scholarly journals Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Xiaoyan Wang ◽  
Danyong Liu ◽  
XiHe Zhang ◽  
LiuMing Yang ◽  
Zhengyuan Xia ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Edema ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Wild Type Mouse ◽  
Vascular Leakage ◽  
Inflammatory Disorder ◽  
Tnf Α

AbstractAcute lung injury (ALI) represents a frequent sepsis-induced inflammatory disorder. Mesenchymal stromal cells (MSCs) elicit anti-inflammatory effects in sepsis. This study investigated the mechanism of exosomes from adipose-derived MSCs (ADMSCs) in sepsis-induced ALI. The IL-27r−/− (WSX-1 knockout) or wild-type mouse model of sepsis was established by cecal ligation and puncture (CLP). The model mice and lipopolysaccharide (LPS)-induced macrophages were treated with ADMSC-exosomes. The content of Dil-labeled exosomes in pulmonary macrophages, macrophages CD68+ F4/80+ in whole lung tissues, and IL-27 content in macrophages were detected. The mRNA expression and protein level of IL27 subunits P28 and EBI3 in lung tissue and the levels of IL-6, TNF-α, and IL-1β were measured. The pulmonary edema, tissue injury, and pulmonary vascular leakage were measured. In vitro, macrophages internalized ADMSC-exosomes, and ADMSC-exosomes inhibited IL-27 secretion in LPS-induced macrophages. In vivo, IL-27 knockout attenuated CLP-induced ALI. ADMSC-exosomes suppressed macrophage aggregation in lung tissues and inhibited IL-27 secretion. ADMSC-exosomes decreased the contents of IL-6, TNF-α, and IL-1β, reduced pulmonary edema and pulmonary vascular leakage, and improved the survival rate of mice. Injection of recombinant IL-27 reversed the protective effect of ADMSC-exosomes on sepsis mice. Collectively, ADMSC-exosomes inhibited IL-27 secretion in macrophages and alleviated sepsis-induced ALI in mice.

α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

2012 ◽  
Vol 303 (10) ◽  
pp. F1443-F1453 ◽  
Author(s):  
Chung-Hsi Hsing ◽  
Chiou-Feng Lin ◽  
Edmund So ◽  
Ding-Ping Sun ◽  
Tai-Chi Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Histone H3 ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Effects ◽  
Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

scholarly journals Down-regulation of SNHG16 alleviates the acute lung injury in sepsis rats through miR-128-3p/HMGB3 axis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Junli Sun ◽  
Keke Xin ◽  
Chenghui Leng ◽  
Jianlin Ge
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Western Blot ◽  
Cell Viability ◽  
Inflammatory Diseases ◽  
Cecal Ligation ◽  
Inflammatory Factors ◽  
Lung Epithelial

Abstract Background Long noncoding RNAs contribute to various inflammatory diseases, including sepsis. We explore the role of small nucleolar RNA host gene 16 (SNHG16) in sepsis-mediated acute lung injury (ALI) and inflammation. Methods A sepsis-induced ALI rat model was constructed by the cecal ligation and perforation method. The profiles of SNHG16, miR-128-3p, and high-mobility group box 3 (HMGB3) were monitored by quantitative reverse transcription PCR and Western blot. The pathologic changes of lung tissues were evaluated by Hematoxylin–Eosin staining, immunohistochemistry, and dry and wet method. Meanwhile, the pro-inflammatory factors and proteins were determined by ELISA and Western blot. In contrast, a sepsis model in BEAS-2B was induced with lipopolysaccharide (LPS) to verify the effects of SNHG16/miR-128-3p/HMGB3 on lung epithelial cell viability and apoptosis. Results As a result, SNHG16 and HMGB3 were up-regulated, while miR-128-3p was down-regulated in sepsis-induced ALI both in vivo and in vitro. Inhibiting SNHG16 reduced the apoptosis and inflammation in the sepsis-induced ALI model. Overexpressing SNHG16 promoted LPS-mediated lung epithelial apoptosis and inhibited cell viability and inflammation, while miR-128-3p had the opposite effects. Mechanistically, SNHG16 targeted miR-128-3p and attenuated its expression, while miR-128-3p targeted the 3′ untranslated region of HMGB3. Conclusions Overall, down-regulating SNHG16 alleviated the sepsis-mediated ALI by regulating miR-128-3p/HMGB3.

