Senkyunolide I protect against lung injury via inhibiting formation of neutrophil extracellular trap in a murine model of cecal ligation and puncture

Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis-associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide a sedative effect to improve sleep. However, its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP). Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6, and IL-1β. A fear conditioning test was performed, and the results showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, and p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in the hippocampus homogenate. Sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

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Activated Platelets Autocrine 5-Hydroxytryptophan Aggravates Sepsis-Induced Acute Lung Injury by Promoting Neutrophils Extracellular Traps Formation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.777989 ◽

2022 ◽

Vol 9 ◽

Author(s):

Yumeng Huang ◽

Qian Ji ◽

Yanyan Zhu ◽

Shengqiao Fu ◽

Shuangwei Chen ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Cecal Ligation ◽

Neutrophil Extracellular Trap ◽

Wild Type ◽

Specific Mechanism ◽

Extracellular Traps ◽

Activated Platelets ◽

Extracellular Trap ◽

Rate Limiting

Excessive neutrophil extracellular trap (NET) formation is an important contributor to sepsis-induced acute lung injury (ALI). Recent reports indicate that platelets can induce neutrophil extracellular trap formation. However, the specific mechanism remains unclear. Tph1 gene, which encodes the rate-limiting enzyme for peripheral 5-hydroxytryptophan (5-HT) synthesis, was knocked out in mice to simulate peripheral 5-HT deficiency. Cecal ligation and puncture (CLP) surgery was performed to induce sepsis. We found that peripheral 5-HT deficiency reduced NET formation in lung tissues, alleviated sepsis-induced lung inflammatory injury, and reduced the mortality rate of CLP mice. In addition, peripheral 5-HT deficiency was shown to reduce the accumulation of platelets and NETs in the lung of septic mice. We found that platelets from wild-type (WT), but not Tph1 knockout (Tph1−/−), mice promote lipopolysaccharide (LPS)-induced NET formation. Exogenous 5-HT intervention increased LPS-induced NET formation when Tph1−/− platelets were co-cultured with WT neutrophils. Therefore, our study uncovers a mechanism by which peripheral 5-HT aggravated sepsis-induced ALI by promoting NET formation in the lung of septic mice.

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Senkyunolide I Protects Against Sepsis-associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

10.21203/rs.3.rs-117431/v1 ◽

2020 ◽

Author(s):

Jian Xie ◽

Zhen-zhen Zhao ◽

Peng Li ◽

Cheng-long Zhu ◽

Yu Guo ◽

...

Keyword(s):

Sleep Deprivation ◽

Cognitive Dysfunction ◽

Murine Model ◽

Inflammatory Responses ◽

Cecal Ligation ◽

Tunel Staining ◽

Cecal Ligation And Puncture ◽

Inflammatory Signaling ◽

Tnf Α ◽

Senkyunolide I

Abstract Background: Sepsis may lead to sleep deprivation, which will promote the development of neuroinflammation and mediate the progression of sepsis associated encephalopathy (SAE). Senkyunolide I, an active component derived from an herb medicine, has been shown to provide sedative effect to improve sleep. But its role in sepsis is unclear. The present study was performed to investigate whether Senkyunolide I protected against SAE in a murine model of cecal ligation and puncture (CLP).Methods: The male C57BL/6 mice were used to investigate the effects of Senkyunolide I on SAE. The related protein of the sleep deprivation and inflammatory signaling pathway was detected by western blot. The activation of microglia and the neuronal apoptosis were separately detected by immunofluorescence staining and TUNEL staining.Results: Here, we showed that Senkyunolide I treatment improved the 7-day survival rate and reduced the excessive release of cytokines including TNF-α, IL-6 and IL-1β. A fear conditioning test was performed and the result showed that Senkyunolide I attenuated CLP-induced cognitive dysfunction. Senkyunolide I treatment also decreased the phosphorylation levels of inflammatory signaling proteins, including p-ERK, p-JNK, p-P38, p-P65, and the level of inflammatory cytokines, including TNF-α, IL-6 and IL-1β, in the hippocampus homogenate. The sleep deprivation was attenuated by Senkyunolide I administration, as demonstrated by the modification of the BDNF and c-FOS expression. When sleep deprivation was induced manually, the protective effect of Senkyunolide I against inflammatory responses and cognitive dysfunction was reversed. Conclusion: Our data demonstrated that Senkyunolide I could protect against sepsis-associated encephalopathy in a murine model of sepsis via relieving sleep deprivation.

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c-Abl kinase regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis

Laboratory Investigation ◽

10.1038/s41374-021-00683-6 ◽

2021 ◽

Author(s):

Avin Hawez ◽

Zhiyi Ding ◽

Dler Taha ◽

Raed Madhi ◽

Milladur Rahman ◽

...

Keyword(s):

Lung Injury ◽

Plasma Levels ◽

Kinase Inhibitor ◽

Cecal Ligation ◽

Abdominal Sepsis ◽

Lung Damage ◽

Neutrophil Extracellular Trap ◽

Lung Edema ◽

Abl Kinase ◽

Extracellular Trap

AbstractSepsis is associated with exaggerated neutrophil responses although mechanisms remain elusive. The aim of this study was to investigate the role of c-Abelson (c-Abl) kinase in neutrophil extracellular trap (NET) formation and inflammation in septic lung injury. Abdominal sepsis was induced by cecal ligation and puncture (CLP). NETs were detected by electron microscopy in the lung and by confocal microscopy in vitro. Plasma levels of DNA-histone complexes, interleukin-6 (IL-6) and CXC chemokines were quantified. CLP-induced enhanced phosphorylation of c-Abl kinase in circulating neutrophils. Administration of the c-Abl kinase inhibitor GZD824 not only abolished activation of c-Abl kinase in neutrophils but also reduced NET formation in the lung and plasma levels of DNA-histone complexes in CLP mice. Moreover, inhibition of c-Abl kinase decreased CLP-induced lung edema and injury. Administration of GDZ824 reduced CLP-induced increases in the number of alveolar neutrophils. Inhibition of c-Abl kinase also markedly attenuated levels of CXC chemokines in the lung and plasma as well as IL-6 levels in the plasma of septic animals. Taken together, this study demonstrates that c-Abl kinase is a potent regulator of NET formation and we conclude that c-Abl kinase might be a useful target to ameliorate lung damage in abdominal sepsis.

