Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon, Tanyalak; Yao, Changfu; Stripp, Barry R.; Noble, Paul W.; Chen, Peter C.

doi:10.3390/ijms21072269

Cited by 261 publications

(200 citation statements)

References 227 publications

(335 reference statements)

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“…Although apoptosis and reprogramming of lung epithelial cells play a prominent role in IPF, the molecular details remain uncertain [20,29]. p38 is required for maintaining AEC II homeostasis as a physiological function, whereas extracellular stimuli-mediated enhancement of p38 is attributed to lung inflammation and immune responses and is associated with apoptosis in AEC II [30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we designed the study to elucidate new therapeutic target genes for IPF based on the notion that p38 positively regulates the development of pulmonary fibrosis. Mice with stepwise changes in the intrinsic activity of p38, specifically in alveolar epithelial type II cells (AEC II), were subjected to the pulmonary fibrosis model by BLM because AEC II could play a critical role in the progression of IPF [20]. RNA sequencing of total RNA derived from the lungs followed by transcriptome analysis was performed.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

Matsuda

Kim

Sugiyama

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease that is caused by the dysregulation of alveolar epithelial type II cells (AEC II). The mechanisms involved in the progression of IPF remain incompletely understood, although the immune response accompanied by p38 mitogen-activated protein kinase (MAPK) activation may contribute to some of them. This study aimed to examine the association of p38 activity in the lungs with bleomycin (BLM)-induced pulmonary fibrosis and its transcriptomic profiling. Accordingly, we evaluated BLM-induced pulmonary fibrosis during an active fibrosis phase in three genotypes of mice carrying stepwise variations in intrinsic p38 activity in the AEC II and performed RNA sequencing of their lungs. Stepwise elevation of p38 signaling in the lungs of the three genotypes was correlated with increased severity of BLM-induced pulmonary fibrosis exhibiting reduced static compliance and higher collagen content. Transcriptome analysis of these lung samples also showed that the enhanced p38 signaling in the lungs was associated with increased transcription of the genes driving the p38 MAPK pathway and differentially expressed genes elicited by BLM, including those related to fibrosis as well as the immune system. Our findings underscore the significance of p38 MAPK in the progression of pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

Matsuda

Kim

Sugiyama

et al. 2020

IJMS

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“…The pathophysiology of IPF, an age-related and rapidly progressive lung disease remain poorly understood. Sustained injury to alveolar epithelial type II (AE2) cells leading to aberrant pathways activation has been proposed as a major hallmark of the IPF lung epithelium (6,33,44). Up to date, no appropriate in vitro models have been developed to explore the cellular mechanism underlying this disease.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Roque

Cuevas-Mora²,

Sales³

et al. 2020

Preprint

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The current hypothesis suggests that Idiopathic pulmonary fibrosis (IPF) arises as a result of chronic injury to alveolar epithelial cells and aberrant activation of multiple signaling pathways. Dysfunctional IPF lung epithelium manifests many hallmarks of aging tissues, including cellular senescence, mitochondrial dysfunction, metabolic dysregulation, and loss of proteostasis. Unfortunately, this disease is often fatal within 3-5 years from diagnosis, and there is no effective treatment. One of the major limitations to the development of novel treatments in IPF is that current models of the disease fail to resemble several features seen in elderly IPF patients. In this study, we sought to develop an in vitro epithelial injury model using repeated low levels of bleomycin to mimic the phenotypic and functional characteristics of the IPF lung epithelium. Consistent with the hallmarks of the aging lung epithelium, we found that chronic-injured epithelial cells exhibited features of senescence cells, including an increase in β-galactosidase staining, induction of p53 and p21, mitochondrial dysfunction, excessive ROS production, and proteostasis alteration. Next, combined RNA sequencing, untargeted metabolomics, and lipidomics were performed to investigate the dynamic transcriptional, metabolic, and lipidomic profiling of our in vitro model. We identified that a total of 8,484 genes with different expression variations between the exposed group and the control group. According to our GO enrichment analysis, the down-regulated genes are involved in multiple biosynthetic and metabolic processes. In contrast, the up-regulated genes in our treated cells are responsible for epithelial cell migration and regulation of epithelial proliferation. Furthermore, metabolomics and lipidomics data revealed that overrepresented pathways were amino acid, fatty acid, and glycosphingolipid metabolism. This result suggests that by using our in vitro model, we were able to mimic the transcriptomic and metabolic alterations of those seen in the lung epithelium of IPF patients. We believe this model will be ideally suited for use in uncovering novel insights into the gene expression and molecular pathways of the IPF lung epithelium and performing screening of pharmaceutical compounds.

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“…AT2 cells are therefore active regulators of fibrosis. As they collaterally get damaged, this leads to the induction of the fibrotic phenotype, which includes the activation of resident fibroblast by profibrotic factors such as TGF-β ( Yao et al, 2019 ; Parimon et al, 2020 ).…”

Section: Interaction Between Alveolar Epithelial Type 2 (At2) Stem Cementioning

confidence: 99%

Use of the Reversible Myogenic to Lipogenic Transdifferentiation Switch for the Design of Pre-clinical Drug Screening in Idiopathic Pulmonary Fibrosis

Lingampally

Jones

Bagari

et al. 2020

Front. Bioeng. Biotechnol.

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Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Cited by 261 publications

References 227 publications

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Use of the Reversible Myogenic to Lipogenic Transdifferentiation Switch for the Design of Pre-clinical Drug Screening in Idiopathic Pulmonary Fibrosis

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