Therapeutic targets in lung tissue remodelling and fibrosis

Liu, Gang; Philp, Ashleigh M.; Corte, Tamera J.; Travis, Mark A.; Schilter, Heidi; Hansbro, Nicole G.; Burns, Christopher J.; Eapen, Mathew Suji; Sohal, Sukhwinder Singh; Burgess, Janette K.

doi:10.1016/j.pharmthera.2021.107839

Cited by 133 publications

(111 citation statements)

References 432 publications

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“…Function analysis found that the risk score-related DEGs are mainly enriched in epithelial cell proliferation and extracellular matrix organization, etc. In addition, these DEGs were identified enriched in the cytokine–cytokine receptor interaction, TGF-β signaling pathways, focal adhesion, and ECM–receptor interaction signaling pathways, all of them are the most crucial pathways involved in the development of IPF ( 60 – 62 ). These results indicated that the FRGs may regulate the development and progression of IPF by modulating these major pathways.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis

Wang

Zhang

et al. 2021

Front. Med.

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with unknown etiology and unfavorable prognosis. Ferroptosis is a form of regulated cell death with an iron-dependent way that is involved in the development of various diseases. Whereas the prognostic value of ferroptosis-related genes (FRGs) in IPF remains uncertain and needs to be further elucidated.Methods: The FerrDb database and the previous studies were screened to explore the FRGs. The data of patients with IPF were obtained from the GSE70866 dataset. Wilcoxon's test and univariate Cox regression analysis were applied to identify the FRGs that are differentially expressed between normal and patients with IPF and associated with prognosis. Next, a multigene signature was constructed by the least absolute shrinkage and selection operator (LASSO)-penalized Cox model in the training cohort and evaluated by using calibration and receiver operating characteristic (ROC) curves. Then, 30% of the dataset samples were randomly selected for internal validation. Finally, the potential function and pathways that might be affected by the risk score-related differently expressed genes (DEGs) were further explored.Results: A total of 183 FRGs were identified by the FerrDb database and the previous studies, and 19 of them were differentially expressed in bronchoalveolar lavage fluid (BALF) between IPF and healthy controls and associated with prognosis (p < 0.05). There were five FRGs (aconitase 1 [ACO1], neuroblastoma RAS viral (v-ras) oncogene homolog [NRAS], Ectonucleotide pyrophosphatase/phosphodiesterase 2 [ENPP2], Mucin 1 [MUC1], and ZFP36 ring finger protein [ZFP36]) identified as risk signatures and stratified patients with IPF into the two risk groups. The overall survival rate in patients with high risk was significantly lower than that in patients with low risk (p < 0.001). The calibration and ROC curve analysis confirmed the predictive capacity of this signature, and the results were further verified in the validation group. Risk score-related DEGs were found enriched in ECM-receptor interaction and focal adhesion pathways.Conclusion: The five FRGs in BALF can be used for prognostic prediction in IPF, which may contribute to improving the management strategies of IPF.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis

Wang

Zhang

et al. 2021

Front. Med.

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“…Transforming growth factor (TGF)-β1 pathways are likely to contribute to driving EMT in COPD, via nuclear transcription factors such as pSMAD2/3 with reduction in the inhibitory SMAD7 [ 13 , 30 ]. Interestingly, TGF-β1 pathways are also suggested to play a crucial role in the development of myofibroblasts from tissue fibroblasts through activation of the SMAD pathway [ 26 , 31 ], so although we believe EMT to be a key mechanism in COPD pathogenesis [ 32 ], it is unlikely to be the only growth factor driven mechanism operating throughout the whole thickness of the SA wall [ 33 ]. In addition to the TGF-β1 pathway, we and others have previously shown that the transcription factor clusters of β-catenin/Snail1/Twist is upregulated and with nuclear translocation in smokers and COPD, and their expression is closely related to both EMT activity and lung function [ 28 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: potential role of epithelial–mesenchymal transition

Eapen

Hackett

et al. 2021

ERJ Open Res

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IntroductionPrevious reports showed epithelial mesenchymal transition (EMT) as an active process that contributes to small airway (SA) fibrotic pathology. Myofibroblasts are highly active pro-fibrotic cells that secrete excessive and altered extracellular matrix (ECM). Here we relate SA myofibroblast presence with airway remodelling, physiology and EMT activity in smokers and COPD patients.MethodsLung resections from non-smoker controls (NC), normal lung function smokers (NLFS), COPD current (CS) and ex-smokers (ES) were stained with anti-human αSMA, collagen 1, and fibronectin. αSMA+ive cells were computed in reticular basement membrane (Rbm), lamina propria (LP), and adventitia and presented per mm of Rbm and mm2 of LP. Collagen-1 and fibronectin are presented as a percentage change from normal. All analysis including airway thickness were measured using Image-pro-plus 7.0.ResultsWe found an increase in sub-epithelial LP (especially) and adventitia thickness in all pathological groups compared to NC. Increases in αSMA+ive myofibroblasts were observed in sub-epithelial Rbm, LP, and adventitia in both the smoker and COPD groups compared to NCs. Further, the increase in the myofibroblast population in the LP was strongly associated with decrease in lung function, LP thickening, increase in ECM protein deposition, and finally EMT activity in epithelial cells.ConclusionsThis is the first systematic characterisation of small airway myofibroblasts in COPD based on their localisation, with statistically significant correlations between them and other pan-airway structural, lung function, and ECM protein changes. Finally, we suggest that EMT may be involved in such changes.

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“…TGF-β1-induced fibroblast activation and myofibroblast differentiation, thereby increasing the production of ECM, is an important process in the pathogenesis of IPF [24]. Within 0-1600 nM, ZB has no obvious toxicity to NIH3T3 cells and has an inhibitory effect on cell proliferation caused by TGF-β1 (Figure 2A-B Data was noted as the means ± SD, n=3.…”

Section: Zb Alleviates the Migration And Activation Of Fibroblastsmentioning

confidence: 97%

Zanubrutinib Attenuated Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

Wei

Gu³

et al. 2021

Preprint

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease with high mortality and limited treatment. So far, the only drugs approved for the treatment of IPF are Nintedanib and Pirfenidone. Zanubrutinib, a BTK small molecule inhibitor, is approved for the treatment of mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In this study, we explored the potential effect and mechanisms of zanubrutinib on pulmonary fibrosis in vivo and in vitro. Methods: In the in vivo experiments, different doses of zanubrutinib were administered in a mouse model of bleomycin-induced pulmonary fibrosis, and pathological manifestations and lung function indexes were evaluated. The in vitro experiments were used a TGF-β1-treated fibroblast model to evaluate the effect of zanubrutinib on the activation and autophagy phenotype of fibroblasts and explored the underlying signaling pathways mechanism. Results: In vivo experiments proved that zanubrutinib effectively attenuated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro mechanism study indicated that zanubrutinib could suppress collagen deposition, myofibroblast activation by inhibiting the TGF-β1/Smad pathway and induce autophagy through the TGF-β1/mTOR pathway. Conclusions: Zanubrutinib could alleviate bleomycin- induced lung fibrosis in mice by inhibiting the TGF-β1 signaling pathway.

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Therapeutic targets in lung tissue remodelling and fibrosis

Cited by 133 publications

References 432 publications

Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis

Ferroptosis-Related Genes in Bronchoalveolar Lavage Fluid Serves as Prognostic Biomarkers for Idiopathic Pulmonary Fibrosis

Increased myofibroblasts in the small airways, and relationship to remodelling and functional changes in smokers and COPD patients: potential role of epithelial–mesenchymal transition

Zanubrutinib Attenuated Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

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