Recently, Ferlito and his colleagues reported that septic mice exhibited increased expression of CHOP and treatment with H 2 S increased the survival rate in an experimental model of sepsis by inhibiting the CHOP expression, suggesting the participation of ER stress in sepsis [80]. They have highlighted a major role for CHOP, which act as an amplifier of the inflammatory response in the pathogenesis of sepsis, and the ability of H 2 S treatment to counter CHOP signaling via upregulation of Nrf2 [80].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Ferlito and his colleagues reported that septic mice exhibited increased expression of CHOP and treatment with H 2 S increased the survival rate in an experimental model of sepsis by inhibiting the CHOP expression, suggesting the participation of ER stress in sepsis [80]. They have highlighted a major role for CHOP, which act as an amplifier of the inflammatory response in the pathogenesis of sepsis, and the ability of H 2 S treatment to counter CHOP signaling via upregulation of Nrf2 [80]. Moreover, the ER stress pathway involving CHOP is activated in immunostimulated macrophages, suggesting an important role for this response in the pathogenesis of LPS-induced inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic Reticulum Stress in Sepsis

Khan

Yang

Wang

2015

Shock

115

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Sepsis is an enormous public health issue and the leading cause of death in critically ill patients in intensive care units (ICU). Overwhelming inflammation, characterized by cytokine storm, oxidative threats, and neutrophil sequestration is an underlying component of sepsis-associated organ failure. Despite recent advances in sepsis research, there is still no effective treatment available beyond the standard of care and supportive therapy. To reduce sepsis-related mortality, a better understanding of the biological mechanism associated with the sepsis is essential. Endoplasmic reticulum (ER), a subcellular organelle is responsible for the facilitation of protein folding and assembly and involved in several other physiological activities. Under the stress and inflammation condition, ER loses the homeostasis in its function, which is termed as ER stress. During ER stress, unfolded protein response (UPR) is activated to restore ER function to its normal balance. However, once the stress is beyond the compensatory capacity of UPR or protracted, the apoptosis would be initiated by triggering cell injuries, even to cell death. As such, ER stress and UPR are reported to be implicated in several pathological and inflammatory conditions. Although the detrimental role of ER stress during infections has been demonstrated, there is growing evidences that ER stress participate in the pathogenesis of sepsis. In this review, we summarize the current research in the context of ER stress and UPR signaling associated with sepsis and its related clinical conditions, such as trauma- hemorrhage, and ischemia/reperfusion (I/R) injury. We also discuss the potential implication of ER stress as a novel therapeutic target and prognostic marker in patients with sepsis.

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“…On the other hand, Endo et al found that the ER stress pathway involving CHOP was activated and played a role in the pathogenesis of septic organ injury [37] . Interestingly, a recent study also demonstrated that CHOP inhibition effectively decreased the organ damage and increased the overall survival rate in septic mice [43] . Thus, it is worthwhile to further investigate BBR's potent therapeutic effect on septic organ injury with a focus on CHOP.…”

Section: Wwwchinapharcom Zhao Gl Et Almentioning

confidence: 98%

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress

et al. 2016

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Aim: Berberine (BBR), an isoquinoline-derived alkaloid isolated from Rhizoma coptidis, exerts cardioprotective effects. Because endoplasmic reticulum (ER) stress plays a pivotal role in myocardial ischemia/reperfusion (MI/R)-induced apoptosis, it was interesting to examine whether the protective effects of BBR resulted from modulating ER stress levels during MI/R injury, and to define the signaling mechanisms in this process. Methods: Male rats were treated with BBR (200 mg·kg -1 ·d -1 , ig) for 2 weeks, and then subjected to MI/R surgery. Cardiac dimensions and function were assessed using echocardiography. Myocardial infarct size and apoptosis was examined. Total serum LDH levels and CK activities, superoxide production, MDA levels and the antioxidant SOD activities in heart tissue were determined. An in vitro study was performed on cultured rat embryonic myocardium-derived cells H9C2 exposed to simulated ischemia/reperfusion (SIR). The expression of apoptotic, ER stress-related and signaling proteins were assessed using Western blot analyses. Results: Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage. Furthermore, pretreatment with BBR suppressed MI/R-induced ER stress, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues. Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues, and co-treatment with AG490, a specific JAK2/STAT3 inhibitor, blocked not only the protective effects of BBR, but also the inhibition of BBR on MI/R-induced ER stress. In H9C2 cells, treatment with BBR (50 μmol/L) markedly reduced SIR-induced cell apoptosis, oxidative stress and ER stress, which were abolished by transfection with JAK2 siRNA. Conclusion: BBR ameliorates MI/R injury in rats by activating the AK2/STAT3 signaling pathway and attenuating ER stress-induced apoptosis.Keywords: berberine; myocardial ischemia/reperfusion injury; apoptosis; ER stress; oxidative stress; JAK2/STAT3; AG490 Acta Pharmacologica Sinica (2016) 37: 354-367; doi: 10.1038/aps.2015 published online 25 Jan 2016 Original Article # These authors contributed equally to this work. * To whom correspondence should be addressed. E-mail yunwangww@163.com (Yun WANG);shiqiangyu210@126.com (Shi-qiang YU) Received 2015-08-26 Accepted 2015-11-20 IntroductionIschemic heart disease remains the leading cause of mortality and disability worldwide. Although timely reperfusion therapy is the primary treatment, reperfusion itself results in major cardiac damage, commonly referred to as myocardial ischemia/reperfusion (MI/R) injury [1,2] . The endoplasmic reticulum (ER) is a multifunctional organelle in eukaryotic cells, which participates in the biosynthesis and folding of proteins. MI/R injury is known to result in the accumulation of unfolded proteins in the ER, which causes a severe unfolded protein response (UPR). Persistent UPR eventually ...

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H2S Increases Survival during Sepsis: Protective Effect of CHOP Inhibition

Cited by 67 publications

References 63 publications

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Endogenous Hydrogen Sulfide Ameliorates NOX4 Induced Oxidative Stress in LPS-Stimulated Macrophages and Mice

Endoplasmic Reticulum Stress in Sepsis

Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress

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