scholarly journals Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1211
Author(s):  
Dmytro Petukhov ◽  
Mark Richter-Dayan ◽  
Zvi Fridlender ◽  
Raphael Breuer ◽  
Shulamit B. Wallach-Dayan
Keyword(s):  
Lung Injury ◽  
Cell Motility ◽  
Tissue Regeneration ◽  
Nuclear Translocation ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Alveolar Epithelial Cells ◽  
P53 Signaling

CD44, an adhesion-molecule promoting cell-migration, is shown here to increase in stress conditions following bleomycin-induced apoptosis in alveolar epithelial cells (AECs), a main target of lung injury. In vivo, it inhibits tissue regeneration and leads to fibrosis. We show that some AECs survive by the ataxia-telangiectasia mutated kinase/ATM pathway, and undergo a CD44-mediated epithelial-mesenchymal transdifferentiation (EMT) with migratory capacities in vitro, and in vivo. We assessed apoptosis vs. proliferation of AECs following bleomycin, ATM/P53 signaling pathway in AECs, and CD44 involvement in EMT, cell motility and tissue regeneration in vitro and in vivo. Expression of survival genes, CD44, and ATM/p53 pathway was elevated in AECs surviving bleomycin injury, as were the markers of EMT (downregulation of E-cadherin, upregulation of N-cadherin and vimentin, nuclear translocation of β-catenin). Inhibition of CD44 decreased AECs transdifferentiation. Bleomycin-treated chimeric CD44KO-mice had decreased EMT markers, ATM, and mesenchymal cells (α-SMA+) accumulation in lung, increased surfactant-b, diminished lung mesenchymal cell motility, and increased lung tissue regenerative capacity following bleomycin injury, as indicated by lung collagen content and semiquantitave morphological index scoring. Thus, AECs surviving lung injury are plastic and undergo ATM-mediated, CD44-dependent transdifferentiation, preventing tissue regeneration and promoting fibrosis. Synthetic or natural compounds that downregulate CD44 may improve tissue regeneration following injury.

scholarly journals A Subanesthetic Dose of Isoflurane during Postconditioning Ameliorates Zymosan-Induced Neutrophil Inflammation Lung Injury and Mortality in Mice

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Hui Wang ◽  
Jing Fan ◽  
Nan-lin Li ◽  
Jun-tang Li ◽  
Shi-fang Yuan ◽  
...  
Keyword(s):  
Lung Injury ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Weight Ratio ◽  
Polymorphonuclear Neutrophils ◽  
Mouse Lung ◽  
Endothelial Adhesion Molecule ◽  
Primary Mouse

Anesthetic isoflurane (ISO) has immunomodulatory effects. In the present study, we investigated whether a subanesthetic dose of ISO (0.7%) protected against zymosan (ZY) induced inflammatory responses in the murine lung and isolated neutrophils. At 1 and 6 hrs after ZY administration intraperitoneally, ISO was inhaled for 1 hr, and 24 hrs later, lung inflammation and injury were assessed. We found that ISO improved the survival rate of mice and mitigated lung injury as characterized by the histopathology, wet-to-dry weight ratio, protein leakage, and lung function index. ISO significantly attenuated ZY-induced lung neutrophil recruitment and inflammation. This was suggested by the downregulation of (a) endothelial adhesion molecule expression and myeloperoxidase (MPO) activity in lung tissue and polymorphonuclear neutrophils (b) chemokines, and (c) proinflammatory cytokines in BALF. Furthermore, ZY-induced nuclear translocation and DNA-binding activity of NF-κB p65 were also reduced by ISO. ISO treatment inhibited iNOS expression and activity, as well as subsequent nitric oxide generation. Consistent with thesein vivoobservations,in vitrostudies confirmed that ISO blocked NF-κB and iNOS activation in primary mouse neutrophils challenged by ZY. These results provide evidence that 0.7% ISO ameliorates inflammatory responses in ZY-treated mouse lung and primary neutrophils.

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.