scholarly journals BMX Represses Thrombin-PAR1–Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis

2020 ◽  
Vol 126 (4) ◽  
pp. 471-485 ◽  
Author(s):  
Zhao Li ◽  
Mingzhu Yin ◽  
Haifeng Zhang ◽  
Weiming Ni ◽  
Richard W. Pierce ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cecal Ligation ◽  
Endothelial Permeability ◽  
Vascular Leakage ◽  
Lung Epithelial Cells ◽  
Negative Regulator ◽  
Cecal Ligation And Puncture ◽  
Early Sepsis

Rationale: BMX (bone marrow kinase on the X chromosome) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown. Objective: We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture models. Methods and Results: The cecal ligation and puncture model was applied to WT (wild type) and BMX-KO (BMX global knockout) mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect transendothelial electrical resistance in vitro and, the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early cecal ligation and puncture–induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells by 2- to 3-fold. The expression of BMX in macrophages, neutrophils, platelets, and lung epithelial cells was undetectable compared with that in endothelial cells, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-PAR1 (protease-activated receptor-1) signaling in endothelial cells by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pretreatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early cecal ligation and puncture–induced sepsis. Conclusions: Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.

scholarly journals Osthole Protects against Acute Lung Injury by Suppressing NF-κB-Dependent Inflammation

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Yiyi Jin ◽  
Jianchang Qian ◽  
Xin Ju ◽  
Xiaodong Bao ◽  
Li Li ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Nuclear Translocation ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Peritoneal Macrophages ◽  
Anti Inflammatory

Inflammation is a key factor in the pathogenesis of ALI. Therefore, suppression of inflammatory response could be a potential strategy to treat LPS-induced lung injury. Osthole, a natural coumarin extract, has been reported to protect against acute kidney injury through an anti-inflammatory mechanism, but its effect on ALI is poorly understood. In this study, we investigated whether osthole ameliorates inflammatory sepsis-related ALI. Results from in vitro studies indicated that osthole treatment inhibited the LPS-induced inflammatory response in mouse peritoneal macrophages through blocking the nuclear translocation of NF-κB. Consistently, the in vivo studies indicated that osthole significantly prolonged the survival of septic mice which was accompanied by inflammation suppression. In the ALI mouse model, osthole effectively inhibited the development of lung tissue injury, leukocytic recruitment, and cytokine productions, which was associated with inhibition of NF-κB nuclear translocation. These findings provide evidence that osthole was a potent inhibitor of NF-κB and inflammatory injury and suggest that it could be a promising anti-inflammatory agent for therapy of septic shock and acute lung injury.

scholarly journals TGF-β-R2 is required for HBP induced acute lung injury and vascular leakage for TGF-[beta]/Smad/Rho signaling pathway activation

2022 ◽  
Author(s):  
Zixuan Liu ◽  
Mingming Chen ◽  
Yini Sun ◽  
Xu Li ◽  
Liu Cao ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Vascular Leakage ◽  
Polymorphonuclear Neutrophils ◽  
Heparin Binding

