Olaparib attenuates sepsis-induced acute multiple organ injury via ERK-mediated CD14 expression

2021 ◽  
pp. 153537022110156
Author(s):  
Zhixia Chen ◽  
Yihui Chen ◽  
Xianwei Jin ◽  
Ying Liu ◽  
Zhenzhen Shao ◽  
...  
Keyword(s):  
Sham Group ◽  
Cecal Ligation ◽  
Lavage Fluid ◽  
Peritoneal Macrophages ◽  
Multiple Organ ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Erk Activation ◽  
Tnf Α ◽  
Multiple Organ Injury

Sepsis is characterized by persistent systemic inflammation, which can cause multi-organ dysfunction. The poly polymerase-1 inhibitor olaparib possesses anti-inflammatory properties. This study aimed to assess the effects of olaparib (pre- and post-treatments) on sepsis, and to investigate whether it could suppress CD14 expression via the ERK pathway in polymicrobial sepsis and peritoneal macrophages models. Sepsis was induced by cecal ligation and puncture in C57BL/6 male mice. Fifty mice were randomly divided into five groups: The sham group was treated with vehicle or olaparib, the cecal ligation and puncture group with vehicle or with olaparib (5 mg/kg i.p.) 1 h before or 2 h after surgery. Olaparib pretreatment significantly improved the survival of septic mice ( P <  0.001). Pre- and post-treatment of mice with olaparib partly alleviated cecal ligation and puncture-induced organ injury by decreasing the amounts of the pro-inflammatory mediators TNF-α and IL-6 as well as bacterial burden in the serum, peritoneal lavage fluid, and organs ( P <  0.05). The protective effect of olaparib was associated with CD14 suppression via inhibition of ERK activation. Olaparib facilitated negative regulation of ERK-mediated CD14 expression, which may contribute to multi-organ injury in sepsis.

Interleukin-10 Gene Transfer: Prevention of Multiple Organ Injury in a Murine Cecal Ligation and Puncture Model of Sepsis

2006 ◽  
Vol 31 (1) ◽  
pp. 105-115 ◽  
Author(s):  
Burhan Kabay ◽  
Cetin Kocaefe ◽  
Atac Baykal ◽  
Hilmi Özden ◽  
Cengiz Baycu ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Cecal Ligation ◽  
Interleukin 10 ◽  
Multiple Organ ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Puncture Model ◽  
Multiple Organ Injury

scholarly journals Tripterygium glycoside improves regulatory T cells and attenuates acute organ dysfunction in septic mice

2021 ◽  
Vol 19 ◽  
pp. 205873922110008
Author(s):  
Xiaoming Zhang ◽  
Xiaojie Zhou
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cecal Ligation ◽  
Multiple Organ ◽  
Protective Effects ◽  
Cecal Ligation And Puncture ◽  
Mice Model ◽  
Tnf Α ◽  
Lung And Kidney ◽  
Pro Inflammatory Cytokines

Sepsis is a fatal infectious disease accompanied by multiple organ failure. Immune dysfunction and inflammatory response play an important role in the progression of the disease. Tripterygium glycoside (TG) has immune suppression and anti-inflammatory effects. Here, we investigated the effects of TG on cecal ligation and puncture (CLP)-induced sepsis. Septic mice model was induced by cecal ligation and puncture(CLP), after administration of TG, specimens are collected at designated time points. Histopathology changes of lung tissues and Kidney tissues were observed under light microscope, magnetic microbeads were used to isolate splenic CD4+CD25+ regulatory T cells (Tregs), and phenotypes were then analyzed by flow cytometry. ELISA method was employed to detect the concentrations of plasma TNF-α, IL-6, and IL-10. Nuclear p-NF-κB and Cytoplasmic IkB-a was detected by western blot. TG administration significantly alleviated lung and kidney inflammatory injury and improved the survival of septic mice. Furthermore, the suppressive function of regulatory T cells was enhanced and plasma expression of IL-10 was increased following TG treatment. The NF-B signaling pathway and secretion of plasma TNF-α and IL-6 was notably inhibited in septic mice treated with TG. TG exerts protective effects through improving regulatory T cells and attenuating pro-inflammatory cytokines in septic mice.

scholarly journals Divergent roles of endothelial NF-κB in multiple organ injury and bacterial clearance in mouse models of sepsis

