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Molecular and Cellular Mechanisms of Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 May 2023) | Viewed by 117487

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Guest Editor
Morphologic and Molecular Pathology Unit, Sant'Andrea University Hospital, 00189 Rome, Italy
Interests: lung pathology; interstitial lung disease; idiopathic pulmonary fibrosis; molecular pathology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is time to shed light on the molecular and cellular mechanisms of lung fibrosis!

Lungs are exposed to many insults with every breath we take, showing an extraordinary ability to repair damaged cells and tissues. A complex interplay between genetic background and the environment drives the response of lung tissues to acquired damage, and lung fibrosis is, in most cases, the final result of a maladaptive response to this complex interaction. Lung fibrosis causes a decline in pulmonary function, with patients suffering a worse quality of life and poor prognosis with early mortality.

Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive interstitial lung disease (ILD), in which progressive lung scarring involves the lungs interstitium; although thought to be rare, its incidence has recently increased in the Western world and is similar to some types of cancer. At the present time, therapeutical options for treating IPF and other ILD are scarce and show little benefit. 

This Special Issue is awaiting the submission of scientific research articles and reviews that describe the molecular and cellular mechanisms driving the progression of fibrosing lung diseases, with a particular focus on IPF, for a better understanding of their pathogenesis and the development of diagnostic markers, as well as the discovery of molecular targets suitable for tailored therapies.

Dr. Massimiliano Mancini
Guest Editor

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Keywords

  • lung fibrosis
  • idiopathic pulmonary fibrosis
  • interstitial lung disease
  • molecular pathways
  • cellular aging and senescence

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Published Papers (32 papers)

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16 pages, 10574 KiB  
Article
miR-29a-3p Regulates Autophagy by Targeting Akt3-Mediated mTOR in SiO2-Induced Lung Fibrosis
by Peiyuan Li, Xiaohui Hao, Jiaxin Liu, Qinxin Zhang, Zixuan Liang, Xinran Li and Heliang Liu
Int. J. Mol. Sci. 2023, 24(14), 11440; https://doi.org/10.3390/ijms241411440 - 14 Jul 2023
Cited by 10 | Viewed by 1790
Abstract
Silicosis is a refractory pneumoconiosis of unknown etiology that is characterized by diffuse lung fibrosis, and microRNA (miRNA) dysregulation is connected to silicosis. Emerging evidence suggests that miRNAs modulate pulmonary fibrosis through autophagy; however, its underlying molecular mechanism remains unclear. In agreement with [...] Read more.
Silicosis is a refractory pneumoconiosis of unknown etiology that is characterized by diffuse lung fibrosis, and microRNA (miRNA) dysregulation is connected to silicosis. Emerging evidence suggests that miRNAs modulate pulmonary fibrosis through autophagy; however, its underlying molecular mechanism remains unclear. In agreement with miRNA microarray analysis, the qRT-PCR results showed that miR-29a-3p was significantly decreased in the pulmonary fibrosis model both in vitro and in vivo. Increased autophagosome was observed via transmission electron microscopy in lung epithelial cell models and lung tissue of silicosis mice. The expression of autophagy-related proteins LC3α/β and Beclin1 were upregulated. The results from using 3-methyladenine, an autophagy inhibitor, or rapamycin, an autophagy inducer, together with TGF-β1, indicated that autophagy attenuates fibrosis by protecting lung epithelial cells. In TGF-β1-treated TC-1 cells, transfection with miR-29a-3p mimics activated protective autophagy and reduced alpha-smooth muscle actin and collagen I expression. miRNA TargetScan predicted, and dual-luciferase reporter experiments identified Akt3 as a direct target of miR-29a-3p. Furthermore, Akt3 expression was significantly elevated in the silicosis mouse model and TGF-β1-treated TC-1 cells. The mammalian target of rapamycin (mTOR) is a central regulator of the autophagy process. Silencing Akt3 inhibited the transduction of the mTOR signaling pathway and activated autophagy in TGF-β1-treated TC-1 cells. These results show that miR-29a-3p overexpression can partially reverse the fibrotic effects by activating autophagy of the pulmonary epithelial cells regulated by the Akt3/mTOR pathway. Therefore, targeting miR-29a-3p may provide a new therapeutic strategy for silica-induced pulmonary fibrosis. Full article
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23 pages, 19114 KiB  
Article
Innovative Pre-Clinical Data Using Peptides to Intervene in the Evolution of Pulmonary Fibrosis
by Karina Smidt Simon, Luísa Coutinho Coelho, Paulo Henrique de Holanda Veloso, Jr., Cesar Augusto Melo-Silva, José Athayde Vasconcelos Morais, João Paulo Figueiró Longo, Florencio Figueiredo, Leonora Viana, Ildinete Silva Pereira, Veronica Moreira Amado, Marcia Renata Mortari and Anamelia Lorenzetti Bocca
Int. J. Mol. Sci. 2023, 24(13), 11049; https://doi.org/10.3390/ijms241311049 - 4 Jul 2023
Cited by 1 | Viewed by 1738
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive, relentless, and deadly disease. Little is known about its pathogenetic mechanisms; therefore, developing efficient pharmacological therapies is challenging. This work aimed to apply a therapeutic alternative using immunomodulatory peptides in a chronic pulmonary fibrosis murine model. BALB/c mice were intratracheally instilled with bleomycin (BLM) and followed for 30 days. The mice were treated with the immune modulatory peptides ToAP3 and ToAP4 every three days, starting on the 5th day post-BLM instillation. ELISA, qPCR, morphology, and respiratory function analyses were performed. The treatment with both peptides delayed the inflammatory process observed in the non-treated group, which showed a fibrotic process with alterations in the production of collagen I, III, and IV that were associated with significant alterations in their ventilatory mechanics. The ToAP3 and ToAP4 treatments, by lung gene modulation patterns, indicated that distinct mechanisms determine the action of peptides. Both peptides controlled the experimental IPF, maintaining the tissue characteristics and standard function properties and regulating fibrotic-associated cytokine production. Data obtained in this work show that the immune response regulation by ToAP3 and ToAP4 can control the alterations that cause the fibrotic process after BLM instillation, making both peptides potential therapeutic alternatives and/or adjuvants for IPF. Full article
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20 pages, 66915 KiB  
Article
Empagliflozin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by Modulating Sesn2/AMPK/Nrf2 Signaling and Targeting Ferroptosis and Autophagy
by Hemat El-Sayed El-Horany, Marwa Mohamed Atef, Muhammad Tarek Abdel Ghafar, Mohamed. H. Fouda, Nahla Anas Nasef, Islam Ibrahim Hegab, Duaa S. Helal, Walaa Elseady, Yasser Mostafa Hafez, Rasha Youssef Hagag, Monira Abdelmoaty Seleem, Mai Mahmoud Saleh, Doaa A. Radwan, Amal Ezzat Abd El-Lateef and Rania Nagi Abd-Ellatif
Int. J. Mol. Sci. 2023, 24(11), 9481; https://doi.org/10.3390/ijms24119481 - 30 May 2023
Cited by 13 | Viewed by 4110
Abstract
Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms [...] Read more.
Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate the ameliorative effect of EMPA against bleomycin (BLM)-induced PF and the potential mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA treated, and EMPA+BLM treated. EMPA significantly improved the histopathological injuries illustrated by both hematoxylin and eosin and Masson’s trichrome-stained lung tissue sections, as confirmed by electron microscopic examination. It significantly reduced the lung index, hydroxyproline content, and transforming growth factor β1 levels in the BLM rat model. It had an anti-inflammatory effect, as evidenced by a decrease in the inflammatory cytokines’ tumor necrosis factor alpha and high mobility group box 1, inflammatory cell infiltration into the bronchoalveolar lavage fluid, and the CD68 immunoreaction. Furthermore, EMPA mitigated oxidative stress, DNA fragmentation, ferroptosis, and endoplasmic reticulum stress, as evidenced by the up-regulation of nuclear factor erythroid 2-related factor expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, and a decrease in C/EBP homologous protein levels. This protective potential could be explained on the basis of autophagy induction via up-regulating lung sestrin2 expression and the LC3 II immunoreaction observed in this study. Our findings indicated that EMPA protected against BLM-induced PF-associated cellular stress by enhancing autophagy and modulating sestrin2/adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling. Full article
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11 pages, 1260 KiB  
Article
Serum Progranulin Level Might Differentiate Non-IPF ILD from IPF
by Nóra Melinda Tóth, Veronika Müller, Tamás Nagy, Lőrinc Polivka, Péter Horváth, Anikó Bohács and Noémi Eszes
Int. J. Mol. Sci. 2023, 24(11), 9178; https://doi.org/10.3390/ijms24119178 - 24 May 2023
Cited by 1 | Viewed by 1748
Abstract
Diagnosing interstitial lung disease (ILD) can be a challenging process. New biomarkers may support diagnostic decisions. Elevated serum progranulin (PGRN) levels have been reported in liver fibrosis and dermatomyositis-associated acute interstitial pneumonia. Our aim was to assess the role of PGRN in the [...] Read more.
Diagnosing interstitial lung disease (ILD) can be a challenging process. New biomarkers may support diagnostic decisions. Elevated serum progranulin (PGRN) levels have been reported in liver fibrosis and dermatomyositis-associated acute interstitial pneumonia. Our aim was to assess the role of PGRN in the differential diagnosis of idiopathic pulmonary fibrosis (IPF) and other ILDs. Serum levels of PGRN were measured by enzyme-linked immunosorbent assay in stable IPF (n = 40), non-IPF ILD (n = 48) and healthy controls (n = 17). Patient characteristics, lung function, CO diffusion (DLCO), arterial blood gases, 6-min walk test, laboratory parameters and high-resolution (HR)CT pattern were assessed. In stable IPF, PGRN levels did not differ from healthy controls; however, serum PGRN levels were significantly higher in non-IPF ILD patients compared to healthy subjects and IPF (53.47 ± 15.38 vs. 40.99 ± 5.33 vs. 44.66 ± 7.77 ng/mL respectively; p < 0.01). The HRCT pattern of usual interstitial pneumonia (UIP) was associated with normal PGRN level, while for non-UIP patterns, significantly elevated PGRN level was measured. Elevated serum PGRN levels may be associated with non-IPF ILD, especially non-UIP patterns and might be helpful in cases of unclear radiological patterns in the differentiation between IPF and other ILDs. Full article
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22 pages, 4484 KiB  
Article
Proteomic Fingerprint of Lung Fibrosis Progression and Response to Therapy in Bleomycin-Induced Mouse Model
by Lucrezia Principi, Erica Ferrini, Roberta Ciccimarra, Lisa Pagani, Clizia Chinello, Paolo Previtali, Andrew Smith, Gino Villetti, Matteo Zoboli, Francesca Ravanetti, Franco Fabio Stellari, Fulvio Magni and Isabella Piga
Int. J. Mol. Sci. 2023, 24(5), 4410; https://doi.org/10.3390/ijms24054410 - 23 Feb 2023
Cited by 7 | Viewed by 3256
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by the aberrant accumulation of extracellular matrix in the lungs. nintedanib is one of the two FDA-approved drugs for IPF treatment; however, the exact pathophysiological mechanisms of fibrosis progression and response to therapy are still poorly understood. In this work, the molecular fingerprint of fibrosis progression and response to nintedanib treatment have been investigated by mass spectrometry-based bottom-up proteomics in paraffin-embedded lung tissues from bleomycin-induced (BLM) pulmonary fibrosis mice. Our proteomics results unveiled that (i) samples clustered depending on the tissue fibrotic grade (mild, moderate, and severe) and not on the time course after BLM treatment; (ii) the dysregulation of different pathways involved in fibrosis progression such as the complement coagulation cascades, advanced glycation end products (AGEs) and their receptors (RAGEs) signaling, the extracellular matrix-receptor interaction, the regulation of actin cytoskeleton, and ribosomes; (iii) Coronin 1A (Coro1a) as the protein with the highest correlation when evaluating the progression of fibrosis, with an increased expression from mild to severe fibrosis; and (iv) a total of 10 differentially expressed proteins (padj-value ≤ 0.05 and Fold change ≤−1.5 or ≥1.5), whose abundance varied in the base of the severity of fibrosis (mild and moderate), were modulated by the antifibrotic treatment with nintedanib, reverting their trend. Notably, nintedanib significantly restored lactate dehydrogenase B (Ldhb) expression but not lactate dehydrogenase A (Ldha). Notwithstanding the need for further investigations to validate the roles of both Coro1a and Ldhb, our findings provide an extensive proteomic characterization with a strong relationship with histomorphometric measurements. These results unveil some biological processes in pulmonary fibrosis and drug-mediated fibrosis therapy. Full article
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27 pages, 3082 KiB  
Article
First Characterization of the Transcriptome of Lung Fibroblasts of SSc Patients and Healthy Donors of African Ancestry
by Ludivine Renaud, Kristy M. Waldrep, Willian A. da Silveira, Joseph M. Pilewski and Carol A. Feghali-Bostwick
Int. J. Mol. Sci. 2023, 24(4), 3645; https://doi.org/10.3390/ijms24043645 - 11 Feb 2023
Cited by 3 | Viewed by 2336
Abstract
Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc patients. Racial disparity is noted in SSc as African Americans (AA) have a [...] Read more.
Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc patients. Racial disparity is noted in SSc as African Americans (AA) have a higher frequency and severity of disease than European Americans (EA). Using RNAseq, we determined differentially expressed genes (DEGs; q < 0.1, log2FC > |0.6|) in primary pulmonary fibroblasts from SSc lungs (SScL) and normal lungs (NL) of AA and EA patients to characterize the unique transcriptomic signatures of AA-NL and AA-SScL fibroblasts using systems-level analysis. We identified 69 DEGs in “AA-NL vs. EA-NL” and 384 DEGs in “AA-SScL vs. EA-SScL” analyses, and a comparison of disease mechanisms revealed that only 7.5% of DEGs were commonly deregulated in AA and EA patients. Surprisingly, we also identified an SSc-like signature in AA-NL fibroblasts. Our data highlight differences in disease mechanisms between AA and EA SScL fibroblasts and suggest that AA-NL fibroblasts are in a “pre-fibrosis” state, poised to respond to potential fibrotic triggers. The DEGs and pathways identified in our study provide a wealth of novel targets to better understand disease mechanisms leading to racial disparity in SSc-PF and develop more effective and personalized therapies. Full article
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17 pages, 4413 KiB  
Article
Genetic Variant Overlap Analysis Identifies Established and Putative Genes Involved in Pulmonary Fibrosis
by Karlijn Groen, Joanne J. van der Vis, Aernoud A. van Batenburg, Karin M. Kazemier, Jan C. Grutters and Coline H. M. van Moorsel
Int. J. Mol. Sci. 2023, 24(3), 2790; https://doi.org/10.3390/ijms24032790 - 1 Feb 2023
Cited by 2 | Viewed by 1932
Abstract
In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a [...] Read more.
