Pleural Mesothelial Cell Activation in Idiopathic Pulmonary Fibrosis

The pathogenesis of idiopathic pulmonary fibrosis (IPF) involves a complex interplay of cell types and signaling pathways. Recurrent alveolar epithelial cell (AEC) injury may occur in the context of predisposing factors (e.g., genetic, environmental, epigenetic, immunologic, and gerontologic), leading to metabolic dysfunction, senescence, aberrant epithelial cell activation, and dysregulated epithelial repair. The dysregulated epithelial cell interacts with mesenchymal, immune, and endothelial cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation. Recent single-cell RNA sequencing studies of IPF lungs support the epithelial injury model. These studies have uncovered a novel type of AEC with characteristics of an aberrant basal cell, which may disrupt normal epithelial repair and propagate a profibrotic phenotype. Here, we review the pathogenesis of IPF in the context of novel bioinformatics tools as strategies to discover pathways of disease, cell-specific mechanisms, and cell-cell interactions that propagate the profibrotic niche. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Idiopathic Pulmonary Fibrosis: Pathogenesis and the Emerging Role of Long Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms21020524 ◽

2020 ◽

Vol 21 (2) ◽

pp. 524 ◽

Cited By ~ 2

Author(s):

Marina R. Hadjicharalambous ◽

Mark A. Lindsay

Keyword(s):

Chronic Disease ◽

Epithelial Cell ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Activation ◽

Lung Fibroblast ◽

Biological Processes ◽

Aberrant Expression ◽

Non Coding Rnas

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disease characterized by excessing scarring of the lungs leading to irreversible decline in lung function. The aetiology and pathogenesis of the disease are still unclear, although lung fibroblast and epithelial cell activation, as well as the secretion of fibrotic and inflammatory mediators, have been strongly associated with the development and progression of IPF. Significantly, long non-coding RNAs (lncRNAs) are emerging as modulators of multiple biological processes, although their function and mechanism of action in IPF is poorly understood. LncRNAs have been shown to be important regulators of several diseases and their aberrant expression has been linked to the pathophysiology of fibrosis including IPF. This review will provide an overview of this emerging role of lncRNAs in the development of IPF.

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TGF-β-Induced CCR8 Promoted Macrophage Transdifferentiation into Myofibroblast-Like Cells

10.21203/rs.3.rs-757594/v1 ◽

2021 ◽

Author(s):

Haijun Liu ◽

Qingzhou Guan ◽

Peng Zhao ◽

Jiansheng Li

Keyword(s):

Cell Migration ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Activation ◽

The Body ◽

Dependent Manner ◽

Whole Process ◽

Autophagy Inhibitor ◽

Underlying Mechanisms ◽

And Migration

Abstract Background: Idiopathic pulmonary fibrosis (IPF) is an unknown interstitial disease characterized by tissue fibrosis for which there currently is no effective treatment. Macrophages, as the main immune cells in lung tissue, are involved in the whole process of pulmonary fibrosis. In recent years, intercellular transformation has been widespread concerned in pulmonary fibrosis researchers. The macrophages which have flexible heterogeneity and plasticity participate in different physiological processes of the body. Cell chemokine receptor 8 (CCR8) expressed in a variety of cells plays a significant chemotactic role in inducing cell activation and migration. And it could also promote the differentiation of macrophages under certain environmental conditions. The current study is intended to explore the role of CCR8 in macrophage transdifferentiation into myofibroblast cells in idiopathic pulmonary fibrosis.Methods: We conducted experiments using Ccr8-specific small interfering RNA (siRNA), autophagy inhibitor (3-methyladenine,3-MA) and agonist (rapamycin) to explore the underlying mechanisms of macrophage transdifferentiation into myofibroblast cells in TGF-β induced pulmonary fibrosis. Results: The results indicated that TGF-β treatment increased the CCR8 protein level in a time- and a dose-dependent manner in MH-S, as well as macrophage transdifferentiation-related markers, including Vimentin, Collagen 1, and a-SMA, and cell migration. In addition, levels of autophagy were enhanced in macrophages treated with TGF-β. We found that 3-MA, an autophagy inhibitor decreased the expression levels of macrophage transdifferentiation-related markers and attenuated the cell migration. Furthermore, inhibition of CCR8 through using Ccr8-specific siRNA reduced the levels of autophagy and macrophage transdifferentiation-related markers, and inhibited the cell migration. Enhancing autophagy with rapamycin attenuated the inhibition effect of Ccr8-specific siRNA on macrophage migration and the increase of myofibroblast marker proteins.Conclusions: Our findings showed that the macrophages exposed to TGF-β had the potential to transdifferentiate into myofibroblasts and CCR8 was involved in the process. The effect of CCR8 in TGF-β-induced macrophage transdifferentiation occurs mainly through autophagy. Targeting the CCR8 may become a novel therapeutic strategy for the treatment of IPF.

