Duvelisib attenuates bleomycin‐induced pulmonary fibrosis via inhibiting the <scp>PI</scp>3<scp>K</scp>/Akt/m<scp>TOR</scp> signalling pathway

Li, Xiaohe; Ma, Xiaoyang; Yang, Miao; Zhang, Jianwei; Xi, Buri; Li, Wenqi; Chen, Li; Yang, Yue; Liu, Hongli; Wei, Luqing; Zhou, Honggang; Yang, Cheng

doi:10.1111/jcmm.17665

Cited by 10 publications

(5 citation statements)

References 40 publications

(78 reference statements)

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“…Previous animal studies have revealed that PI3K-γ activation induced epithelial-mesenchymal transition and contributed to bleomycin-induced pulmonary fibrosis [33][34][35]. However, a PI3K-γ inhibitor can attenuate bleomycin-induced pulmonary fibrosis [36]. Our recent study demonstrated that the PI3K-γ pathway mediates MV-induced aggravation of epithelial-mesenchymal transition and pulmonary fibrosis after bleomycin-induced ALI [23].…”

Section: Discussionmentioning

confidence: 78%

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Medel

Li,

Yu,

Huang

et al. 2024

Preprint

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Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase- (PI3K-) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K- remain unclear. We hypothesized MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K- pathway. Five days after receiving a single bolus of 0.075 units bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of -smooth muscle actin, PI3K- expression, and myonuclear apoptosis (P &lt; 0.05). Decreased diaphragm contractility and peroxisome proliferator activated receptor- coactivator-1 levels were also observed (P &lt; 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K- activity (P &lt; 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated through PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

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Section: Discussionmentioning

confidence: 78%

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Medel

Li,

Yu,

Huang

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Previous animal studies have revealed that PI3K-γ activation induced epithelial–mesenchymal transition and contributed to bleomycin-induced pulmonary fibrosis [ 35 , 36 , 37 ]. However, a PI3K-γ inhibitor can attenuate bleomycin-induced pulmonary fibrosis [ 38 ]. Our recent study demonstrated that the PI3K-γ pathway mediates MV-induced aggravation of epithelial–mesenchymal transition and lung fibrosis after bleomycin-induced ALI [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model

Li,

Yu,

Huang

et al. 2024

IJMS

View full text Add to dashboard Cite

Mechanical ventilation (MV), used in patients with acute lung injury (ALI), induces diaphragmatic myofiber atrophy and contractile inactivity, termed ventilator-induced diaphragm dysfunction. Phosphoinositide 3-kinase-γ (PI3K-γ) is crucial in modulating fibrogenesis during the reparative phase of ALI; however, the mechanisms regulating the interactions among MV, myofiber fibrosis, and PI3K-γ remain unclear. We hypothesized that MV with or without bleomycin treatment would increase diaphragm muscle fibrosis through the PI3K-γ pathway. Five days after receiving a single bolus of 0.075 units of bleomycin intratracheally, C57BL/6 mice were exposed to 6 or 10 mL/kg of MV for 8 h after receiving 5 mg/kg of AS605240 intraperitoneally. In wild-type mice, bleomycin exposure followed by MV 10 mL/kg prompted significant increases in disruptions of diaphragmatic myofibrillar organization, transforming growth factor-β1, oxidative loads, Masson’s trichrome staining, extracellular collagen levels, positive staining of α-smooth muscle actin, PI3K-γ expression, and myonuclear apoptosis (p < 0.05). Decreased diaphragm contractility and peroxisome proliferator-activated receptor-γ coactivator-1α levels were also observed (p < 0.05). MV-augmented bleomycin-induced diaphragm fibrosis and myonuclear apoptosis were attenuated in PI3K-γ-deficient mice and through AS605240-induced inhibition of PI3K-γ activity (p < 0.05). MV-augmented diaphragm fibrosis after bleomycin-induced ALI is partially mediated by PI3K-γ. Therapy targeting PI3K-γ may ameliorate MV-associated diaphragm fibrosis.