In only around 40% of families with pulmonary fibrosis (PF) a suspected genetic cause can be found. Genetic overlap analysis of Whole Exome Sequencing (WES) data may be a powerful tool to discover new shared variants in novel genes for PF. As a proof of principle, we first selected unrelated PF patients for whom a genetic variant was detected (n = 125) in established PF genes and searched for overlapping variants. Second, we performed WES (n = 149) and identified novel potentially deleterious variants shared by at least two unrelated PF patients. These variants were genotyped in validation cohorts (n = 2748). In 125 unrelated patients, a potentially deleterious variant was detected in known PF genes of which 15 variants in six genes overlapped, involving 51 patients. Overlap analysis of WES data identified two novel variants of interest: TOM1L2 c.421T > C p.(Y141H) and TDP1c.1373dupG p.(S459fs*5), neither gene had been related to pulmonary fibrosis before. Both proteins were present in the alveolar epithelium. No apparent characteristics of telomere disease were observed. This study underlines the potential of searching for overlapping rare potentially deleterious variants to identify disease-associated variants and genes. A previously unreported variant was found in two putative new PF genes, but further research is needed to determine causality. Full article
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20 pages, 8804 KiB  
Article
Multi-Step Extracellular Matrix Remodelling and Stiffening in the Development of Idiopathic Pulmonary Fibrosis
by Constança Júnior, Anna Ulldemolins, Maria Narciso, Isaac Almendros, Ramon Farré, Daniel Navajas, Javier López, Mar Eroles, Felix Rico and Núria Gavara
Int. J. Mol. Sci. 2023, 24(2), 1708; https://doi.org/10.3390/ijms24021708 - 15 Jan 2023
Cited by 9 | Viewed by 2881
Abstract
The extracellular matrix (ECM) of the lung is a filamentous network composed mainly of collagens, elastin, and proteoglycans that provides structural and physical support to its populating cells. Proliferation, migration and overall behaviour of those cells is greatly determined by micromechanical queues provided [...] Read more.
The extracellular matrix (ECM) of the lung is a filamentous network composed mainly of collagens, elastin, and proteoglycans that provides structural and physical support to its populating cells. Proliferation, migration and overall behaviour of those cells is greatly determined by micromechanical queues provided by the ECM. Lung fibrosis displays an aberrant increased deposition of ECM which likely changes filament organization and stiffens the ECM, thus upregulating the profibrotic profile of pulmonary cells. We have previously used AFM to assess changes in the Young’s Modulus (E) of the ECM in the lung. Here, we perform further ECM topographical, mechanical and viscoelastic analysis at the micro- and nano-scale throughout fibrosis development. Furthermore, we provide nanoscale correlations between topographical and elastic properties of the ECM fibres. Firstly, we identify a softening of the ECM after rats are instilled with media associated with recovery of mechanical homeostasis, which is hindered in bleomycin-instilled lungs. Moreover, we find opposite correlations between fibre stiffness and roughness in PBS- vs bleomycin-treated lung. Our findings suggest that changes in ECM nanoscale organization take place at different stages of fibrosis, with the potential to help identify pharmacological targets to hinder its progression. Full article
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10 pages, 1846 KiB  
Article
Endothelin-1 as a Biomarker of Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease Associated with Autoimmune Diseases
by Verónica Pulito-Cueto, Fernanda Genre, Raquel López-Mejías, Víctor Manuel Mora-Cuesta, David Iturbe-Fernández, Virginia Portilla, María Sebastián Mora-Gil, Javier Gonzalo Ocejo-Vinyals, Oreste Gualillo, Ricardo Blanco, Alfonso Corrales, Iván Ferraz-Amaro, Santos Castañeda, José Manuel Cifrián Martínez, Belén Atienza-Mateo, Sara Remuzgo-Martínez and Miguel Ángel González-Gay
Int. J. Mol. Sci. 2023, 24(2), 1275; https://doi.org/10.3390/ijms24021275 - 9 Jan 2023
Cited by 11 | Viewed by 2670
Abstract
The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis [...] Read more.
The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity. Full article
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26 pages, 4195 KiB  
Article
BAL Proteomic Signature of Lung Adenocarcinoma in IPF Patients and Its Transposition in Serum Samples for Less Invasive Diagnostic Procedures
by Lorenza Vantaggiato, Enxhi Shaba, Paolo Cameli, Laura Bergantini, Miriana d’Alessandro, Alfonso Carleo, Giusy Montuori, Luca Bini, Elena Bargagli and Claudia Landi
Int. J. Mol. Sci. 2023, 24(2), 925; https://doi.org/10.3390/ijms24020925 - 4 Jan 2023
Cited by 3 | Viewed by 2941
Abstract
Idiopathic pulmonary fibrosis (IPF) is a form of chronic and irreversible fibrosing interstitial pneumonia of unknown etiology. Although antifibrotic treatments have shown a reduction of lung function decline and a slow disease progression, IPF is characterize by a very high mortality. Emerging evidence [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a form of chronic and irreversible fibrosing interstitial pneumonia of unknown etiology. Although antifibrotic treatments have shown a reduction of lung function decline and a slow disease progression, IPF is characterize by a very high mortality. Emerging evidence suggests that IPF increases the risk of lung carcinogenesis. Both diseases show similarities in terms of risk factors, such as history of smoking, concomitant emphysema, and viral infections, besides sharing similar pathogenic pathways. Lung cancer (LC) diagnosis is often difficult in IPF patients because of the diffuse lung injuries and abnormalities due to the underlying fibrosis. This is reflected in the lack of optimal therapeutic strategies for patients with both diseases. For this purpose, we performed a proteomic study on bronchoalveolar lavage fluid (BALF) samples from IPF, LC associated with IPF (LC-IPF) patients, and healthy controls (CTRL). Molecular pathways involved in inflammation, immune response, lipid metabolism, and cell adhesion were found for the dysregulated proteins in LC-IPF, such as TTHY, APOA1, S10A9, RET4, GDIR1, and PROF1. The correlation test revealed a relationship between inflammation- and lipid metabolism-related proteins. PROF1 and S10A9, related to inflammation, were up-regulated in LC-IPF BAL and serum, while APOA1 and APOE linked to lipid metabolism, were highly abundant in IPF BAL and low abundant in IPF serum. Given the properties of cytokine/adipokine of the nicotinamide phosphoribosyltransferase, we also evaluated its serum abundance, highlighting its down-regulation in LC-IPF. Our retrospective analyses of BAL samples extrapolated some potential biomarkers of LC-IPF useful to improve the management of these contemporary pathologies. Their differential abundance in serum samples permits the measurement of these potential biomarkers with a less invasive procedure. Full article
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15 pages, 3273 KiB  
Article
Inhibition of Oncogenic Src Ameliorates Silica-Induced Pulmonary Fibrosis via PI3K/AKT Pathway
by Xiaohui Hao, Yixuan Jin, Yiyang Zhang, Shifeng Li, Jie Cui, Hailan He, Lingli Guo, Fang Yang and Heliang Liu
Int. J. Mol. Sci. 2023, 24(1), 774; https://doi.org/10.3390/ijms24010774 - 1 Jan 2023
Cited by 13 | Viewed by 3282
Abstract
Silicosis is a refractory disease. Previous studies indicate that damaged alveolar epithelial cells act as a driver in pulmonary fibrosis. Our results show that epithelial cells that acquire the mesenchymal phenotype are associated with the pathogenesis of silicosis. c-Src kinase, a non-receptor tyrosine [...] Read more.