High glucose promotes nascent nephron apoptosis via NF-κB and p53 pathways

2011 ◽  
Vol 300 (1) ◽  
pp. F147-F156 ◽  
Author(s):  
Yun-Wen Chen ◽  
Isabelle Chenier ◽  
Shiao-Ying Chang ◽  
Stella Tran ◽  
Julie R. Ingelfinger ◽  
...  
Keyword(s):  
High Glucose ◽  
Nuclear Translocation ◽  
Dominant Negative ◽  
In Vivo Studies ◽  
Ros Generation ◽  
Small Interfering Rnas ◽  
Kidney Size ◽  
P53 Signaling

A hyperglycemic environment in utero reduces kidney size and nephron number due to nascent nephron apoptosis. However, the underlying mechanisms are incompletely understood. The present study investigated whether the nascent nephron apoptosis promoted by high glucose is mediated via the transcription factor NF-κB and p53 signaling pathways. Neonatal mouse kidneys from the offspring of nondiabetic, diabetic, and insulin-treated diabetic dams were used for in vivo studies, and MK4 cells, an embryonic metanephric mesenchymal (MM) cell line, were used for in vitro studies. Neonatal kidneys of the offspring of diabetic mothers exhibited an increased number of apoptotic cells and reactive oxygen species (ROS) generation, enhanced NF-κB activation, and nuclear translocation of its subunits (p50 and p65 subunits) as well as phosphorylation (Ser 15) of p53 compared with kidneys of offspring of nondiabetic mothers. Insulin treatment of diabetic dams normalized these parameters in the offspring. In vitro, high-glucose (25 mM) induced ROS generation and significantly increased MK4 cell apoptosis and caspase-3 activity via activation of NF-κB pathway, with p53 phosphorylation and nuclear translocation compared with normal glucose (5 mM). These changes in a high-glucose milieu were prevented by transient transfection of small interfering RNAs for dominant negative IκBα or IKK or p53. Our data demonstrate that high glucose-induced nascent nephron apoptosis is mediated, at least in part, via ROS generation and the activation of NF-κB and p53 pathways.

scholarly journals Nur77 attenuates endothelin-1 expression via downregulation of NF-κB and p38 MAPK in A549 cells and in an ARDS rat model

2016 ◽  
Vol 311 (6) ◽  
pp. L1023-L1035 ◽  
Author(s):  
Yujie Jiang ◽  
Yi Zeng ◽  
Xia Huang ◽  
Yueqiu Qin ◽  
Weigui Luo ◽  
...  
Keyword(s):  
Lung Injury ◽  
P38 Mapk ◽  
Rat Model ◽  
Nuclear Export ◽  
Nuclear Translocation ◽  
A549 Cells ◽  
Orphan Receptor ◽  
Endothelin 1

Acute respiratory distress syndrome (ARDS) is characterized by inflammatory injury to the alveolar and capillary barriers that results in impaired gas exchange and severe acute respiratory failure. Nuclear orphan receptor Nur77 has emerged as a regulator of gene expression in inflammation, and its role in the pathogenesis of ARDS is not clear. The objective of this study is to investigate the potential role of Nur77 and its underlying mechanism in the regulation of endothelin-1 (ET-1) expression in lipopolysaccharide (LPS)-induced A549 cells and an ARDS rat model. We demonstrate that LPS induced Nur77 expression and nuclear export in A549 cells. Overexpression of Nur77 markedly decreased basal and LPS-induced ET-1 expression in A549 cells, whereas knockdown of Nur77 increased the ET-1 expression. LPS-induced phosphorylation and nuclear translocation of NF-κB and p38 MAPK were blocked by Nur77 overexpression and augmented by Nur77 knockdown in A549 cells. In vivo, LPS induced Nur77 expression in lung in ARDS rats. Pharmacological activation of Nur77 by cytosporone B (CsnB) inhibited ET-1 expression in ARDS rats, decreased LPS-induced phosphorylation of NF-κB and p38 MAPK, and relieved lung, liver, and kidney injury. Pharmacological deactivation of Nur77 by 1,1-bis-(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH, C-DIM8) had no effect on ET-1 expression and lung injury. These results indicated that Nur77 decreases ET-1 expression by suppressing NF-κB and p38 MAPK in LPS-stimulated A549 cells in vitro, and, in an LPS-induced ARDS rat model, CsnB reduced ET-1 expression and lung injury in ARDS rats.

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.

