Role of CXCL12/CXCR4-Mediated Circulating Fibrocytes in Pulmonary Fibrosis

Xie, Linshen; Zhao, Liqiang

doi:10.7150/jbm.18949

Cited by 5 publications

(7 citation statements)

References 78 publications

(103 reference statements)

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“…Remarkably, it has been indicated recently that the homologous CXCR4 agonist CXCL12 was administered in ARDS experimental models and could produce lung protection [ 41 ]. When compared with the affinity of CXCL12, the affinity of CXCR4 was lower on lung function after isolated lung ischemia–reperfusion injury [ 42 ]. Studies have found that the overexpression of CXCR4 in MSCs can increase the chemotaxis and invasiveness of MSCs to CXCL12.…”

Section: Discussionmentioning

confidence: 99%

“…MSCs can reduce the collagen differentiation and collagen deposition of fibroblasts by secreting the protein caltin-1 to maintain the stability and integrity of endothelial cells to promote tissue homeostasis [ 27 , 45 ]. However, Xie [ 42 ] et al pointed out that CXCL12 can attract many CXCR4[+] fibrocytes to gather and migrate to the lung tissues to promote tissue repair and malignant fibrosis. CXCR4 is regulated by multiple cytokines and different pathways and mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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Mesenchymal stem cells inhibited the apoptosis of alveolar epithelial cells caused by ARDS through CXCL12/CXCR4 axis

Yin

et al. 2022

Bioengineered

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Mesenchymal stem cells (MSCs) have a wide range of anti-inflammatory and immunomodulatory effects and have been observed to have potential therapeutic potential in the clinical treatment of various diseases. We pretreated lung cancer cells A549 with tumor necrosis factor (TNF-α), knocked down the key chemokine receptor CXCR4 on MSCs using lentivirus, and induced acute respiratory distress syndrome (ARDS) mouse model using lipopolysaccharide (LPS) and CXCL12 expression in vivo by adeno-associated virus (AAV-rh10) infection in mice. By co-culturing the MSCs with A549 and in vivo experiments, we observed the effects of MSCs on cell biological functions after inflammatory stimulation, oxidative stress, and the amelioration of lung injury in ARDS mice. TNF-α inhibited A549 proliferation and promoted apoptosis, scorch death-related factor activity, and oxidative stress factor were increased and CXCL12 levels in the cell supernatant were decreased. The co-culture of MSCs was able to increase cell activity and decrease oxidative stress factor levels, and this effect was not present after the knockdown of CXCR4 in MSCs. In vivo transplantation of MSCs significantly attenuated lung injury in ARDS, inhibited serum pro-inflammatory factors in mice, and down-regulated expression of apoptotic and focal factors in lung tissues while blocking CXCR4 or CXCL12 lost the repairing effect of MSCs on ARDS lung tissues. After the co-culture of MSC and lung cancer cells, the expression of CXCR4 on the surface of lung cancer cells was significantly increased, and more CXCR4 and CXCL12 acted together to activate more pro-survival pathways and inhibit apoptosis induced by TNF-α.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells inhibited the apoptosis of alveolar epithelial cells caused by ARDS through CXCL12/CXCR4 axis

Yin

et al. 2022

Bioengineered

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“…Fibrocytes secrete a variety of cytokines to augment fibrotic lesions by activating resident fibroblasts. 40 Fibrocytes are an important source of fibroblasts and myofibroblasts. In one study, circulating fibrocytes indicated a poor prognosis in IPF, 41 with circulating fibrocyte counts in the blood of patients with AE-IPF found to be elevated by up to 10-fold in comparison with the values in stable IPF.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of serum cytokines during acute exacerbation of idiopathic interstitial pneumonias treated with thrombomodulin