Heparin-binding protein (HBP), as a granule protein secreted by polymorphonuclear neutrophils (PMNs) participates in the pathophysiological process of sepsis. It has been reported that HBP is a biomarker of sepsis, which is related to the severity of septic shock and organ dysfunction. HBP binds to vascular endothelial cells as one of the primary target sites. However, it is still unclear whether HBP-binding protein receptors exist on the surface of ECs. The effect of HBP on vascular permeability in sepsis and its mechanism needs to be explored. We conducted in vivo and in vitro study. We demonstrated that HBP bound to transforming growth factor-β receptor type 2 (TGF-β-R2) as a ligand. GST pull-down analysis reveals that HBP mainly interacts with the extracellular domain of TGF-β-R2. HBP induced acute lung injury (ALI) and vascular leakage via activation of TGF-β/SMAD2/3 signaling pathway. Permeability assay suggests TGF-β-R2 is necessary for HBP-induced increased permeability. We also defined the role of HBP and its potential membrane receptor TGF-β-R2 in the blood-gas barrier in the pathogenesis of HBP-related ALI.

scholarly journals Human Umbilical Cord-Derived Mesenchymal Stem Cells Alleviate Acute Lung Injury Caused by Severe Burn via Secreting TSG-6 and Inhibiting Inflammatory Response

2021 ◽  
Author(s):  
Xiaohong Hu ◽  
Lingying Liu ◽  
Yu Wang ◽  
Zhongyuan Li ◽  
Yonghui Yu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Function ◽  
Human Umbilical Cord ◽  
Ct Scanner ◽  
Severe Burn ◽  
Positive Effects ◽  
Tnf Α ◽  
Anti Inflammatory Cytokine

Abstract Objectives To investigate whether hUC-MSCs attenuated severe burn-induced ALI and the effects were based on TSG-6 secreted from hUC-MSCs. Method Rat model was established and evaluated as follows：Anires2005 animal pulmonary function tester for pulmonary function; micro-CT scanner for lung imaging manifestations; cytokine expression was measured by ELISA assay, and both inflammatory cell infiltration and lung injury were assessed by immunohistochemistry assay. Results In vitro, TSG-6 levels in serum from the burn group were significantly increased than that of the sham group. In vivo, TSG-6 levels of lung tissues and serum in the burn+ hUC-MSCs group were significantly increased than those of that in the burn group. Higher parameters of airway resistance（Ri, Re, etc）were markedly decreased, and the disordered lung texture and funicular density shadows were significantly improved after hUC-MSCs administration. Both in lung tissues and serum, increased levels of proinflammatory cytokines（TNF-α, IL-1β, IL-6）were remarkably decreased, but anti-inflammatory cytokine IL-10 increased after hUC-MSCs administration (p<0.05). These significant positive effects after hUC-MSCs transplantation did not occur in the Burn+siTSG-6 group. Conclusion Intra-tracheal implantation of hUC-MSCs has been an effective treatment for severe burn-induced ALI via promoting TSG-6 secretion and inhibiting inflammatory reaction in lung tissue.

scholarly journals TNF-α Induces Neutrophil Apoptosis Delay and Promotes Intestinal Ischemia-Reperfusion-Induced Lung Injury through Activating JNK/FoxO3a Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Daili Chen ◽  
Chaojin Chen ◽  
Xue Xiao ◽  
Ziyan Huang ◽  
Xiaolei Huang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Inflammatory Factors ◽  
Causative Factors ◽  
Tnf Α ◽  
Intestinal Ischemia Reperfusion ◽  
Injury Status