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Juglone Attenuates Sepsis-Induced Acute Lung Injury via Suppression of the TLR4/Nf-κb Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:201-206 ◽

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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Inactivation of Nf-κb Pathway by Taxifolin Attenuates Sepsis-Induced Acute Lung Injury

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:176-182 ◽

2019 ◽

Vol 18 (2) ◽

pp. 176-182

Author(s):

Chen Weiyan ◽

Deng Wujian ◽

Chen Songwei

Keyword(s):

Acute Lung Injury ◽

B Cells ◽

Lung Injury ◽

Signaling Pathway ◽

Light Chain ◽

Cecal Ligation ◽

Nuclear Factor ◽

Kappa Light Chain ◽

Cecal Ligation And Puncture ◽

Light Chain Enhancer

Acute lung injury is a clinical syndrome consisting of a wide range of acute hypoxemic respiratory failure disorders. Sepsis is a serious complication caused by an excessive immune response to pathogen-induced infections, which has become a major predisposing factor for acute lung injury. Taxifolin is a natural flavonoid that shows diverse therapeutic benefits in inflammation- and oxidative stress-related diseases. In this study, we investigated the role of taxifolin in a mouse model of cecal ligation and puncture-induced sepsis. Cecal ligation and puncture-operated mice presented damaged alveolar structures, thickened alveolar walls, edematous septa, and hemorrhage compared to sham-treated controls. Cecal ligation and puncture mice also showed increased wet-to-dry (W/D) lung weight ratio and elevated total protein concentration and lactate dehydrogenase level in bronchoalveolar lavage fluid. Taxifolin treatment protected animals against sepsis-induced pulmonary damage and edema. Septic mice presented compromised antioxidant capacity, whereas the administration of taxifolin prior to cecal ligation and puncture surgery decreased malondialdehyde concentration and enhanced the levels of reduced glutathione and superoxide dismutase in mice with sepsis-induced acute lung injury. Moreover, cecal ligation and puncture-operated mice showed markedly higher levels of proinflammatory cytokines relative to sham-operated group, while taxifolin treatment effectively mitigated sepsis-induced inflammation in mouse lungs. Further investigation revealed that taxifolin suppressed the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in cecal ligation and puncture-challenged mice by regulating the phosphorylation of p65 and IκBα. In conclusion, our study showed that taxifolin alleviated sepsis-induced acute lung injury via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, suggesting the therapeutic potential of taxifolin in the treatment sepsis-induced acute lung injury.

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Heme oxygenase-1 modulates thrombomodulin and activated protein c levels to attenuate lung injury in cecal ligation and puncture–induced acute lung injury mice

Experimental Lung Research ◽

10.3109/01902148.2012.660559 ◽

2012 ◽

Vol 38 (4) ◽

pp. 173-182 ◽

Cited By ~ 11

Author(s):

Dongsheng Fei ◽

Xianglin Meng ◽

Kai Kang ◽

Chuanchuan Nan ◽

Mingran Zhao ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Heme Oxygenase ◽

Protein C ◽

Cecal Ligation ◽

Activated Protein C ◽

Heme Oxygenase 1 ◽

Cecal Ligation And Puncture

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Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture

Journal of Surgical Research ◽

10.1016/j.jss.2014.10.027 ◽

2015 ◽

Vol 194 (2) ◽

pp. 528-536 ◽

Cited By ~ 19

Author(s):

Zhansheng Hu ◽

Zhilong Gu ◽

Meina Sun ◽

Ke Zhang ◽

Penghui Gao ◽

...

Keyword(s):

Lung Injury ◽

Ursolic Acid ◽

Cecal Ligation ◽

Cecal Ligation And Puncture

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Bilobalide Ameliorates Sepsis Induced Acute Lung Injury by Inactivating Toll-Like Receptor 4/Myeloid Differentiation Factor 88/Nuclear Factor-Kappa B Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:277-282 ◽

2020 ◽

Vol 19 (3) ◽

pp. 277-282

Author(s):

Tian Liu ◽

Siyi Jiang ◽

Shengwei Jia ◽

Fuxiang Fan

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Nuclear Factor Kappa B ◽

Cecal Ligation ◽

Myeloid Differentiation ◽

Nuclear Factor ◽

Cecal Ligation And Puncture ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Myeloid Differentiation Factor

Acute lung injury refers to the injury of alveolar epithelial cells and pulmonary capillary endothelial cells caused by noncardiac factors. To better combat the disease, there is an urgent need to develop more effective drugs. Sepsis is a syndrome of systemic inflammation caused by infection, and the molecular mechanism by which sepsis induces acute lung injury has not been clearly determined. Bilobalide is a unique component of Ginkgo biloba. Although it has multiple biological functions, its role in sepsis induced acute lung injury needs further study. In this study, we found that bilobalide alleviated cecal ligation and puncture induced acute lung injury. Additionally, bilobalide regulated cecal ligation and puncture induced lung injury through toll-like receptor 4/myeloid differentiation factor 88/nuclear factor-kappa B pathway. We therefore conclude that bilobalide may be a potential drug for the treatment of sepsis induced acute lung injury.

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