et al. 2021

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BackgroundAcute exacerbation (AE) has been reported to herald a poor prognosis in idiopathic pulmonary fibrosis and is now thought to do so in idiopathic interstitial pneumonias (IIPs). However, the pathophysiology of AE-IIPs is not sufficiently understood. In our previously reported SETUP trial, we found better survival in patients with AE-IIPs treated with corticosteroids and thrombomodulin than in those treated with corticosteroids alone. In that study, we collected serum samples to evaluate changes in cytokine levels and retrospectively examined the prognostic significance and pathophysiological role of serum cytokines in patients with AE-IIPs.MethodsThis study included 28 patients from the SETUP trial for whom serial serum samples had been prospectively obtained. AE-IIPs were diagnosed using the Japanese Respiratory Society criteria. All patients were treated with intravenous thrombomodulin and corticosteroids from 2014 to 2016. Serum levels of 27 cytokines were measured using Bio-Plex. The high-resolution CT pattern at the time of diagnosis of AE was classified as diffuse or non-diffuse.ResultsUnivariate analysis revealed that higher serum levels of interleukin (IL)-2, IL-7, IL-9, IL-12, IL13, basic fibroblast growth factor, granulocyte-macrophage colony-stimulating factor, interferon-γ inducible protein-10, platelet-derived growth factor and regulated on activation, normal T cell expressed and secreted (RANTES) at AE were significant predictors of 90-day survival. The HRCT pattern was also a significant clinical predictor of 90-day survival. Multivariate analysis with stepwise selection identified a higher serum RANTES level at AE to be a significant predictor of 90-day survival, including after adjustment for HRCT pattern. Multivariate analysis with stepwise selection suggested that a marked increase in the serum IL-10 level on day 8 could predict 90-day mortality.ConclusionsA higher serum RANTES level at AE the time of diagnosis predicted a good survival outcome, and an elevated serum IL-10 level on day 8 predicted a poor survival outcome.Trial registration numberUMIN000014969.

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“…It has been reported in the past that SDF-1 regulates the migration of stem cells via its receptor CXCR4 and attenuates bleomycin-induced fibrosis in mice models [15]. Contrarily, there are other studies suggesting that SDF-1-dependent recruitment of CXCR4+ fibrocytes further aggravates the disease [16,17]. However, attempts were made to test CXCR4 antagonist as a potential antifibrotic agent that showed promising results in preclinical settings [18,19], but unfortunately could not be translated successfully into clinical application [20].…”

Section: Introductionmentioning

confidence: 96%

Anti-Fibrotic Effect of SDF-1β Overexpression in Bleomycin-Injured Rat Lung

Fytianos

Schliep²,

Mykoniati³

et al. 2022

Pharmaceutics

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Rational: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease and is associated with high mortality due to a lack of effective treatment. Excessive deposition of the extracellular matrix by activated myofibroblasts in the alveolar space leads to scar formation that hinders gas exchange. Therefore, selectively removing activated myofibroblasts with the aim to repair and remodel fibrotic lungs is a promising approach. Stromal-derived growth factor (SDF-1) is known to stimulate cellular signals which attract stem cells to the site of injury for tissue repair and remodeling. Here, we investigate the effect of overexpression of SDF-1β on lung structure using the bleomycin-injured rat lung model. Methods: Intratracheal administration of bleomycin was performed in adult male rats (F344). Seven days later, in vivo electroporation-mediated gene transfer of either SDF-1β or the empty vector was performed. Animals were sacrificed seven days after gene transfer and histology, design-based stereology, flow cytometry, and collagen measurement were performed on the tissue collected. For in vitro experiments, lung fibroblasts obtained from IPF patients were used. Results: Seven days after SDF-1β gene transfer to bleomycin-injured rat lungs, reduced total collagen, reduced collagen fibrils, improved histology and induced apoptosis of myofibroblasts were observed. Furthermore, it was revealed that TNF-α mediates SDF-1β-induced apoptosis of myofibroblasts; moreover, SDF-1β overexpression increased alveolar epithelial cell numbers and proliferation in vivo and also induced their migration in vitro. Conclusions: Our study demonstrates a new antifibrotic mechanism of SDF-1β overexpression and suggests SDF-1β as a potential new approach for the treatment of lung fibrosis.

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Role of CXCL12/CXCR4-Mediated Circulating Fibrocytes in Pulmonary Fibrosis

Cited by 5 publications

References 78 publications

Mesenchymal stem cells inhibited the apoptosis of alveolar epithelial cells caused by ARDS through CXCL12/CXCR4 axis

Mesenchymal stem cells inhibited the apoptosis of alveolar epithelial cells caused by ARDS through CXCL12/CXCR4 axis

Prognostic significance of serum cytokines during acute exacerbation of idiopathic interstitial pneumonias treated with thrombomodulin

Anti-Fibrotic Effect of SDF-1β Overexpression in Bleomycin-Injured Rat Lung

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