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“…Fei Qi et al found that lncRNA TUG1 induced autophagy and suppressed inflammation and EMT through inhibition of the PI3K/Akt/mTOR signaling pathway, resulting in an improved pulmonary fibrosis phenotype [33]. Xiaohe Li et al obtained similar outcomes that Duvelisib silenced the expression of fibroblasts in the lungs of patients with IPF and activated autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway [34]. The PI3K-Akt signaling pathway also plays an important role in the progression of cancers.…”

Section: Prediction and Validation Of Candidate Drugsmentioning

confidence: 97%

TRIM2, S100A14, CYP4B1, LMO7, and SFN are signature genes in the progression of idiopathic pulmonary fibrosis epithelial cells to their lung adenocarcinoma comorbidities: a comprehensive analysis based on single-cell RNA sequencing data and RNA transcriptome data

Zhou

Tan

Zhang

2023

Preprint

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Background Patients with idiopathic pulmonary fibrosis (IPF) have a significantly higher prevalence of lung adenocarcinoma (LUAD) than normal subjects, but the underlying association is unclear. This study aims to reveal the potential mechanisms by which IPF progresses to LUAD comorbidity. Methods The raw data involved in the study were obtained from the Gene Expression Omnibus (GEO) database. Sc-RNA seq data were applied to identify specific cell types for disease. Differential expression analysis and Weighted Gene Co-Expression Network Analysis (WGCNA) were used to screen for differentially expressed genes (DEGs) and modular signature genes (MSGs) shared by IPF and LUAD. Genes intersecting DEGs and MSGs were considered hub genes. After performing 3 kinds of machine learning algorithms on epithelial cell-derived hub genes, we captured epithelial cell-derived signature genes (EDSGs) shared. External cohort data were exploited to validate the robustness of EDSGs. We adopted immunohistochemical staining to reveal the protein expression levels of EDSGs. K-M plots denoted the survival prognosis of EDSGs in LUAD patients. Based on EDSGs, we constructed a TF-Gene-miRNA regulatory network and predicted the candidate drugs. Molecular docking can validate the strength of action between candidate drugs and EDSGs. Results Epithelial cells were a specific cell type shared by IPF and LUAD. And then we obtained 650 DEGs and 1773 MSGs, which were shared by IPF and LUAD. As for 379 hub genes, we performed pathway and functional enrichment analysis, aiming to explore the molecular mechanisms shared. By analyzing sc-RNA seq data, we identified 1234 marker genes of IPF epithelial cell-derived and 1481 of LUAD. And these epithelial cell-derived marker genes shared 8 genes with 379 hub genes. Furthermore, through the machine learning algorithm, we got 5 EDSGs, including TRIM2, S100A14, CYP4B1, LMO7, and SFN. The ROC curves validated that EDSGs have high accuracy in predicting the onset of LUAD comorbidity in IPF patients. The TF-Gene-miRNA network revealed potential regulatory mechanisms of EDSGs. And molecular docking suggested strong binding activity between Thalidomide, Docetaxel, and Imatinib and their corresponding targets. Conclusion Our study preliminarily identified potential mechanisms for the progression of IPF to its LUAD comorbidity, which will inform subsequent studies.

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Duvelisib attenuates bleomycin‐induced pulmonary fibrosis via inhibiting the PI3K/Akt/mTOR signalling pathway

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 40 publications

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Medel

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Medel

Suppression of Ventilation-Induced Diaphragm Fibrosis through the Phosphoinositide 3-Kinase-γ in a Murine Bleomycin-Induced Acute Lung Injury Model

TRIM2, S100A14, CYP4B1, LMO7, and SFN are signature genes in the progression of idiopathic pulmonary fibrosis epithelial cells to their lung adenocarcinoma comorbidities: a comprehensive analysis based on single-cell RNA sequencing data and RNA transcriptome data

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