scholarly journals miR-145a Regulation of Pericyte Dysfunction in a Murine Model of Sepsis

2020 ◽  
Vol 222 (6) ◽  
pp. 1037-1045 ◽  
Author(s):  
Yan Wu ◽  
Pengfei Li ◽  
Andrew J Goodwin ◽  
James A Cook ◽  
Perry V Halushka ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Systemic Disease ◽  
Survival Rates ◽  
Cecal Ligation ◽  
Microvascular Dysfunction ◽  
Vascular Leakage ◽  
Organ Injury ◽  
Mouse Lung ◽  
Friend Leukemia

Abstract Background Sepsis is a life-threatening systemic disease with severe microvascular dysfunction. Pericytes preserve vascular homeostasis. To our knowledge, the potential roles of microRNAs in sepsis-induced pericyte dysfunction have not been explored. Methods We determined lung pericyte expression of miR-145a in cecal ligation and puncture (CLP)–induced sepsis. Mouse lung pericytes were isolated and transfected with a miR-145a mimic, followed by stimulation with lipopolysaccharide (LPS). We measured inflammatory cytokine levels. To assess the functions of miR-145a in vivo, we generated a pericyte-specific miR-145a–knockout mouse and determined sepsis-induced organ injury, lung and renal vascular leakage, and mouse survival rates. We used RNA sequencing and Western blotting to analyze the signaling pathways regulated by miR-145a. Results CLP led to decreased miR-145a expression in lung pericytes. The miR-145a mimic inhibited LPS-induced increases in cytokines. In CLP-induced sepsis, pericytes lacking miR-145a exhibited increased lung and kidney vascular leakage and reduced survival rates. We found that miR-145a could suppress LPS-induced NF-κB activation. In addition, we confirmed that the transcription factor Friend leukemia virus integration 1 (Fli-1) is a target of miR-145a and that Fli-1 activates NF-κB signaling. Conclusion Our results demonstrated that pericyte miR-145a mediates sepsis-associated microvascular dysfunction, potentially by means of Fli-1–mediated modulation of NF-κB signaling.

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 New Soluble Angiopoietin Analog of C4BP-ANG1 Prevents Pathological Vascular Leakage

2020 ◽  
Author(s):  
Pan Liu ◽  
Michael Ryczko ◽  
Xinfang Xie ◽  
Aftab Taiyab ◽  
Heather Sheardown ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Vascular Inflammation ◽  
Vascular Leakage ◽  
Organ Injury ◽  
Complement Protein ◽  
C Terminus ◽  
Vascular Stability ◽  
Important Regulator

AbstractVascular leak is a key driver of organ injury in diseases such as Acute Respiratory Distress Syndrome caused by viruses, including COVID-19. Strategies that reduce enhanced permeability and vascular inflammation are promising therapeutic targets. Activation of the Angiopoietin-1 (Angpt1)-Tie2 tyrosine kinase signaling pathway is an important regulator of vascular quiescence. Here we describe the design and construction of a new soluble ANGPT1 mimetic that is a potent activator of endothelial Tie2 in vitro and in vivo. Using a chimeric fusion strategy, we replaced the extracellular matrix (ECM) binding and oligomerization domain of ANGPT1 with a heptameric scaffold derived from the C-terminus of serum complement protein C4-binding protein α (C4BP). We refer to this new fusion protein biologic as C4BP-ANG1, which forms a stable heptamer and induces TIE2 phosphorylation in cultured cells, and in the lung following i.v. injection of mice. Injection of C4BP-ANG1 ameliorates VEGF- and lipopolysaccharide-induced vascular leakage, in keeping with the known functions of Angpt1-Tie2 in maintaining quiescent vascular stability, and therefore is a promising candidate treatment for inflammatory endothelial dysfunction.

scholarly journals PRODUCTION OF FRIEND LEUKEMIA VIRUS IN A MOUSE LUNG CELL LINE

1967 ◽  
Vol 20 (3) ◽  
pp. 225-236 ◽  
Author(s):  
HIROSHI YOSHIKURA ◽  
YASUKO HIROKAWA ◽  
MASA-ATSU YAMADA ◽  
HARUO SUGANO
Keyword(s):  
Cell Line ◽  
Leukemia Virus ◽  
Mouse Lung ◽  
Friend Leukemia ◽  
Friend Leukemia Virus ◽  
Lung Cell Line

scholarly journals Beneficial effect of STAT3 decoy oligodeoxynucleotide transfection on organ injury and mortality in mice with cecal ligation and puncture-induced sepsis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Samar Imbaby ◽  
Naoyuki Matsuda ◽  
Kengo Tomita ◽  
Kohshi Hattori ◽  
Sailesh Palikhe ◽  
...  
Keyword(s):  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Signal Transducers ◽  
Significant Survival ◽  
Upstream Kinase ◽  
Stat3 Decoy