Silicosis is a refractory disease. Previous studies indicate that damaged alveolar epithelial cells act as a driver in pulmonary fibrosis. Our results show that epithelial cells that acquire the mesenchymal phenotype are associated with the pathogenesis of silicosis. c-Src kinase, a non-receptor tyrosine kinase, has been shown to be a positive regulator of organ fibrosis, but specific mechanisms remain unclear and rarely researched in silicosis. The activated Phosphatidylinositol-3 kinases/AKT(PI3K/AKT) pathway promotes fibrosis. We aimed to determine whether c-Src regulates fibrosis via the PI3K/AKT signaling pathway in the development of silicosis. C57/BL mice were intratracheally perfused with 10 mg silica suspension to establish a model of silicosis. In vivo, silica particles induced lung fibrosis. The profibrotic cytokine transforming growth factor-β1 (TGF-β1) exhibited a high expression in pulmonary fibrosis. The phosphorylated c-Src protein was increased and the PI3K/AKT pathway was activated in model lung tissue. In vitro, silica increased the expression of TGF-β1- and TGF-β1-induced mesenchymal phenotype and fibrosis in a mouse epithelial cells line. siRNA-Src inhibited the c-Src, the phosphorylation of the PI3K/AKT pathway, and the mesenchymal phenotype induced by TGF-β1. LY294002, a specific inhibitor of PI3K, suppressed the phosphorylation of PI3K/AKT but did not affect Src activation. SU6656, a selective Src inhibitor, attenuated fibrosis in silicosis model. In summary, c-Src promotes fibrosis via the PI3K/AKT pathway in silica-induced lung fibrosis, and Src kinase inhibitors are potentially effective for silicosis treatment. Full article
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19 pages, 4765 KiB  
Article
Candida Administration in 5/6 Nephrectomized Mice Enhanced Fibrosis in Internal Organs: An Impact of Lipopolysaccharide and (1→3)-β-D-Glucan from Leaky Gut
by Somkanya Tungsanga, Kanyarat Udompornpitak, Jesadakorn Worasilchai, Tharit Ratana-aneckchai, Dhammika Leshan Wannigama, Pisut Katavetin and Asada Leelahavanichkul
Int. J. Mol. Sci. 2022, 23(24), 15987; https://doi.org/10.3390/ijms232415987 - 15 Dec 2022
Cited by 6 | Viewed by 2221
Abstract
Uremic toxins and gut dysbiosis in advanced chronic kidney disease (CKD) can induce gut leakage, causing the translocation of gut microbial molecules into the systemic circulation. Lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG) are the major gut microbial molecules of Gram-negative bacteria and fungi, respectively, [...] Read more.
Uremic toxins and gut dysbiosis in advanced chronic kidney disease (CKD) can induce gut leakage, causing the translocation of gut microbial molecules into the systemic circulation. Lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG) are the major gut microbial molecules of Gram-negative bacteria and fungi, respectively, and can induce inflammation in several organs. Here, the fibrosis in the kidney, liver, and heart was investigated in oral C. albicans-administered 5/6 nephrectomized (Candida-5/6 Nx) mice. At 20 weeks post 5/6 Nx, Candida-5/6 Nx mice demonstrated increased 24 h proteinuria, liver enzymes, and serum cytokines (TNF-α, IL-6, and IL-10), but not weight loss, systolic blood pressure, hematocrit, serum creatinine, or gut-derived uremic toxins (TMAO and indoxyl sulfate), compared to in 5/6 Nx alone. The gut leakage in Candida-5/6 Nx was more severe, as indicated by FITC-dextran assay, endotoxemia, and serum BG. The areas of fibrosis from histopathology, along with the upregulated gene expression of Toll-like receptor 4 (TLR-4) and Dectin-1, the receptors for LPS and BG, respectively, were higher in the kidney, liver, and heart. In vitro, LPS combined with BG increased the supernatant IL-6 and TNF-α, upregulated the genes of pro-inflammation and pro-fibrotic processes, Dectin-1, and TLR-4 in renal tubular (HK-2) cells and hepatocytes (HepG2), when compared with LPS or BG alone. This supported the pro-inflammation-induced fibrosis and the possible LPS–BG additive effects on kidney and liver fibrosis. In conclusion, uremia-induced leaky gut causes the translocation of gut LPS and BG into circulation, which activates the pro-inflammatory and pro-fibrotic pathways, causing internal organ fibrosis. Our results support the crosstalk among several organs in CKD through a leaky gut. Full article
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11 pages, 726 KiB  
Article
Radiological Assessment in Idiopathic Pulmonary Fibrosis (IPF) Patients According to MUC5B Polymorphism
by Elisabetta Cocconcelli, Nicol Bernardinello, Chiara Giraudo, Gioele Castelli, Clorinda Greco, Roberta Polverosi, Marina Saetta, Paolo Spagnolo and Elisabetta Balestro
Int. J. Mol. Sci. 2022, 23(24), 15890; https://doi.org/10.3390/ijms232415890 - 14 Dec 2022
Cited by 2 | Viewed by 1553
Abstract
The MUC5B rs35705950 mutant T allele is the strongest genetic risk factor for familial and sporadic IPF. We sought to determine whether MUC5B genotype influences radiological patterns of IPF at diagnosis, as well as their change over time, in patients on antifibrotic therapy. [...] Read more.
The MUC5B rs35705950 mutant T allele is the strongest genetic risk factor for familial and sporadic IPF. We sought to determine whether MUC5B genotype influences radiological patterns of IPF at diagnosis, as well as their change over time, in patients on antifibrotic therapy. Among eighty-eight IPF patients, previously genotyped for MUC5B rs35705950, we considered seventy-eight patients who were evaluated for radiological quantification of the following features both at treatment initiation (HRCT1) and after 1 year (HRCT2): ground glass opacities (AS), reticulations (IS) and honeycombing (HC). Of the evaluated patients, 69% carried at least one copy of the T allele (TT/TG). Carriers of the T allele displayed similar FVC loss in the first year of treatment as GG carriers, but overall survival at the end of follow-up was longer in the TT/TG group, compared to the GG group. In the GG group, both the AS and HC increased significantly, whereas in the TT/TG group only HC increased over the first year of treatment. MUC5B rs35705950 GG carriers are associated with increased ground glass and honeycombing extent over time and worse survival than T allele carriers. Longitudinal HRCT may help define the prognostic role of the MUC5B rs35705950 genotype. Full article
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14 pages, 4083 KiB  
Article
Are There Differences in Inflammatory and Fibrotic Pathways between IPAF, CTD-ILDs, and IIPs? A Single-Center Pilot Study
by Patrycja Rzepka-Wrona, Szymon Skoczyński and Adam Barczyk
Int. J. Mol. Sci. 2022, 23(23), 15205; https://doi.org/10.3390/ijms232315205 - 2 Dec 2022
Cited by 5 | Viewed by 1910
Abstract
In this pilot study, we aim to determine differences in pathogenetic pathways between interstitial pneumonia with autoimmune features (IPAF), connective-tissue-disease-associated interstitial lung diseases (CTD-ILDs), and idiopathic interstitial pneumonias (IIPs). Forty participants were recruited: 9 with IPAF, 15 with CTD-ILDs, and 16 with IIPs. [...] Read more.