2008 ◽  
Vol 205 (6) ◽  
pp. 1303-1315 ◽  
Author(s):  
Xiaobing Ye ◽  
Jianqiang Ding ◽  
Xiaozhou Zhou ◽  
Guoqian Chen ◽  
Shu Fang Liu
Keyword(s):  
Host Defense ◽  
Pathogenic Bacteria ◽  
Cecal Ligation ◽  
Endothelial Permeability ◽  
Neutrophil Infiltration ◽  
Nuclear Factor Κb ◽  
Multiple Organ ◽  
Organ Injury ◽  
Selective Blockade ◽  
Multiple Organ Injury

To define the roles of endothelial-intrinsic nuclear factor κB (NF-κB) activity in host defense and multiple organ injury in response to sepsis, we generated double transgenic (TG) mice (EC-rtTA/I-κBαmt) that conditionally overexpress a degradation-resistant form of the NF-κB inhibitor I-κBα (I-κBαmt) selectively on vascular endothelium. The EC-rtTA/I-κBαmt mice had no basal, but a relatively high level of doxycycline-inducible, I-κBαmt expression. I-κBαmt expression was detected in endothelial cells, but not in fibroblasts, macrophages, and whole blood cells, confirming that transgene expression was restricted to the endothelium. When subjected to endotoxemia, EC-rtTA/I-κBαmt mice showed endothelial-selective blockade of NF-κB activation, repressed expression of multiple endothelial adhesion molecules, reduced neutrophil infiltration into multiple organs, decreased endothelial permeability, ameliorated multiple organ injury, reduced systemic hypotension, and abrogated intravascular coagulation. When subjected to cecal ligation and puncture–induced sepsis, the TG mice had less severe multiple organ injury and improved survival compared with wild-type (WT) mice. WT and EC-rtTA/I-κBαmt mice had comparable capacity to clear three different pathogenic bacteria. Our data demonstrate that endothelial NF-κB activity is an essential mediator of septic multiple organ inflammation and injury but plays little role in the host defense response to eradicate invading pathogenic bacteria.

The selective guanylate cyclase inhibitor ODQ reduces multiple organ injury in rodent models of Gram-positive and Gram-negative shock

2001 ◽  
Vol 29 (8) ◽  
pp. 1599-1608 ◽  
Author(s):  
Kai Zacharowski ◽  
Reinhard Berkels ◽  
Antje Olbrich ◽  
Prabal K. Chatterjee ◽  
Salvatore Cuzzocrea ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Multiple Organ ◽  
Organ Injury ◽  
Rodent Models ◽  
Gram Positive ◽  
Gram Negative ◽  
Multiple Organ Injury ◽  
Negative Shock

scholarly journals Ubiquitin-Specific Protease 25 Aggravates Acute Pancreatitis and Acute Pancreatitis-Related Multiple Organ Injury by Destroying Tight Junctions Through Activation of The STAT3 Pathway

2022 ◽  
Vol 9 ◽  
Author(s):  
Zhengru Liu ◽  
Mingming Qi ◽  
Shan Tian ◽  
Qian Yang ◽  
Jian Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Tight Junctions ◽  
Multiple Organ ◽  
Organ Injury ◽  
Pancreatic Acinar Cells ◽  
Stat3 Pathway ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Multiple Organ Injury

Ubiquitin-specific protease 25 (USP25) plays an important role in inflammation and immunity. However, the role of USP25 in acute pancreatitis (AP) is still unclear. To evaluate the role of USP25 in AP, we conducted research on clinical AP patients, USP25wild-type(WT)/USP25 knockout (USP25−/−) mice, and pancreatic acinar cells. Our results showed that serum USP25 concentration was higher in AP patients than in healthy controls and was positively correlated with disease severity. AP patients’ serum USP25 levels after treatment were significantly lower than that at the onset of AP. Moreover, USP25 expression was upregulated in cerulein-induced AP in mice, while USP25 deficiency attenuates AP and AP-related multiple organ injury. In vivo and in vitro studies showed that USP25 exacerbates AP by promoting the release of pro-inflammatory factors and destroying tight junctions of the pancreas. We showed that USP25 aggravates AP and AP-related multiple organ injury by activating the signal transducer and activator of transcription 3 (STAT3) pathway. Targeting the action of USP25 may present a potential therapeutic option for treating AP.

scholarly journals Senkyunolide I Protects against Sepsis-Associated Encephalopathy by Attenuating Sleep Deprivation in a Murine Model of Cecal Ligation and Puncture

2021 ◽  
Vol 2021 ◽  
pp. 1-11
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 ◽  
Signaling Proteins ◽  
Cecal Ligation And Puncture ◽  
Inflammatory Signaling ◽  
Tnf Α ◽  
Senkyunolide I

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.

Sign in / Sign up

Export Citation Format

Share Document