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

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.

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

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.

MiR‐155 regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis

2021 ◽  
Author(s):  
Avin Hawez ◽  
Dler Taha ◽  
Anwar Algaber ◽  
Raed Madhi ◽  
Milladur Rahman ◽  
...  
Keyword(s):  
Lung Injury ◽  
Abdominal Sepsis ◽  
Neutrophil Extracellular Trap ◽  
Trap Formation ◽  
Extracellular Trap

Attenuation of lung injury using simvastatin in a rat sepsis model

2012 ◽  
Vol 3 (1) ◽  
pp. 1
Author(s):  
Vítor Brasil Medeiros ◽  
Ítalo Medeiros de Azevedo ◽  
Amália Cínthia Meneses Rego ◽  
Irami Araújo-Filho ◽  
Marília Daniela Ferreira Carvalho ◽  
...  
Keyword(s):  
Lung Injury ◽  
Plasma Levels ◽  
Tissue Injury ◽  
Interleukin 1 ◽  
Cecal Ligation ◽  
Abdominal Sepsis ◽  
Saline Group ◽  
Male Wistar Rats ◽  
Group 2 ◽  
Group 1

Purpose: Considering that statins have pleiotrophic effects, we hypothesized that vimvastatin therapy could help in the setting of sepsis and lung injury. The aim of this study was to address the effect of simvastatin pretreatment on lung injury in rats with abdominal sepsis. Methods: Thirty male Wistar rats weighing 235±26g were used and distributed into the three groups: group 1, n=10 (sham), treated with oral injection of saline (10mL/Kg) 24 hs before and again immediately before surgery; group 2, n=10 (abdominal sepsis+saline), cecal ligation and puncture (CLP) and treatment with saline as group 1; group 3, n=10 (abdominal sepsis+simvastatin), CLP and treatment with oral injection (gavage) of 10mg/Kg of simvastatin suspension (10mg/ml) 24 hs before and again immediately before surgery. Commercial ELISA kits were used for measurement of tumor necrosis factor-alfa (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Lung tissue from all animals was studied with light microscopy to determine the distribution and amount of lung injury. Results: TNF-α plasma expression was significantly lower in rats treated with simvastatin (172.8±25 pg/mL) than in rats treated with 0.9% saline (298.5±63 pg/ml). IL-1 plasma levels showed a drastic decrease (53.3±7 pg/mL) in simvastatin treated rats, compared with the sepsis/saline group rats (127.6±28 pg/mL). The plasma levels of IL-6 in the sepsis/simvastatin treated rats (53.3±7 pg/mL) were lower than in sepsis/saline treated rats (134.6±15mL). In control rats the plasma cytokines were significantly less expressive (28.4±6) than in the other groups. Representative lung histology demonstrated marked inflammation characterized by abundant interstitial neutrophils and edema in group sepsis/saline. Induced inflammation was greatly reduced by simvastatin pretreatment. Conclusion: In conclusion, our data suggest that simvastatin protects the lung against tissue injury in abdominal sepsis via inhibition of cytokines expression.

YiQiFuMai Lyophilized Injection Attenuates Sepsis-Induced Acute Lung Injury via TLR4/Src/VE-cadherin/p120-catenin Signaling Pathway

2020 ◽  
Author(s):  
Xue-wei Pan ◽  
Li-xuan Xue ◽  
Qian-liu Zhou ◽  
Jia-zhi Zhang ◽  
Yu-jie Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Cecal Ligation ◽  
Inflammatory Cells ◽  
Underlying Mechanism ◽  
Lavage Fluid ◽  
Lung Edema ◽  
P120 Catenin