In this pilot study, we aim to determine differences in pathogenetic pathways between interstitial pneumonia with autoimmune features (IPAF), connective-tissue-disease-associated interstitial lung diseases (CTD-ILDs), and idiopathic interstitial pneumonias (IIPs). Forty participants were recruited: 9 with IPAF, 15 with CTD-ILDs, and 16 with IIPs. Concentration of transforming growth factor beta (TGF-β1), surfactant proteins A and D (SP-A, SP-D), interleukin 8 (IL-8), and chemokine 1 (CXCL1) were assessed with ELISA assay in bronchoalveolar lavage (BAL) fluid. We revealed that IL-8 and TGF-β1 concentrations were significantly lower in the IPAF group than in the CTD-ILD group (p = 0.008 and p = 0.019, respectively), but similar to the concentrations in the IIP group. There were significant correlations of IL-8 (rs = 0.46; p = 0.003) and CXCL1 (rs = 0.52; p = 0.001) and BAL total cell count (TCC). A multivariate regression model revealed that IL-8 (β = 0.32; p = 0.037) and CXCL1 (β = 0.45; p = 0.004) are significant predictors of BAL TCC. We revealed that IL-8 and TGF-β1 BAL concentrations vary in patients with different ILDs and found that IL-8 is a predictor of BAL TCC in IPAF. However, this needs to be confirmed in a multicenter cooperative study (ClinicalTrials.gov Identifier: NCT03870828). Full article
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12 pages, 2894 KiB  
Article
B4GALT1 as a New Biomarker of Idiopathic Pulmonary Fibrosis
by Claudia De Vitis, Michela D’Ascanio, Andrea Sacconi, Dario Pizzirusso, Valentina Salvati, Massimiliano Mancini, Giorgia Scafetta, Roberto Cirombella, Francesca Ascenzi, Sara Bruschini, Antonella Esposito, Silvia Castelli, Claudia Salvucci, Leonardo Teodonio, Bruno Sposato, Angela Catizone, Arianna Di Napoli, Andrea Vecchione, Gennaro Ciliberto, Salvatore Sciacchitano, Alberto Ricci and Rita Manciniadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2022, 23(23), 15040; https://doi.org/10.3390/ijms232315040 - 30 Nov 2022
Cited by 6 | Viewed by 2176
Abstract
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring of the lung that involves the pulmonary interstitium. The disease may rapidly progress, leading to respiratory failure, and the long-term survival is poor. There are no accurate biomarkers available so far. Our [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring of the lung that involves the pulmonary interstitium. The disease may rapidly progress, leading to respiratory failure, and the long-term survival is poor. There are no accurate biomarkers available so far. Our aim was to evaluate the expression of the B4GALT1 in patients with IPF. Analysis of B4GALT1 gene expression was performed in silico on two gene sets, retrieved from the Gene Expression Omnibus database. Expression of B4GALT1 was then evaluated, both at the mRNA and protein levels, on lung specimens obtained from lung biopsies of 4 IPF patients, on one IPF-derived human primary cell and on 11 cases of IPF associated with cancer. In silico re-analysis demonstrated that the B4GALT1 gene was overexpressed in patients and human cell cultures with IPF (p = 0.03). Network analysis demonstrated that B4GALT1 upregulation was correlated with genes belonging to the EMT pathway (p = 0.01). The overexpression of B4GALT1 was observed, both at mRNA and protein levels, in lung biopsies of our four IPF patients and in the IPF-derived human primary cell, in other fibrotic non-lung tissues, and in IPF associated with cancer. In conclusion, our results indicate that B4GALT1 is overexpressed in IPF and could represent a novel marker of this disease. Full article
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18 pages, 4087 KiB  
Article
Cell-Specific Response of NSIP- and IPF-Derived Fibroblasts to the Modification of the Elasticity, Biological Properties, and 3D Architecture of the Substrate
by Natalia Janiszewska, Barbara Orzechowska, Kamil Awsiuk, Jakub Rysz, Svitlana Tymetska and Joanna Raczkowska
Int. J. Mol. Sci. 2022, 23(23), 14714; https://doi.org/10.3390/ijms232314714 - 25 Nov 2022
Cited by 3 | Viewed by 1675
Abstract
The fibrotic fibroblasts derived from idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) are surrounded by specific environments, characterized by increased stiffness, aberrant extracellular matrix (ECM) composition, and altered lung architecture. The presented research was aimed at investigating the effect of biological, [...] Read more.
The fibrotic fibroblasts derived from idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) are surrounded by specific environments, characterized by increased stiffness, aberrant extracellular matrix (ECM) composition, and altered lung architecture. The presented research was aimed at investigating the effect of biological, physical, and topographical modification of the substrate on the properties of IPF- and NSIP-derived fibroblasts, and searching for the parameters enabling their identification. Soft and stiff polydimethylsiloxane (PDMS) was chosen for the basic substrates, the properties of which were subsequently tuned. To obtain the biological modification of the substrates, they were covered with ECM proteins, laminin, fibronectin, and collagen. The substrates that mimicked the 3D structure of the lungs were prepared using two approaches, resulting in porous structures that resemble natural lung architecture and honeycomb patterns, typical of IPF tissue. The growth of cells on soft and stiff PDMS covered with proteins, traced using fluorescence microscopy, confirmed an altered behavior of healthy and IPF- and NSIP-derived fibroblasts in response to the modified substrate properties, enabling their identification. In turn, differences in the mechanical properties of healthy and fibrotic fibroblasts, determined using atomic force microscopy working in force spectroscopy mode, as well as their growth on 3D-patterned substrates were not sufficient to discriminate between cell lines. Full article
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13 pages, 7565 KiB  
Article
Effect of Sex Differences in Silicotic Mice
by Fuyu Jin, Yaqian Li, Xiaojing Wang, Xinyu Yang, Tian Li, Hong Xu, Zhongqiu Wei and Heliang Liu
Int. J. Mol. Sci. 2022, 23(22), 14203; https://doi.org/10.3390/ijms232214203 - 17 Nov 2022
Cited by 5 | Viewed by 1791
Abstract
Mechanisms of silicosis, caused by the inhalation of silica are still unclear, and the effect of sex on silicosis has rarely been reported. The purpose of this study was to investigate whether sex affects the silicotic lesions and the progressive fibrotic responses in [...] Read more.
Mechanisms of silicosis, caused by the inhalation of silica are still unclear, and the effect of sex on silicosis has rarely been reported. The purpose of this study was to investigate whether sex affects the silicotic lesions and the progressive fibrotic responses in silicosis. Our study showed that sex had no significant effect on the area of silicon nodules and the collagen deposition after a one-time bronchial perfusion of silica. Immunohistochemical staining showed that CD68 and the transforming growth factor-β1 (TGF-β1) were positive in male and female silicotic mice. In addition, the western blot results showed that the fibrosis-related factors type I collagen (COL I), α-smooth muscle actin (α-SMA), vimentin, TGF-β1, p-SMAD2/3, inflammatory-related factors interleukin 6 (IL 6), interleukin 1β (IL 1β), and senescence-related factors p16 and p21 were up-regulated in silicotic mice and there was no difference between female or male mice exposed to silica. The expression of TGF-β1, p-SMAD2/3, p16, and p21 were downregulated in the early stage of female silicotic mice, compared to the males. Thus, despite differences in the expression of certain factors, there was no overall difference in the progressive fibrosis between female and male mice in silicosis. These results thus provide a new perspective for studying the pathological development of silicosis. Full article
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21 pages, 4273 KiB  
Article
An Agent-Based Model of Radiation-Induced Lung Fibrosis
by Nicolò Cogno, Roman Bauer and Marco Durante
Int. J. Mol. Sci. 2022, 23(22), 13920; https://doi.org/10.3390/ijms232213920 - 11 Nov 2022
Cited by 7 | Viewed by 2625
Abstract
Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype [...] Read more.
Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models. Full article
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13 pages, 2726 KiB  
Article
ADAR1 Isoforms Regulate Let-7d Processing in Idiopathic Pulmonary Fibrosis
by Gabriela Díaz-Piña, Karla Rubio, Rosa M. Ordoñez-Razo, Guillermo Barreto, Eduardo Montes, Carina Becerril, Alfonso Salgado, Héctor Cabrera-Fuentes, Arnoldo Aquino-Galvez, Angeles Carlos-Reyes and Victor Ruiz
Int. J. Mol. Sci. 2022, 23(16), 9028; https://doi.org/10.3390/ijms23169028 - 12 Aug 2022
Cited by 3 | Viewed by 3100
Abstract
Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by [...] Read more.
Double-stranded RNA adenosine deaminase 1 (ADAR1) is significantly down-regulated in fibroblasts derived from Idiopathic Pulmonary Fibrosis (IPF) patients, and its overexpression restored levels of miRNA-21, PELI1, and SPRY2. There are two ADAR1 isoforms in humans, ADAR1-p110 and ADAR1-p150, generated by an alternative promoter. Let-7d is considered an essential microRNA in Pulmonary Fibrosis (PF). In silico analysis revealed COL3A1 and SMAD2, proteins involved in the development of IPF, as Let-7d targets. We analyzed the role of ADAR1-p110 and ADAR1-p150 isoforms in the regulation of Let-7d maturation and the effect of this regulation on the expression of COL3A1 and SMAD2 in IPF fibroblast. We demonstrated that differential expression and subcellular distribution of ADAR1 isoforms in fibroblasts contribute to the up-regulation of pri-miR-Let-7d and down-regulation of mature Let-7d. Induction of overexpression of ADAR1 reestablishes the expression of pri-miR-Let-7d and Let-7d in lung fibroblasts. The reduction of mature Let-7d upregulates the expression of COL3A1 and SMAD2. Thus, ADAR1 isoforms and Let-7d could have a synergistic role in IPF, which is a promising explanation in the mechanisms of fibrosis development, and the regulation of both molecules could be used as a therapeutic approach in IPF. Full article
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14 pages, 3056 KiB  
Article
Effect of Hypoxia on Pulmonary Endothelial Cells from Bleomycin-Induced Pulmonary Fibrosis Model Mice
by Daisuke Akahori, Naoki Inui, Yusuke Inoue, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Masato Karayama, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa and Takafumi Suda
Int. J. Mol. Sci. 2022, 23(16), 8996; https://doi.org/10.3390/ijms23168996 - 12 Aug 2022
Cited by 11 | Viewed by 2645
Abstract
Pulmonary fibrosis is a progressive and fatal disorder characterized by dysregulated repair after recurrent injury. Destruction of the lung architecture with excess extracellular matrix deposition induces respiratory failure with hypoxia and progressive dyspnea. The impact of hypoxia on pulmonary endothelial cells during pulmonary [...] Read more.
Pulmonary fibrosis is a progressive and fatal disorder characterized by dysregulated repair after recurrent injury. Destruction of the lung architecture with excess extracellular matrix deposition induces respiratory failure with hypoxia and progressive dyspnea. The impact of hypoxia on pulmonary endothelial cells during pulmonary fibrogenesis is unclear. Using a magnetic-activated cell sorting system, pulmonary endothelial cells were isolated from a mouse model of pulmonary fibrosis induced by intratracheally administered bleomycin. When endothelial cells were exposed to hypoxic conditions, a hypoxia-inducible factor (HIF)-2α protein was detected in CD31- and α-smooth muscle actin (SMA)-positive cells. Levels of plasminogen activator inhibitor 1, von Willebrand factor, and matrix metalloproteinase 12 were increased in endothelial cells isolated from bleomycin-treated mice exposed to hypoxic conditions. When endothelial cells were cultured under hypoxic conditions, levels of fibrotic mediators, transforming growth factor-β and connective tissue growth factor, were elevated only in endothelial cells from bleomycin-treated and not from saline-treated lungs. The increased expression of α-SMA and mesenchymal markers and collagen production in bleomycin- or hypoxia-stimulated endothelial cells were further elevated in endothelial cells from bleomycin-treated mouse lungs cultured under hypoxic conditions. Exposure to hypoxia damaged endothelial cells and enhanced fibrogenesis-related damage in bleomycin-treated pulmonary endothelial cells. Full article
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18 pages, 5919 KiB  
Article
3′5-Dimaleamylbenzoic Acid Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice
by Karina González-García, Armando López-Martínez, Juan Manuel Velázquez-Enríquez, Cecilia Zertuche-Martínez, Gabriela Carrasco-Torres, Luis Manuel Sánchez-Navarro, Saúl Villa-Treviño, Rafael Baltiérrez-Hoyos and Verónica Rocío Vásquez-Garzón
Int. J. Mol. Sci. 2022, 23(14), 7943; https://doi.org/10.3390/ijms23147943 - 19 Jul 2022
Cited by 4 | Viewed by 2987
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by parenchymal scarring, leading progressively to alveolar architecture distortion, respiratory failure, and eventually death. Currently, there is no effective treatment for IPF. Previously, 3′5-dimaleamylbenzoic acid (3′5-DMBA), a maleimide, demonstrated pro-apoptotic, anti-inflammatory, and anti-cancer [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by parenchymal scarring, leading progressively to alveolar architecture distortion, respiratory failure, and eventually death. Currently, there is no effective treatment for IPF. Previously, 3′5-dimaleamylbenzoic acid (3′5-DMBA), a maleimide, demonstrated pro-apoptotic, anti-inflammatory, and anti-cancer properties; however, its potential therapeutic effects on IPF have not been addressed. Bleomycin (BLM) 100 U/kg was administered to CD1 mice through an osmotic minipump. After fourteen days of BLM administration, 3′5-DMBA (6 mg/kg or 10 mg/kg) and its vehicle carboxymethylcellulose (CMC) were administered intragastrically every two days until day 26. On day 28, all mice were euthanized. The 3′5-DMBA effect was assessed by histological and immunohistochemical staining, as well as by RT-qPCR. The redox status on lung tissue was evaluated by determining the glutathione content and the GSH/GSSG ratio. 3′5-DMBA treatment re-established typical lung histological features and decreased the expression of BLM-induced fibrotic markers: collagen, α-SMA, and TGF-β1. Furthermore, 3′5-DMBA significantly reduced the expression of genes involved in fibrogenesis. In addition, it decreased reduced glutathione and increased oxidized glutathione content without promoting oxidative damage to lipids, as evidenced by the decrease in the lipid peroxidation marker 4-HNE. Therefore, 3′5-DMBA may be a promising candidate for IPF treatment. Full article
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13 pages, 5867 KiB  
Article
Thalidomide Alleviates Pulmonary Fibrosis Induced by Silica in Mice by Inhibiting ER Stress and the TLR4-NF-κB Pathway
by Yaqian Li, Wenchen Cai, Fuyu Jin, Xiaojing Wang, Wenjing Liu, Tian Li, Xinyu Yang, Heliang Liu, Hong Xu and Fang Yang
Int. J. Mol. Sci. 2022, 23(10), 5656; https://doi.org/10.3390/ijms23105656 - 18 May 2022
Cited by 13 | Viewed by 2811
Abstract
Silicosis is the most prevalent occupational disease in China. It is a form of pulmonary fibrosis caused by the inhalation of silicon particles. As there is no cure for the potentially lethal and progressive condition, the treatment of silicotic fibrosis is an important [...] Read more.