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Pleural mesothelial cell migration into lung parenchyma by calpain contributes to idiopathic pulmonary fibrosis

Journal of Cellular Physiology ◽

10.1002/jcp.30500 ◽

2021 ◽

Author(s):

Li‐Ling Zhou ◽

Pei‐Pei Cheng ◽

Xin‐Liang He ◽

Li‐Mei Liang ◽

Meng Wang ◽

...

Keyword(s):

Cell Migration ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Mesothelial Cell ◽

Lung Parenchyma

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Wilms' tumor 1 (Wt1) regulates pleural mesothelial cell plasticity and transition into myofibroblasts in idiopathic pulmonary fibrosis

The FASEB Journal ◽

10.1096/fj.13-236828 ◽

2013 ◽

Vol 28 (3) ◽

pp. 1122-1131 ◽

Cited By ~ 47

Author(s):

Suman Karki ◽

Ranu Surolia ◽

Thomas David Hock ◽

Purusotham Guroji ◽

Jason S. Zolak ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Wilms Tumor ◽

Mesothelial Cell ◽

Cell Plasticity ◽

Wilms Tumor 1

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Systemic Immune Cell Activation in a Subgroup of Patients with Idiopathic Pulmonary Fibrosis

Respiration ◽

10.1159/000072007 ◽

2003 ◽

Vol 70 (3) ◽

pp. 262-269 ◽

Cited By ~ 26

Author(s):

Jiri Homolka ◽

Manfred W. Ziegenhagen ◽

Karoline I. Gaede ◽

Peter Entzian ◽

Gernot Zissel ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Activation ◽

Immune Cell ◽

Immune Cell Activation

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Heme Oxygenase-1 Regulates Pleural Mesothelial Cell Differentiation And Migration In Idiopathic Pulmonary Fibrosis

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5570 ◽

2012 ◽

Author(s):

Jason S. Zolak ◽

Rajesh Jagirdar ◽

Qiang Ding ◽

Rui M. Liu ◽

Octavio Oliva ◽

...

Keyword(s):

Cell Differentiation ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Heme Oxygenase ◽

Mesothelial Cell ◽

Heme Oxygenase 1 ◽

And Migration

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Enhanced Bruton’s tyrosine kinase in B-cells and autoreactive IgA in patients with idiopathic pulmonary fibrosis

Respiratory Research ◽

10.1186/s12931-019-1195-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 4

Author(s):

Peter Heukels ◽

Jennifer A. C. van Hulst ◽

Menno van Nimwegen ◽

Carian E. Boorsma ◽

Barbro N. Melgert ◽

...

Keyword(s):

B Cells ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Tyrosine Kinase ◽

B Cell ◽

Disease Progression ◽

Germinal Center ◽

Lung Fibrosis ◽

Cell Activation ◽

B Cell Activation

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is thought to be triggered by repeated alveolar epithelial cell injury. Current evidence suggests that aberrant immune activation may contribute. However, the role of B-cell activation remains unclear. We determined the phenotype and activation status of B-cell subsets and evaluated the contribution of activated B-cells to the development of lung fibrosis both in humans and in mice. Methods B-cells in blood, mediastinal lymph node, and lung single-cell suspensions of IPF patients and healthy controls (HC) were characterized using 14-color flow cytometry. Mice were exposed to bleomycin to provoke pulmonary fibrosis. Results More IgA+ memory B-cells and plasmablasts were found in blood (n = 27) and lungs (n = 11) of IPF patients compared to HC (n = 21) and control lungs (n = 9). IPF patients had higher levels of autoreactive IgA in plasma, which correlated with an enhanced decline of forced vital capacity (p = 0.002, r = − 0.50). Bruton’s tyrosine kinase expression was higher in circulating IPF B-cells compared to HC, indicating enhanced B-cell activation. Bleomycin-exposed mice had increased pulmonary IgA+ germinal center and plasma cell proportions compared to control mice. The degree of lung fibrosis correlated with pulmonary germinal center B-cell proportions (p = 0.010, r = 0.88). Conclusion Our study demonstrates that IPF patients have more circulating activated B-cells and autoreactive IgA, which correlate with disease progression. These B-cell alterations were also observed in the widely used mouse model of experimental pulmonary fibrosis. Autoreactive IgA could be useful as a biomarker for disease progression in IPF.

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