Abstract Background: Sepsis is a severe disorder leading to a clinically critical syndrome of multiple organ dysfunction syndrome. Most patients with sepsis will be associated with acute lung injury (ALI), which is an independent risk factors of organ failure and death in patients with sepsis at the same time. YiQiFuMai Lyophilized Injection (YQFM) is a modern traditional Chinese prescription preparation, which could ameliorate ALI induced by lipopolysaccharide (LPS) or fine particulate matter. The current study aimed to investigate the effect of YQFM on sepsis-induced ALI and the underlying mechanism.Methods: Male C57BL/6J mice were treated with cecal ligation and puncture (CLP) after tail intravenous injected with YQFM (1, 2 and 4 g/kg). The measurements of lung edema, evans blue leakage, myeloperoxidase content, inflammatory cells in bronchoalveolar lavage fluid, histopathological assay and expression of associated proteins were performed at 18 h after CLP.Results: The results illustrated that YQFM inhibited pulmonary edema and inflammatory response, thus ameliorated ALI in sepsis mice. Furthermore, the expression of TLR4 and phosphorylated Src was down-regulated, and the expression of p120-catenin and VE-cadherin was restored by YQFM administration.Conclusion: Our study suggested the therapeutic potential of YQFM on treating sepsis-induced ALI via regulating TLR4/Src/VE-cadherin/p120-catenin signaling pathway.

Role Of Neutrophil Extracellular Trap (NET) In Acute Lung Injury

2010 ◽  
Author(s):  
Mona Saffarzadeh ◽  
Markus A. Queisser ◽  
Christiane Jünemann ◽  
Klaus T. Preissner
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Neutrophil Extracellular Trap ◽  
Extracellular Trap

scholarly journals Human Resistin Promotes Neutrophil Proinflammatory Activation and Neutrophil Extracellular Trap Formation and Increases Severity of Acute Lung Injury

2014 ◽  
Vol 192 (10) ◽  
pp. 4795-4803 ◽  
Author(s):  
Shaoning Jiang ◽  
Dae Won Park ◽  
Jean-Marc Tadie ◽  
Murielle Gregoire ◽  
Jessy Deshane ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Neutrophil Extracellular Trap ◽  
Trap Formation ◽  
Extracellular Trap ◽  
Human Resistin

Proinflammatory role of neutrophil extracellular traps in abdominal sepsis

2014 ◽  
Vol 307 (7) ◽  
pp. L586-L596 ◽  
Author(s):  
Lingtao Luo ◽  
Su Zhang ◽  
Yongzhi Wang ◽  
Milladur Rahman ◽  
Ingvar Syk ◽  
...  
Keyword(s):  
Lung Injury ◽  
Peritoneal Cavity ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Neutrophil Extracellular Traps ◽  
Abdominal Sepsis ◽  
Extracellular Dna ◽  
Extracellular Traps ◽  
Proinflammatory Role

Excessive neutrophil activation is a major component in septic lung injury. Neutrophil-derived DNA may form extracellular traps in response to bacterial invasions. The aim of the present study was to investigate the potential role of neutrophil extracellular traps (NETs) in septic lung injury. Male C57BL/6 mice were treated with recombinant human (rh)DNAse (5 mg/kg) after cecal ligation and puncture (CLP). Extracellular DNA was stained by Sytox green, and NET formation was quantified by confocal microscopy and cell-free DNA in plasma, peritoneal cavity, and lung. Blood, peritoneal fluid, and lung tissue were harvested for analysis of neutrophil infiltration, NET levels, tissue injury, as well as CXC chemokine and cytokine formation. We observed that CLP caused increased formation of NETs in plasma, peritoneal cavity, and lung. Administration of rhDNAse not only eliminated NET formation in plasma, peritoneal cavity, and bronchoalveolar space but also reduced lung edema and tissue damage 24 h after CLP induction. Moreover, treatment with rhDNAse decreased CLP-induced formation of CXC chemokines, IL-6, and high-mobility group box 1 (HMGB1) in plasma, as well as CXC chemokines and IL-6 in the lung. In vitro, we found that neutrophil-derived NETs had the capacity to stimulate secretion of CXCL2, TNF-α, and HMGB1 from alveolar macrophages. Taken together, our findings show that NETs regulate pulmonary infiltration of neutrophils and tissue injury via formation of proinflammatory compounds in abdominal sepsis. Thus we conclude that NETs exert a proinflammatory role in septic lung injury.