Background. Intestinal ischemia is a common clinical critical illness. Intestinal ischemia-reperfusion (IIR) leads to acute lung injury (ALI), but the causative factors of ALI are unknown. The aim of this study was to reveal the causative factors and mechanisms of IIR-induced lung injury. Methods. A mouse model of IIR was developed using C57BL/6 mice, followed by detection of lung injury status and plasma levels of inflammatory factors in sham-operated mice and model mice. Some model mice were treated with a tumor necrosis factor-α (TNF-α) inhibitor lenalidomide (10 mg/kg), followed by observation of lung injury status through hematoxylin and eosin staining and detection of neutrophil infiltration levels through naphthol esterase and Ly6G immunohistochemical staining. Additionally, peripheral blood polymorphonuclear neutrophils (PMNs) were cultured in vitro and then stimulated by TNF-α to mimic in vivo inflammatory stimuli; this TNF-α stimulation was also performed on PMNs after knockdown of FoxO3a or treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125. PMN apoptosis after stimulation was detected using flow cytometry. Finally, the role of PMN apoptosis in IIR-induced lung injury was evaluated in vivo by detecting the ALI status in the model mice administered with ABT-199, a Bcl-2 inhibitor. Results. IIR led to pulmonary histopathological injury and increased lung water content, which were accompanied by increased plasma levels of inflammatory factors, with the TNF-α plasma level showing the most pronounced increase. Inhibition of TNF-α led to effective reduction of lung tissue injury, especially that of the damaging infiltration of PMNs in the lung. In vitro knockdown of FoxO3a or inhibition of JNK activity could inhibit TNF-α-induced PMN apoptosis. Further in vivo experiments revealed that ABT-199 effectively alleviated lung injury and decreased inflammation levels by promoting PMN apoptosis during IIR-induced lung injury. Conclusion. TNF-α activates the JNK/FoxO3a pathway to induce a delay in PMN apoptosis, which promotes IIR-induced lung injury.

Downregulation of blood and bone marrow neutrophils decreases expression of acute lung injury in sheep

1992 ◽  
Vol 263 (5) ◽  
pp. H1492-H1498
Author(s):  
P. J. McKenna ◽  
D. L. Rosolia ◽  
Y. Ishihara ◽  
K. H. Albertine ◽  
N. C. Staub ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Peripheral Blood ◽  
Pulmonary Circulation ◽  
Tissue Injury ◽  
Blood Neutrophils ◽  
Superoxide Release

We have shown that infusion of zymosan-activated plasma (ZAP) in sheep causes acute lung injury and downregulates peripheral blood neutrophils in that elicited superoxide release is reduced for at least 24 h after the infusion. The present study was designed to test the following hypotheses: 1) peripheral blood neutrophils are representative of neutrophils marginated in the pulmonary circulation, 2) blood neutrophils are downregulated because neutrophils developing in bone marrow are similarly affected, and 3) downregulated neutrophils have a reduced capacity to produce tissue injury. In a series of experiments in 21 sheep, we showed that elicited superoxide release was similar in peripheral blood neutrophils and in marginated neutrophils washed out of the pulmonary vascular bed. Measurements of superoxide release from blood and bone marrow neutrophils collected 2-24 h after ZAP infusion revealed progressive downregulation with time and greater downregulation of superoxide release in bone marrow neutrophils compared with peripheral blood neutrophils. Finally, after downregulating peripheral blood neutrophils, subsequent infusion of ZAP in conscious sheep produced sequestration of neutrophils in the pulmonary circulation but failed to produce a sustained increase in lung lymph protein clearance. The results suggest that neutrophil downregulation, as measured in vitro, is expressed in vivo as reduced ability of neutrophils to produce tissue injury when challenged by an activating agent.

scholarly journals Exosomes Derived From Alveolar Epithelial Cells Promote Alveolar Macrophage Activation Mediated by miR-92a-3p in Sepsis-Induced Acute Lung Injury

2021 ◽  
Vol 11 ◽  
Author(s):  
Fen Liu ◽  
Wei Peng ◽  
Jiaquan Chen ◽  
Zeyao Xu ◽  
Rong Jiang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Pulmonary Inflammation ◽  
Cecal Ligation ◽  
Alveolar Epithelial Cells ◽  
Luciferase Reporter ◽  
Alveolar Epithelial