In vivo mitogenic action of HGF on lung epithelial cells: pulmotrophic role in lung regeneration

1996 ◽  
Vol 270 (6) ◽  
pp. L1031-L1039 ◽  
Author(s):  
H. Ohmichi ◽  
K. Matsumoto ◽  
T. Nakamura
Keyword(s):  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Dna Synthesis ◽  
Airway Epithelial Cells ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Lung Regeneration

Hepatocyte growth factor (HGF) has mitogenic, morphogenic, and motogenic activities on epithelial cells and plays important roles in regeneration of the liver and the kidney. We previously found that the expression of HGF gene is rapidly induced in the lung after acute lung injury in experimental animals and that HGF levels are elevated in blood of patients with lung diseases. To search for a possible pulmotrophic function of HGF in lung regeneration, we examined the mitogenic activity of HGF on tracheal epithelial cells in vitro and evaluated the efficacy of HGF-administration on lung regeneration after acute lung injury in mice. HGF markedly stimulated proliferation and DNA synthesis of rat tracheal epithelial cells in primary culture in a dose-dependent manner. The intravenous injection of human recombinant HGF (10 micrograms.mouse-1.day-1) into mice with acute lung injury induced by the intratracheal infusion of 10 mM HCI stimulated DNA synthesis of airway epithelial cells to levels threefold higher than those in mice with no HGF-injections, but it did not stimulate DNA synthesis of alveolar epithelial cells. However, HGF injection at higher dose (100 micrograms.mouse-1.day-1) stimulated DNA synthesis of alveolar epithelial cells in vivo. These results indicate that HGF is a potent mitogen for airway epithelial cells and alveolar epithelial cells in vivo as well as in vitro. HGF may act as pulmotrophic factor responsible for airway and alveolar regeneration during lung regeneration after acute lung injury.

Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment

Blood ◽  
2006 ◽  
Vol 109 (3) ◽  
pp. 1298-1306 ◽  
Author(s):  
Fernando Anjos-Afonso ◽  
Dominique Bonnet
Keyword(s):  
Bone Marrow ◽  
Mesenchymal Cell ◽  
Cell Types ◽  
Mesenchymal Cells ◽  
Hierarchical Organization ◽  
Mesenchymal Progenitor Cells ◽  
Murine Bone Marrow

Abstract It is believed that a primitive cell type that maintains the mesenchymal compartment exists in the bone marrow. However, this putative mesenchymal stem/progenitor cell is yet to be identified and isolated. We are reporting the identification, isolation, and detailed characterization of the most primitive mesenchymal progenitor cells in the adult murine bone marrow, based on the expression of stage-specific embryonic antigen–1 (SSEA-1). This primitive subset can be identified in mesenchymal cell cultures and also directly in the bone marrow, thus ascertaining for the first time their existence in an adult organism. Characterization of SSEA-1+ mesenchymal cells revealed that upon purification these cells gave rise to SSEA-1− mesenchymal cells, whereas the reverse could not be observed. Also, these SSEA-1+ cells have a much higher capacity to differentiate than their negative counterparts, not only to several mesenchymal cell types but also to unconventional cell types such as astrocyte-, endothelial-, and hepatocyte-like cells in vitro. Most importantly, a single-cell–derived population was capable of differentiating abundantly into different mesenchymal cell types in vivo. Altogether we are proposing a hierarchical organization of the mesenchymal compartment, placing SSEA-1+ cells at the apex of this hierarchy.

scholarly journals miR-20b suppresses mitochondrial dysfunction–mediated apoptosis to alleviate hyperoxia-induced acute lung injury by directly targeting MFN1 and MFN2

2020 ◽  
Author(s):  
Genhua Mu ◽  
Yijun Deng ◽  
Zhongqian Lu ◽  
Xing Li ◽  
Yanbin Chen
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
Prolonged Exposure ◽  
Biological Effects ◽  
Pulmonary Inflammation ◽  
Alveolar Epithelial Cells ◽  
Lung Damage

Abstract Supplemental oxygen is commonly used to treat severe respiratory failure, while prolonged exposure to hyperoxia can induce acute lung injury characterized by the accumulation of reactive oxygen species (ROS) and pulmonary inflammation. Dysregulation of microRNAs contributes to multiple diseases, including hyperoxia-induced acute lung injury (HALI). In this study, we explored the roles of miR-20b in mediating the response of type II alveolar epithelial cells (ACE IIs) to hyperoxia and the potential underlying mechanisms. We found that miR-20b was significantly decreased in the lung tissues of HALI models and H2O2-treated ACE IIs. Hyperoxia induced the release of TNF-α, decreased the mitochondrial membrane potential, and led to excessive ROS production and cell apoptosis. Overexpression of miR-20b suppressed the hyperoxia-induced biological effects in ACE IIs. miR-20b negatively regulated the expression levels of Mitofusin 1 (MFN1) and MFN2, the two key proteins of mitochondrial fusion, via complementarily binding to the 3ʹ-untranslated regions of mRNAs. Furthermore, both in vivo and in vitro, upregulation of MFN1 and MFN2 aggravated lung damage and cell apoptosis that were alleviated by miR-20b overexpression. These results provided new insights into the involvement of the miR-20b/MFN1/2 signaling pathway in HALI.