Abstract Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We investigated whether in vivo introduction of synthetic double-stranded STAT3 decoy oligodeoxynucleotides (ODNs) can provide benefits for reducing organ injury and mortality in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We found that STAT3 was rapidly activated in major end-organ tissues following CLP, which was accompanied by activation of the upstream kinase JAK2. Transfection of STAT3 decoy ODNs downregulated pro-inflammatory cytokine/chemokine overproduction in CLP mice. Moreover, STAT3 decoy ODN transfection significantly reduced the increases in tissue mRNAs and proteins of high mobility group box 1 (HMGB1) and strongly suppressed the excessive elevation in serum HMGB1 levels in CLP mice. Finally, STAT3 decoy ODN administration minimized the development of sepsis-driven major end-organ injury and led to a significant survival advantage in mice after CLP. Our results suggest a critical role of STAT3 in the sepsis pathophysiology and the potential usefulness of STAT3 decoy ODNs for sepsis gene therapy.

scholarly journals Cell-free transmission of Fv-4 resistance gene product controlling Friend leukemia virus-induced leukemogenesis: a unique mechanism for interference with viral infection

Blood ◽  
1995 ◽  
Vol 86 (4) ◽  
pp. 1557-1563 ◽  
Author(s):  
M Kitagawa ◽  
S Aizawa ◽  
H Kamisaku ◽  
H Ikeda ◽  
K Hirokawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mononuclear Cells ◽  
Specific Binding ◽  
Leukemia Virus ◽  
Spleen Cells ◽  
Peripheral Blood Mononuclear ◽  
Friend Leukemia ◽  
Bone Marrow Chimeras ◽  
Friend Leukemia Virus

Fv-4 is a mouse gene that dominantly confers resistance to infection by ecotropic murine leukemia virus (MuLV). We previously demonstrated that mixed radiation bone marrow chimeras containing Fv-4r-bearing BALB/c-Fv- 4Wr (C4W) bone marrow and Fv-4r-bearing C3H/He (C3H) bone marrow grafted into C3H recipient mice (C4W+C3H-->C3H) were resistant to Friend leukemia virus (FLV)-induced leukemogenesis, even when they contained as high as 70% C3H-derived cells. This indicates that FLV- sensitive C3H-derived cells are rendered refractory to infection and/or transformation with FLV when they coexist in mice with Fv-4r-bearing cells. To investigate the mechanism of Fv-4 resistance to FLV-induced leukemogenesis, we first examined the expression of Fv-4r env antigen in the peripheral blood mononuclear cells (PBMC) of these chimeras. The Fv-4r env antigen was present not only on C4W-derived cells, but also on Fv-4r-bearing C3H-derived cells in C4W+C3H-->C3H mixed bone marrow chimeras. The Fv-4r env antigen that binds to the cells surface of C3H cells was found in sera from normal C4W mice, C4W-->C3H chimeras, and C4W+C3H-->C3H mixed chimeras. The serum Fv-4r env antigen binds to ecotropic MuLV receptors, shown by specific binding to transfectant mink cells expressing ecotropic MuLV receptor, but not to parental mink cells. To determine whether the binding of Fv-4r env antigen to the putative MuLV receptors would block FLV infection, C3H thymocytes or spleen cells that had been preincubated with C4W serum were mixed with FLV and the subsequent production of MuLV specific antigens was examined. C3H thymocytes or spleen cells treated with C4W serum became refractory to binding by FLV. These results provide evidence that the Fv-4r env antigen is released from C4W-derived cells in vivo and binds to cells expressing surface receptors for ecotropic MuLV, thereby protecting them from infection with FLV. The implication of these findings for gene therapy of retrovirus-induced disease such as acquired immune deficiency syndrome (AIDS) is discussed.

scholarly journals Electrical Stimulation at the ST36 Acupoint Protects against Sepsis Lethality and Reduces Serum TNF Levels through Vagus Nerve- and Catecholamine-Dependent Mechanisms

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Albino Villegas-Bastida ◽  
Rafael Torres-Rosas ◽  
Lourdes Andrea Arriaga-Pizano ◽  
Javier Flores-Estrada ◽  
Altamirano Gustavo-Acosta ◽  
...  
Keyword(s):  
Vagus Nerve ◽  
Survival Rates ◽  
Cecal Ligation ◽  
Serum Levels ◽  
Organ Injury ◽  
Serum Samples ◽  
Sepsis Model ◽  
Significant Difference ◽  
Pharmacological Blockade ◽  
Necrosis Factor