Acute lung injury (ALI) induced by sepsis is characterized by disruption of the epithelial barrier and activation of alveolar macrophages (AMs), which leads to uncontrolled pulmonary inflammation. However, effective treatments for ALI are unavailable. The exact mechanism by which the initial mediator of alveolar epithelial cells (AECs) induces inflammation remains elusive. Here we investigated the roles of AEC-derived exosomes in AM activation and sepsis-induced ALI in vivo and in vitro. Cecal ligation and puncture (CLP) was utilized to establish septic lung injury model in rats. The effect of exosomal inhibition by intratracheal GW4869 administration on lung injury was investigated. To assess the effects of AEC-derived exosomes on ALI, we treated the rat alveolar epithelial cell line RLE-6TN with LPS to induce cell damage. Exosomes from conditioned medium of LPS-treated AECs (LPS-Exos) were isolated by ultracentrifugation. The miRNAs in LPS-Exos were screened by miRNA expression profile analysis. The effects of miR-92a-3p on the function of AMs were studied. We found that intratracheal GW4869 administration ameliorated lung injury following CLP-induced ALI. LPS-Exos were taken up by AMs and activated these cells. Consistently, administration of LPS-Exos in rats significantly aggravated pulmonary inflammation and alveolar permeability. Moreover, miR-92a-3p was enriched in LPS-Exos and could be delivered to AMs. Inhibition of miR-92a-3p in AECs diminished the proinflammatory effects of LPS-Exos in vivo and in vitro. Mechanistically, miR-92a-3p activates AMs along with pulmonary inflammation. This process results in activation of the NF-κB pathway and downregulation of PTEN expression, which was confirmed by a luciferase reporter assay. In conclusion, AEC-derived exosomes activate AMs and induce pulmonary inflammation mediated by miR-92a-3p in ALI. The present findings revealed a previously unidentified role of exosomal miR-92a-3p in mediating the crosstalk between injured AEC and AMs. miR-92a-3p in AEC exosomes might represent a novel diagnostic biomarker for ALI, which may lead to a new therapeutic approach.

scholarly journals Chemokine C10 Promotes Disease Resolution and Survival in an Experimental Model of Bacterial Sepsis

2000 ◽  
Vol 68 (11) ◽  
pp. 6108-6114 ◽  
Author(s):  
M. L. Steinhauser ◽  
C. M. Hogaboam ◽  
A. Matsukawa ◽  
N. W. Lukacs ◽  
R. M. Strieter ◽  
...  
Keyword(s):  
Host Defense ◽  
Cecal Ligation ◽  
Peritoneal Macrophages ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Monocyte Chemoattractant Protein 1 ◽  
Tnf Α ◽  
Septic Peritonitis

ABSTRACT Previous studies have suggested that the C-C chemokine C10 is involved in the chronic stages of host defense reactions. The present study addressed the role of C10 in a murine model of septic peritonitis, induced by cecal ligation and puncture (CLP). Unlike other C-C chemokines, C10 levels in the peritoneal wash were increased approximately 30-fold above baseline levels at 48 h after CLP surgery. Immunoneutralization of peritoneal C10 levels with polyclonal anti-C10 antiserum during CLP-induced peritonitis negatively impacted mouse survival over 4 days. In contrast, when 500 ng of recombinant murine C10 was administered immediately after CLP surgery, the 4-day survival rate increased from 20% to over 60%. The C10 therapy appeared to facilitate a rapid and significant enhancement of the levels of tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) and a later increase in interleukin-13 (IL-13) levels in the peritoneal cavity. In vitro studies showed that the combination of IL-1β and C10 markedly augmented TNF-α synthesis by peritoneal macrophages and that C10 synthesis was induced in these cells following their exposure to IL-13. At 24 h after CLP surgery, only 25% of C10-treated mice were bacteremic versus 85% of the control group that exhibited dissemination of bacteria into the circulation. The lack of bacteremia in C10-treated mice appeared to be related, in part, to in vitro evidence that C10 significantly enhanced the bacterial phagocytic activity of peritoneal macrophages. In addition, in vivo evidence suggested that C10 therapy significantly reduced the amount of material that leaked from the damaged gut. Taken together, the results of this study demonstrate that the C10 chemokine rapidly promotes disease resolution in the CLP model through its direct effects on the cellular events critically involved in host defense during septic peritonitis.

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