What have we learned from basic science studies on idiopathic pulmonary fibrosis?

Idiopathic pulmonary fibrosis is a fatal age-related lung disease characterised by progressive and irreversible scarring of the lung. Although the details are not fully understood, there has been tremendous progress in understanding the pathogenesis of idiopathic pulmonary fibrosis, which has led to the identification of many new potential therapeutic targets. In this review we discuss several of these advances with a focus on genetic susceptibility and cellular senescence primarily affecting epithelial cells, activation of profibrotic pathways, disease-enhancing fibrogenic cell types and the role of the remodelled extracellular matrix.

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How the Pathological Microenvironment Affects the Behavior of Mesenchymal Stem Cells in the Idiopathic Pulmonary Fibrosis

International Journal of Molecular Sciences ◽

10.3390/ijms21218140 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8140

Author(s):

Martina Bonifazi ◽

Mariangela Di Vincenzo ◽

Miriam Caffarini ◽

Federico Mei ◽

Michele Salati ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Chronic Disease ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Types ◽

And Control ◽

And Oxidative Stress

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblasts activation, ECM accumulation, and diffused alveolar inflammation. The role of inflammation in IPF is still controversial and its involvement may follow nontraditional mechanisms. It is seen that a pathological microenvironment may affect cells, in particular mesenchymal stem cells (MSCs) that may be able to sustain the inflamed microenvironment and influence the surrounding cells. Here MSCs have been isolated from fibrotic (IPF-MSCs) and control (C-MSCs) lung tissue; first cells were characterized and compared by the expression of molecules related to ECM, inflammation, and other interdependent pathways such as hypoxia and oxidative stress. Subsequently, MSCs were co-cultured between them and with NHLF to test the effects of the cellular crosstalk. Results showed that pathological microenvironment modified the features of MSCs: IPF-MSCs, compared to C-MSCs, express higher level of molecules related to ECM, inflammation, oxidative stress, and hypoxia; notably, when co-cultured with C-MSCs and NHLF, IPF-MSCs are able to induce a pathological phenotype on the surrounding cell types. In conclusion, in IPF the pathological microenvironment affects MSCs that in turn can modulate the behavior of other cell types favoring the progression of IPF.

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Pivotal Role of Matrix Metalloproteinase 13 in Extracellular Matrix Turnover in Idiopathic Pulmonary Fibrosis

PLoS ONE ◽

10.1371/journal.pone.0073279 ◽

2013 ◽

Vol 8 (9) ◽

pp. e73279 ◽

Cited By ~ 44

Author(s):

Takwi Nkyimbeng ◽

Clemens Ruppert ◽

Takayuki Shiomi ◽

Bhola Dahal ◽

György Lang ◽

...

Keyword(s):

Extracellular Matrix ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Matrix Metalloproteinase ◽

Pivotal Role ◽

Matrix Metalloproteinase 13

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Inhibition of miR-199a-5p rejuvenates aged mesenchymal stem cells derived from patients with idiopathic pulmonary fibrosis and improves their therapeutic efficacy in experimental pulmonary fibrosis

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02215-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Linli Shi ◽

Qian Han ◽

Yimei Hong ◽

Weifeng Li ◽

Gencheng Gong ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Signaling Pathway ◽

Cellular Senescence ◽

Therapeutic Efficacy ◽

Sirtuin 1 ◽

Ampk Signaling ◽

Beneficial Effects ◽

Age Related ◽

Control Mscs

Abstract Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. Methods Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. Results Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. Conclusions Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.

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Role of Wnt/PCP pathway on bronchial cell function in Idiopathic Pulmonary Fibrosis

Pneumologie ◽

10.1055/s-0031-1296151 ◽

2011 ◽

Vol 65 (12) ◽

Author(s):

S Barkha ◽

M Gegg ◽

H Lickert ◽

M Königshoff

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Cell Function

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Role of Bcl-xL in hepatocyte growth factor-elicited epithelial protection in idiopathic pulmonary fibrosis

Pneumologie ◽

10.1055/s-0034-1376808 ◽

2014 ◽

Vol 68 (06) ◽

Author(s):

S Skwarna ◽

I Henneke ◽

W Seeger ◽

T Geiser ◽

A Günther ◽

...

Keyword(s):

Growth Factor ◽

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Hepatocyte Growth Factor ◽

Hepatocyte Growth

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Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

Nature Communications ◽

10.1038/s41467-021-24853-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Ian T. Stancil ◽

Jacob E. Michalski ◽

Duncan Davis-Hall ◽

Hong Wei Chu ◽

Jin-Ah Park ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Airway Epithelium ◽

Cell Types ◽

Airway Epithelial Cells ◽

Airway Epithelial ◽

Airway Epithelia ◽

Chronic Lung Diseases ◽

Distal Airway ◽

Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

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Syndecans and Pancreatic Ductal Adenocarcinoma

Biomolecules ◽

10.3390/biom11030349 ◽

2021 ◽

Vol 11 (3) ◽

pp. 349

Author(s):

Nausika Betriu ◽

Juan Bertran-Mas ◽

Anna Andreeva ◽

Carlos E. Semino

Keyword(s):

Extracellular Matrix ◽

Pancreatic Ductal Adenocarcinoma ◽

Cell Types ◽

Ductal Adenocarcinoma ◽

Physiological Processes ◽

Extracellular Matrix Components ◽

Detection And Diagnosis ◽

And Migration ◽

Early Detection And Diagnosis

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

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