Electrical vagus nerve (VN) stimulation during sepsis attenuates tumor necrosis factor (TNF) production through the cholinergic anti-inflammatory pathway, which depends on the integrity of the VN and catecholamine production. To characterize the effect of electroacupuncture at ST36 (EA-ST36) on serum TNF, IL-6, nitrite, and HMGB1 levels and survival rates, based on VN integrity and catecholamine production, a sepsis model was induced in rats using cecal ligation and puncture (CLP). The septic rats were subsequently treated with EA-ST36 (CLP+ST36), and serum samples were collected and analyzed for cytokines levels. The serum TNF, IL-6, nitrite, and HMGB1 levels in the CLP+ST36 group were significantly lower compared with the group without treatment, the survival rates were significantly higher (P<0.05), and the acute organ injury induced by CLP was mitigated by EA-ST36; however, when subdiaphragmatic vagotomy was performed, the serum levels of TNF in the CLP+ST36 group did not show a significant difference compared with the group without electrostimulation, and, similarly, no significant difference in serum TNF levels was found under the pharmacological blockade of catecholamines. These results suggest that in rats with CLP sepsis models EA-ST36 reduces serum TNF levels through VN- and atecholamine-dependent mechanisms.

scholarly journals Long-term culture of bone marrow-derived preleukemic cells from F-MuLV- infected mice

Blood ◽  
1986 ◽  
Vol 68 (1) ◽  
pp. 193-199
Author(s):  
JM Heard ◽  
B Sola ◽  
MA Martial ◽  
S Fichelson ◽  
S Gisselbrecht
Keyword(s):  
Bone Marrow ◽  
Cell Lines ◽  
Bone Marrow Cells ◽  
Leukemia Virus ◽  
Friend Leukemia ◽  
Normal Sensitivity ◽  
Friend Leukemia Virus

The replication-competent Friend leukemia virus (F-MuLV) induces leukemias involving three hematopoietic lineages after a latent period of several months. In an attempt to elucidate the early events of the leukemogenic process, we looked for a method allowing the isolation and the long term in vitro maintenance of preleukemic cells. When established as long-term cultures according to the technique described by Dexter et al, bone marrow cells obtained from 7/7 apparently healthy F-MuLV-infected preleukemic mice led to the accumulation of immature myeloblastic cells, and to the generation of permanent myeloblastic cell lines, which in most cases further became tumorigenic in preirradiated recipient animals. The delays required to obtain cell lines were shorter when the duration of the in vivo infection was longer, suggesting that these cells were committed into the leukemogenic pathway before their transfer into culture flasks. The myelomonocytic preleukemic cells exhibited normal sensitivity to purified preparations of CSFs, but acquired the capacity to grow in the absence of exogenous CSF stimulation. Examination of integrated provirus copies demonstrated that the preleukemic cell proliferation involved a single or a few clones which may progress in vitro from a preleukemic to a fully malignant stage without major modifications of the integrated provirus copies.

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.

scholarly journals The Roles of Traditional Chinese Medicine: Shen-Fu Injection on the Postresuscitation Care Bundle

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Qian Zhang ◽  
Chunsheng Li
Keyword(s):  
Cardiac Arrest ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Survival Rates ◽  
Spontaneous Circulation ◽  
Organ Injury ◽  
Care Bundle ◽  
Early Goal Directed Therapy ◽  
Postresuscitation Care

Survival rates following in-hospital and out-of-hospital cardiac arrests remain disappointingly low. Organ injury caused by ischemia and hypoxia during prolonged cardiac arrest is compounded by reperfusion injury that occurs when a spontaneous circulation is restored. A bundle of procedures, which may need to be administered simultaneously, is required. The procedures include prompt identification and treatment of the cause of cardiac arrest, as well as a definitive airway and ventilation together. Additional benefit is possible with appropriate forms of early goal-directed therapy and achieving therapeutic hypothermia within the first few hours, followed by gradual rewarming and ensuring glycaemic control to be within a range of 6 to 10 mmol/L. All these would be important and need to be continued for at least 24 hours. Previous studies have showed that the effects of Shen-Fu injection (SFI) are based on aconitine properties, supplemented by ginsenoside, which can scavenge free radicals, improve energy metabolism, inhibit inflammatory mediators, suppress cell apoptosis, and alleviate mitochondrial damage. SFI, like many other complex prescriptions of traditional Chinese medicine, was also found to be more effective than any of its ingredient used separately in vivo. As the postresuscitation care bundle is known to be, the present paper focuses on the role of SFI played on the postresuscitation care bundle.

Sign in / Sign up

Export Citation Format

Share Document