scholarly journals Angelica Polysaccharide Ameliorates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 and NF-κB Signaling Pathways in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yan Zhu ◽  
Taocheng Meng ◽  
Aichen Sun ◽  
Jintao Li ◽  
Jinlai Li
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathways ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
Receptor Protein ◽  
Lung Edema ◽  
Caspase 1 ◽  
Tnf Α

Objective. This study aimed to explore the role of angelica polysaccharide (AP) in sepsis-induced acute lung injury (ALI) and its underlying molecular mechanism. Methods. A sepsis model of cecal ligation and puncture (CLP) in male BALB/C mice was used. Then, 24 h after CLP, histopathological changes in lung tissue, lung wet/dry weight ratio, and inflammatory cell infiltration were analyzed. Next, levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-18), as well as the activity of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH), were measured to assess the role of AP. The protein expression of NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3), ASC, and caspase-1 was detected by western blot. In addition, the expression of p-NF-κB p65 and NLRP3 was detected by immunohistochemistry. Results. AP treatment ameliorated CLP-induced lung injury and lung edema, as well as decreased the number of total cells, neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). AP reduced the levels of TNF-α, IL-1β, IL-6, and IL-18 in BALF, as well as in serum. Moreover, AP decreased MPO activity and MDA content, whereas increased SOD and GSH levels. AP inhibited the expression of p-NF-κB p65, p-IκBα, NLRP3, ASC, and caspase-1, while promoted IκBα expression. Conclusion. This study demonstrated that AP exhibits protective effects against sepsis-induced ALI by inhibiting NLRP3 and NF-κB signaling pathways in mice.

scholarly journals miR-20a attenuates acute lung injury in septic rats via targeting TLR4

2021 ◽  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Lung Tissue ◽  
Cecal Ligation ◽  
Normal Group ◽  
Lung Damage ◽  
Luciferase Reporter ◽  
Arterial Bleeding ◽  
Tnf Α

Background: Sepsis is most likely to cause lung damage in patients, and the detection rate and mortality rate are high. Here, we investigated the expression of miR-20a in sepsis-induced acute lung injury (ALI) rats and its effect on inflammatory response, and reveal its possible molecular mechanism. Method: The model of acute lung injury caused by sepsis in rats was established by cecal ligation and puncture. The expression of miR-20a in lung tissue was determined by RT-qPCR. Acute lung injury rats were injected with 5 nmol miR-20a agomir or agomir NC every day for 3 days. Rats were sacrificed by arterial bleeding and lung tissues were removed. Serum interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE staining was used to observe the pathology of lung tissue and calculate the pathological score of lung injury. Western blot to determine the level of TLR4 and nuclear transcription factor κB p65 (NF-κB p65) protein in lung tissue. The luciferase reporter assay was used to verify the binding effect of miR-20a on the 3 non-coding TLR4. Results: We found that compared with that in Normal group, the expression of miR-20a in lung tissues of rats with ALI was decreased (p < 0.05). In miR-20a agomir group, the plasma level of IL-1β, IL-6, and TNF-α was significantly lower than that in agomir NC group and ALI group (p < 0.05), while higher than those in Normal group (p < 0.05). The HE staining results showed that the pathological score of lung injury in rats in miR-20a agomir group was lower than that of agomir NC group and ALI group (p < 0.05). Compared with agomir NC group and ALI group, the expression of TLR4 and NF-κB p65 in miR-20a agomir group was decreased (p < 0.01). The luciferase reporting experiment confirmed that TLR4 was a target gene of miR-20a. Conclusion: To sum up, miR-20a exerts a protective effect on sepsis-induced ALI rats through its anti-inflammatory effect. The targeting of TLR4 by miR-20a may be an effective method to reduce the inflammatory response in sepsis-induced ALI.

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