Inhibition of PIM1 kinase attenuates bleomycin-induced pulmonary fibrosis in mice by modulating the ZEB1/E-cadherin pathway in alveolar epithelial cells

Zhang, Xinyi; Zou, Yun; Liu, Yuqi; Cao, Yumeng; Zhu, Jiali; Zhang, Jianhai; Chen, Xia; Zhang, Rui; Li, Jinbao

doi:10.1016/j.molimm.2020.06.013

Cited by 20 publications

(11 citation statements)

References 38 publications

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“…Evidence connecting persistent lung fibrosis to deficient apoptosis was reported in a recent study demonstrating that conditional deletion of Fas in mesenchymal cells during lung fibrosis resolution impaired apoptosis in these cells and delayed fibrosis resolution ( 11 ). Furthermore, inhibition of PIM1 has also been reported to enhance fibrosis resolution following bleomycin challenge in young mice ( 70 ), suggesting that PIM1 inhibition may represent an effective strategy to block persistent lung fibrosis and promote resolution.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis

et al. 2022

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Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease characterized by myofibroblast accumulation and progressive lung scarring. To identify transcriptional gene programs driving persistent lung fibrosis in aging, we performed RNA-Seq on lung fibroblasts isolated from young and aged mice during the early resolution phase after bleomycin injury. We discovered that, relative to injured young fibroblasts, injured aged fibroblasts exhibited a profibrotic state characterized by elevated expression of genes implicated in inflammation, matrix remodeling, and cell survival. We identified the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and its target nuclear factor of activated T cells-1 (NFATc1) as putative drivers of the sustained profibrotic gene signatures in injured aged fibroblasts. PIM1 and NFATc1 transcripts were enriched in a pathogenic fibroblast population recently discovered in IPF lungs, and their protein expression was abundant in fibroblastic foci. Overexpression of PIM1 in normal human lung fibroblasts potentiated their fibrogenic activation, and this effect was attenuated by NFATc1 inhibition. Pharmacological inhibition of PIM1 attenuated IPF fibroblast activation and sensitized them to apoptotic stimuli. Interruption of PIM1 signaling in IPF lung explants ex vivo inhibited prosurvival gene expression and collagen secretion, suggesting that targeting this pathway may represent a therapeutic strategy to block IPF progression.

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Section: Discussionmentioning

confidence: 99%

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis

et al. 2022

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“…PIMs aid in cell growth and division and are involved in tumorigenesis and regulating oncogenes, and their inhibition is anti-fibrotic. 59 …”

Section: Resultsmentioning

confidence: 99%

A scalable 3D tissue culture pipeline to enable functional therapeutic screening for pulmonary fibrosis

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease targeting the alveolar gas exchange apparatus, leading to death by asphyxiation. IPF progresses on a tissue scale through aberrant matrix remodeling, enhanced cell contraction, and subsequent microenvironment densification. Although two pharmaceuticals modestly slow progression, IPF patient survival averages less than 5 years. A major impediment to therapeutic development is the lack of high-fidelity models that account for the fibrotic microenvironment. Our goal is to create a three-dimensional (3D) platform to enable lung fibrosis studies and recapitulate IPF tissue features. We demonstrate that normal lung fibroblasts encapsulated in collagen microspheres can be pushed toward an activated phenotype, treated with FDA-approved therapies, and their fibrotic function quantified using imaging assays (extracellular matrix deposition, contractile protein expression, and microenvironment compaction). Highlighting the system's utility, we further show that fibroblasts isolated from IPF patient lungs maintain fibrotic phenotypes and manifest reduced fibrotic function when treated with epigenetic modifiers. Our system enables enhanced screening due to improved predictability and fidelity compared to 2D systems combined with superior tractability and throughput compared to 3D systems.

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“…Mounting evidence has demonstrated that ZEB1 is an important mediator of EMT, causes fibrosis, and damages various organs ( Lee et al, 2018 ; Qian et al, 2019 ; Yuan et al, 2020 ). ZEB1, along with E-cadherin, are essential for fibrosis in AECs ( Zhang X et al, 2020 ). In animal models, chronic exposure to MA causes an apparent change in cardiopulmonary functions and pulmonary parenchymal lesions.…”

Section: Discussionmentioning

confidence: 99%

Protein-protein interactions between RUNX3 and ZEB1 in chronic lung injury induced by methamphetamine abuse

et al. 2022

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Methamphetamine (MA) is the most common and highly addictive substance abuse drug. Runt-related transcription factor 3 (RUNX3) and Zinc finger E-box-binding homeobox 1 (ZEB1) are associated with lung inflammation and fibrosis. However, the protein-protein interactions (PPIs) between RUNX3 and ZEB1 and its involvement in MA-induced chronic lung injury is still unclear. In this study, we evaluated lung injury using echocardiography, hematoxylin and eosin staining, and western blot analysis. The viability of alveolar epithelial cells (AECs) was assessed using cell counting kit-8. Molecular Operating Environment software, Search Tool for the Retrieval of Interacting Genes/Proteins database, co-immunoprecipitation, assay and confocal immunofluorescence assay were used to predict and identify the PPIs between RUNX3 and ZEB1. The expression of RUNX3 and ZEB1 were knockdown in AECs using siRNA. The results revealed that MA exposure increased the peak blood flow velocity of the pulmonary artery and the acceleration time of pulmonary artery blood flow. Further, exposure to MA also causes adhesion and fusion of the alveolar walls and altered AEC activity. A decrease in the expression of RUNX3 and an increase in the expression of ZEB1 and its downstream signaling molecules were observed on MA exposure. The PPIs between RUNX3 and ZEB1 were identified. Further, an increase in the protein binding rate of RUNX3-ZEB1 was observed in MA-induced lung injury. These results show interactions between RUNX3 and ZEB1. RUNX3 protects against lung injury; however, ZEB1 expression and the PPIs between ZEB1 and RUNX3 has deleterious effects on chronic lung injury induced by MA exposure. Our results provide a new therapeutic approach for the treatment of chronic lung injury due to MA exposure.

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Inhibition of PIM1 kinase attenuates bleomycin-induced pulmonary fibrosis in mice by modulating the ZEB1/E-cadherin pathway in alveolar epithelial cells

Cited by 20 publications

References 38 publications

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis

Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis

A scalable 3D tissue culture pipeline to enable functional therapeutic screening for pulmonary fibrosis

Protein-protein interactions between RUNX3 and ZEB1 in chronic lung injury induced by methamphetamine abuse

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