Curcumin Suppresses Epithelial Growth Factor Receptor (EGFR) and Proliferative Protein (Ki 67) in Acute Lung Injury and Lung Fibrosis In vitro and In vivo

2020 ◽  
Vol 20 (4) ◽  
pp. 558-563 ◽  
Author(s):  
Sadiya Bi Shaikh ◽  
Ashwini Prabhu ◽  
Yashodhar Prabhakar Bhandary
Keyword(s):  
Acute Lung Injury ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Growth Factor Receptor ◽  
Bioactive Compound ◽  
The Elderly ◽  
Alveolar Epithelial Cells ◽  
Ki 67

Background:: Acute lung injury is one of the common conditions caused due to bleomycin therapy which leads to pulmonary fibrosis, which is one of the severe interstitial lung diseases most commonly affecting the elderly individuals. EGFR and Ki67 can be marked as beneficial markers for detecting pulmonary fibrosis based on which clinicians can guide the therapy. Objective:: The aim of the study was to evaluate the effect of curcumin as an intervention on two prognostic markers EGFR and Ki67 in bleomycin-induced basal alveolar epithelial cells and C57BL/6 mice. Protein expressions and pathological expressions of EGFR and Ki67 were evaluated to analyze the effect of curcumin via both in vitro and in vivo approaches. Methods:: The effect of curcumin was investigated both on cell lines (A549) and animal model (both normal and bleomycin-induced mice, n=6) via techniques like western blotting for protein expression. Techniques like immunofluorescence and immunohistochemistry were carried out and examined under confocal microscopy and phase contrast microscopy to analyze the expressions of the said biomarkers. Bleomycin was used as a causative agent to induce inflammation. Results:: The natural polyphenol curcumin could downregulate the expressions levels of Ki67 and EGFR both in vitro and in vivo. Immunofluorescence analysis of proliferative marker Ki67 showed a reduced expression on curcumin treatment in vitro. The pathological sections from treated lungs showed a significant decrease in EGFR and Ki67 levels when exposed to curcumin. Conclusion:: We conclude that curcumin, a well-known natural bioactive compound holds strong antiproliferative effects on Ki67 and EGFR expressions.We observed that a clinical outcome in the diagnosis of pulmonary fibrosis remains to be unconvincing so far. Curcumin can be considered as a potential therapeutic.

scholarly journals Induction of PDGF receptor-α in rat myofibroblasts during pulmonary fibrogenesis in vivo

1998 ◽  
Vol 274 (1) ◽  
pp. L72-L80 ◽  
Author(s):  
James C. Bonner ◽  
Pamela M. Lindroos ◽  
Annette B. Rice ◽  
Cindy R. Moomaw ◽  
Daniel L. Morgan
Keyword(s):  
Interleukin 1 ◽  
Immunohistochemical Analysis ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Platelet Derived Growth Factor ◽  
Pdgf Receptor ◽  
Collagen Deposition ◽  
Cell Hyperplasia

Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells. Induction of the PDGF receptor-α (PDGF-Rα) in vitro enhances PDGF-induced mitogenesis and chemotaxis. Thus we investigated whether the PDGF-Rα is induced in vivo during pulmonary fibrogenesis using a vanadium pentoxide (V2O5) model of lung injury. PDGF-Rα mRNA expression was induced 24 h postinstillation. PDGF-Rβ mRNA was constitutively expressed and did not increase. Western blotting showed upregulation of PDGF-Rα protein by 48 h, and immunohistochemical analysis localized PDGF-Rα primarily in mesenchymal cells residing within fibrotic lesions. Upregulation of PDGF-Rα in vivo preceded mesenchymal cell hyperplasia (3–7 days) and collagen deposition by day 15. Supernatants from alveolar macrophages treated with V2O5in vitro released upregulatory activity for PDGF-Rα on cultured lung myofibroblasts, and this activity was blocked by the interleukin-1-receptor antagonist. These data suggest that interleukin-1β-mediated induction of PDGF-Rα in vivo is important to lung myofibroblast hyperplasia during fibrogenesis.

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