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Vistusertib improves pulmonary inflammation and fibrosis by modulating inflammatory/oxidative stress mediators via suppressing the mTOR signalling

  • Original Research Paper
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Inflammation Research Aims and scope Submit manuscript

Abstract

Introduction

Inflammation and oxidative stress are key factors in the development of pulmonary fibrosis (PF) by promoting the differentiation of fibroblasts through modulating various pathways including Wnt/β-catenin, TGF-β and mTOR signalling.

Objective and methods

This study aimed to evaluate the effects and elucidate the mechanisms of vistusertib (VSB) in treating pulmonary inflammation/fibrosis, specifically by targeting the mTOR pathway using various in vitro and in vivo models.

Results

Lipopolysaccharide (LPS)-induced inflammation model in macrophages (RAW 264.7), epithelial (BEAS-2B) and endothelial (HMVEC-L) cells revealed that treatment with VSB significantly reduced the IL-6, TNF-α, CCL2, and CCL7 expression. TGF-β induced differentiation was also significantly reduced upon VSB treatment in fibrotic cells (LL29 and DHLF). Further, bleomycin-induced inflammation and fibrosis models demonstrated that treatment with VSB significantly ameliorated the severe inflammation, and lung architectural distortion, by reducing the inflammatory markers expression/levels, inflammatory cells and oxidative stress indicators. Further, fibrosis model results exhibited that, VSB treatment significantly reduced the α-SMA, collagen and TGF-β expressions, improved the lung architecture and restored lung functions.

Conclusion

Overall, this study uncovers the anti-inflammatory/anti-fibrotic effects of VSB by modulating the mTOR activation. Although VSB was tested for lung fibrosis, it can be tested for other fibrotic disorders to improve the patient’s survival and quality of life.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

α-Sma:

α-Smooth muscle actin

AECs:

Alveolar epithelial cells

BMC:

Bleomycin

CCL:

Chemokine (CC-motif) ligand

CD:

Cluster of differentiation

Col1a1:

Collagen1alpha1

DEX:

Dexamethasone

E-CAD:

E-cadherin

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

FBS:

Fetal bovine serum

FN1:

Fibronectin 1

HO-1:

Heme oxygenase-1

IFN:

Interferon

IL:

Interleukins

ILD:

Interstitial lung diseases

IPF:

Idiopathic pulmonary fibrosis

LPS:

Lipopolysaccharide

MCP-1:

Monocyte chemoattractant protein-1

Mmp:

Matrix metalloproteinase

MPO:

Myeloperoxidase

mTOR:

Mammalian target of Rapamycin

NE:

Neutrophil elastase

NO:

Nitric oxide

PBS:

Phosphate buffer saline

PI3K:

Phosphoinositide 3-kinase

PIFD:

PirfenidoneROS: Reactive oxygen species

Tgf-β:

Tumor growth factor-β

TNF:

Tumor necrosis factor

VSB:

Vistusertib

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Acknowledgements

Authors thank the Director, CSIR-IICT, Hyderabad, India, for providing the facilities and funding necessary for the conducting of this work. T.B.S acknowledges the Council of Scientific and Industrial Research, New Delhi for providing SRF. Authors acknowledges Dr Ramesh Ummanni for help on mTOR antibodies.

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Used internal funds of the institute. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Conceptualization: S.R.K, S.B.A; Methodology: T. B.S, S.B.A; In vitro cell culture: T.B.S.; RT-qPCR, Western-blot analysis: T.B.S; In vivo experiments: T.B.S, S.B.A, and C.Yogesh; Manuscript writing - review & editing: T.B.S, S.B.A, and S. R. K.; funding acquisition: S.R.K and S.B.A.

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Correspondence to Sai Balaji Andugulapati or Ramakrishna Sistla.

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Communicated by Anatolii Kubyshkin.

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Shaikh, T.B., Chandra, Y., Andugulapati, S.B. et al. Vistusertib improves pulmonary inflammation and fibrosis by modulating inflammatory/oxidative stress mediators via suppressing the mTOR signalling. Inflamm. Res. 73, 1223–1237 (2024). https://doi.org/10.1007/s00011-024-01894-5

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  • DOI: https://doi.org/10.1007/s00011-024-01894-5

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