Silicosis is the most prevalent occupational disease in China. It is a form of pulmonary fibrosis caused by the inhalation of silicon particles. As there is no cure for the potentially lethal and progressive condition, the treatment of silicotic fibrosis is an important and difficult problem to address. Thalidomide, a drug with anti-inflammatory and immunoregulatory properties, has been reported to have lung-protective effects. The purpose of this study was to observe the therapeutic effect of thalidomide on silicotic mice and to determine the protective mechanism. By using silicotic mice models and MH-S cells, we found the expression of endoplasmic reticulum stress (ER stress) and Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) pathway as well as inflammation-related factors were upregulated in the macrophages of silicotic mice. The same indexes were detected in silica-stimulated MH-S cells, and the results were consistent with those in vivo. That is, silica activated ER stress and the TLR4-NF-κB pathway as well as the inflammatory response in vitro. Treating both silicotic mice and silica-stimulated MH-S cells with thalidomide inhibited ER stress and the TLR4-NF-κB pathway as well as the inflammatory response. The present study demonstrates thalidomide as a potential therapeutic agent against silicosis. Full article
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Review

Jump to: Research

23 pages, 940 KiB  
Review
Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers
by Fotios Drakopanagiotakis, Philipp Markart and Paschalis Steiropoulos
Int. J. Mol. Sci. 2023, 24(12), 10196; https://doi.org/10.3390/ijms241210196 - 15 Jun 2023
Cited by 5 | Viewed by 4499
Abstract
Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture [...] Read more.
Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture through unchecked collagen deposition. Acute exacerbations are dramatic events during the clinical course of ILDs, associated with high morbidity and mortality. Infections, microaspiration, and advanced lung disease might be involved in the pathogenesis of acute exacerbations. Despite clinical scores, the prediction of the onset and outcome of acute exacerbations is still inaccurate. Biomarkers are necessary to characterize acute exacerbations better. We review the evidence for alveolar epithelial cell, fibropoliferation, and immunity molecules as potential biomarkers for acute exacerbations of interstitial lung disease. Full article
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18 pages, 2219 KiB  
Review
Injured Endothelial Cell: A Risk Factor for Pulmonary Fibrosis
by Weiming Zhao, Lan Wang, Yaxuan Wang, Hongmei Yuan, Mengxia Zhao, Hui Lian, Shuaichen Ma, Kai Xu, Zhongzheng Li and Guoying Yu
Int. J. Mol. Sci. 2023, 24(10), 8749; https://doi.org/10.3390/ijms24108749 - 14 May 2023
Cited by 14 | Viewed by 2813
Abstract
The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the extracellular matrix (ECM). However, the pathogenesis of PF is still indistinct. In recent years, many researchers have realized that endothelial cells had [...] Read more.
The pathological features of pulmonary fibrosis (PF) are the abnormal activation and proliferation of myofibroblasts and the extraordinary deposition of the extracellular matrix (ECM). However, the pathogenesis of PF is still indistinct. In recent years, many researchers have realized that endothelial cells had a crucial role in the development of PF. Studies have demonstrated that about 16% of the fibroblasts in the lung tissue of fibrotic mice were derived from endothelial cells. Endothelial cells transdifferentiated into mesenchymal cells via the endothelial–mesenchymal transition (E(nd)MT), leading to the excessive proliferation of endothelial-derived mesenchymal cells and the accumulation of fibroblasts and ECM. This suggested that endothelial cells, a significant component of the vascular barrier, played an essential role in PF. Herein, this review discusses E(nd)MT and its contribution to the activation of other cells in PF, which could provide new ideas for further understanding the source and activation mechanism of fibroblasts and the pathogenesis of PF. Full article
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27 pages, 4773 KiB  
Review
Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation
by Samar A. Antar, Nada A. Ashour, Mohamed E. Marawan and Ahmed A. Al-Karmalawy
Int. J. Mol. Sci. 2023, 24(4), 4004; https://doi.org/10.3390/ijms24044004 - 16 Feb 2023
Cited by 62 | Viewed by 14691
Abstract
Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues [...] Read more.
Most chronic inflammatory illnesses include fibrosis as a pathogenic characteristic. Extracellular matrix (ECM) components build up in excess to cause fibrosis or scarring. The fibrotic process finally results in organ malfunction and death if it is severely progressive. Fibrosis affects nearly all tissues of the body. The fibrosis process is associated with chronic inflammation, metabolic homeostasis, and transforming growth factor-β1 (TGF-β1) signaling, where the balance between the oxidant and antioxidant systems appears to be a key modulator in managing these processes. Virtually every organ system, including the lungs, heart, kidney, and liver, can be affected by fibrosis, which is characterized as an excessive accumulation of connective tissue components. Organ malfunction is frequently caused by fibrotic tissue remodeling, which is also frequently linked to high morbidity and mortality. Up to 45% of all fatalities in the industrialized world are caused by fibrosis, which can damage any organ. Long believed to be persistently progressing and irreversible, fibrosis has now been revealed to be a very dynamic process by preclinical models and clinical studies in a variety of organ systems. The pathways from tissue damage to inflammation, fibrosis, and/or malfunction are the main topics of this review. Furthermore, the fibrosis of different organs with their effects was discussed. Finally, we highlight many of the principal mechanisms of fibrosis. These pathways could be considered as promising targets for the development of potential therapies for a variety of important human diseases. Full article
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31 pages, 886 KiB  
Review
Immune Mechanisms of Pulmonary Fibrosis with Bleomycin
by Yuko Ishida, Yumi Kuninaka, Naofumi Mukaida and Toshikazu Kondo
Int. J. Mol. Sci. 2023, 24(4), 3149; https://doi.org/10.3390/ijms24043149 - 5 Feb 2023
Cited by 37 | Viewed by 8421
Abstract
Fibrosis and structural remodeling of the lung tissue can significantly impair lung function, often with fatal consequences. The etiology of pulmonary fibrosis (PF) is diverse and includes different triggers such as allergens, chemicals, radiation, and environmental particles. However, the cause of idiopathic PF [...] Read more.
Fibrosis and structural remodeling of the lung tissue can significantly impair lung function, often with fatal consequences. The etiology of pulmonary fibrosis (PF) is diverse and includes different triggers such as allergens, chemicals, radiation, and environmental particles. However, the cause of idiopathic PF (IPF), one of the most common forms of PF, remains unknown. Experimental models have been developed to study the mechanisms of PF, and the murine bleomycin (BLM) model has received the most attention. Epithelial injury, inflammation, epithelial–mesenchymal transition (EMT), myofibroblast activation, and repeated tissue injury are important initiators of fibrosis. In this review, we examined the common mechanisms of lung wound-healing responses after BLM-induced lung injury as well as the pathogenesis of the most common PF. A three-stage model of wound repair involving injury, inflammation, and repair is outlined. Dysregulation of one or more of these three phases has been reported in many cases of PF. We reviewed the literature investigating PF pathogenesis, and the role of cytokines, chemokines, growth factors, and matrix feeding in an animal model of BLM-induced PF. Full article
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14 pages, 835 KiB  
Review
The Molecular Mechanisms of Systemic Sclerosis-Associated Lung Fibrosis
by Joe E. Mouawad and Carol Feghali-Bostwick
Int. J. Mol. Sci. 2023, 24(3), 2963; https://doi.org/10.3390/ijms24032963 - 3 Feb 2023
Cited by 14 | Viewed by 3535
Abstract
Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually [...] Read more.
Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune disorder that affects the connective tissues and has the highest mortality rate among the rheumatic diseases. One of the hallmarks of SSc is fibrosis, which may develop systemically, affecting the skin and virtually any visceral organ in the body. Fibrosis of the lungs leads to interstitial lung disease (ILD), which is currently the leading cause of death in SSc. The identification of effective treatments to stop or reverse lung fibrosis has been the main challenge in reducing SSc mortality and improving patient outcomes and quality of life. Thus, understanding the molecular mechanisms, altered pathways, and their potential interactions in SSc lung fibrosis is key to developing potential therapies. In this review, we discuss the diverse molecular mechanisms involved in SSc-related lung fibrosis to provide insights into the altered homeostasis state inherent to this fatal disease complication. Full article
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13 pages, 1549 KiB  
Review
Wilms Tumor 1-Driven Fibroblast Activation and Subpleural Thickening in Idiopathic Pulmonary Fibrosis
by Prathibha R. Gajjala, Priyanka Singh, Varshini Odayar, Harshavardhana H. Ediga, Francis X. McCormack and Satish K. Madala
Int. J. Mol. Sci. 2023, 24(3), 2850; https://doi.org/10.3390/ijms24032850 - 2 Feb 2023
Cited by 1 | Viewed by 3180
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is often fatal due to the formation of irreversible scar tissue in the distal areas of the lung. Although the pathological and radiological features of IPF lungs are well defined, the lack [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is often fatal due to the formation of irreversible scar tissue in the distal areas of the lung. Although the pathological and radiological features of IPF lungs are well defined, the lack of insight into the fibrogenic role of fibroblasts that accumulate in distinct anatomical regions of the lungs is a critical knowledge gap. Fibrotic lesions have been shown to originate in the subpleural areas and extend into the lung parenchyma through processes of dysregulated fibroproliferation, migration, fibroblast-to-myofibroblast transformation, and extracellular matrix production. Identifying the molecular targets underlying subpleural thickening at the early and late stages of fibrosis could facilitate the development of new therapies to attenuate fibroblast activation and improve the survival of patients with IPF. Here, we discuss the key cellular and molecular events that contribute to (myo)fibroblast activation and subpleural thickening in IPF. In particular, we highlight the transcriptional programs involved in mesothelial to mesenchymal transformation and fibroblast dysfunction that can be targeted to alter the course of the progressive expansion of fibrotic lesions in the distal areas of IPF lungs. Full article
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13 pages, 1709 KiB  
Review
The Role of Pulmonary Surfactant Phospholipids in Fibrotic Lung Diseases
by Beatriz Tlatelpa-Romero, Verna Cázares-Ordoñez, Luis F. Oyarzábal and Luis G. Vázquez-de-Lara
Int. J. Mol. Sci. 2023, 24(1), 326; https://doi.org/10.3390/ijms24010326 - 25 Dec 2022
Cited by 14 | Viewed by 5769
Abstract
Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no [...] Read more.
Diffuse parenchymal lung diseases (DPLD) or Interstitial lung diseases (ILD) are a heterogeneous group of lung conditions with common characteristics that can progress to fibrosis. Within this group of pneumonias, idiopathic pulmonary fibrosis (IPF) is considered the most common. This disease has no known cause, is devastating and has no cure. Chronic lesion of alveolar type II (ATII) cells represents a key mechanism for the development of IPF. ATII cells are specialized in the biosynthesis and secretion of pulmonary surfactant (PS), a lipid-protein complex that reduces surface tension and minimizes breathing effort. Some differences in PS composition have been reported between patients with idiopathic pulmonary disease and healthy individuals, especially regarding some specific proteins in the PS; however, few reports have been conducted on the lipid components. This review focuses on the mechanisms by which phospholipids (PLs) could be involved in the development of the fibroproliferative response. Full article
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10 pages, 965 KiB  
Review
Inhibitors of the Sialidase NEU3 as Potential Therapeutics for Fibrosis
by Tejas R. Karhadkar, Wensheng Chen, Darrell Pilling and Richard H. Gomer
Int. J. Mol. Sci. 2023, 24(1), 239; https://doi.org/10.3390/ijms24010239 - 23 Dec 2022
Cited by 2 | Viewed by 2274
Abstract
Fibrosing diseases are a major medical problem, and are associated with more deaths per year than cancer in the US. Sialidases are enzymes that remove the sugar sialic acid from glycoconjugates. In this review, we describe efforts to inhibit fibrosis by inhibiting sialidases, [...] Read more.
Fibrosing diseases are a major medical problem, and are associated with more deaths per year than cancer in the US. Sialidases are enzymes that remove the sugar sialic acid from glycoconjugates. In this review, we describe efforts to inhibit fibrosis by inhibiting sialidases, and describe the following rationale for considering sialidases to be a potential target to inhibit fibrosis. First, sialidases are upregulated in fibrotic lesions in humans and in a mouse model of pulmonary fibrosis. Second, the extracellular sialidase NEU3 appears to be both necessary and sufficient for pulmonary fibrosis in mice. Third, there exist at least three mechanistic ways in which NEU3 potentiates fibrosis, with two of them being positive feedback loops where a profibrotic cytokine upregulates NEU3, and the upregulated NEU3 then upregulates the profibrotic cytokine. Fourth, a variety of NEU3 inhibitors block pulmonary fibrosis in a mouse model. Finally, the high sialidase levels in a fibrotic lesion cause an easily observed desialylation of serum proteins, and in a mouse model, sialidase inhibitors that stop fibrosis reverse the serum protein desialylation. This then indicates that serum protein sialylation is a potential surrogate biomarker for the effect of sialidase inhibitors, which would facilitate clinical trials to test the exciting possibility that sialidase inhibitors could be used as therapeutics for fibrosis. Full article
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42 pages, 1755 KiB  
Review
Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches
by Innokenty A. Savin, Marina A. Zenkova and Aleksandra V. Sen’kova
Int. J. Mol. Sci. 2022, 23(23), 14959; https://doi.org/10.3390/ijms232314959 - 29 Nov 2022
Cited by 74 | Viewed by 10948
Abstract
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over [...] Read more.
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed. Full article
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13 pages, 1005 KiB  
Review
Cellular and Molecular Mechanism of Pulmonary Fibrosis Post-COVID-19: Focus on Galectin-1, -3, -8, -9
by Daniela Oatis, Erika Simon-Repolski, Cornel Balta, Alin Mihu, Gorizio Pieretti, Roberto Alfano, Luisa Peluso, Maria Consiglia Trotta, Michele D’Amico and Anca Hermenean
Int. J. Mol. Sci. 2022, 23(15), 8210; https://doi.org/10.3390/ijms23158210 - 26 Jul 2022
Cited by 16 | Viewed by 4135
Abstract
Pulmonary fibrosis is a consequence of the pathological accumulation of extracellular matrix (ECM), which finally leads to lung scarring. Although the pulmonary fibrogenesis is almost known, the last two years of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [...] Read more.
Pulmonary fibrosis is a consequence of the pathological accumulation of extracellular matrix (ECM), which finally leads to lung scarring. Although the pulmonary fibrogenesis is almost known, the last two years of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its post effects added new particularities which need to be explored. Many questions remain about how pulmonary fibrotic changes occur within the lungs of COVID-19 patients, and whether the changes will persist long term or are capable of resolving. This review brings together existing knowledge on both COVID-19 and pulmonary fibrosis, starting with the main key players in promoting pulmonary fibrosis, such as alveolar and endothelial cells, fibroblasts, lipofibroblasts, and macrophages. Further, we provide an overview of the main molecular mechanisms driving the fibrotic process in connection with Galactin-1, -3, -8, and -9, together with the currently approved and newly proposed clinical therapeutic solutions given for the treatment of fibrosis, based on their inhibition. The work underlines the particular pathways and processes that may be implicated in pulmonary fibrosis pathogenesis post-SARS-CoV-2 viral infection. The recent data suggest that galectin-1, -3, -8, and -9 could become valuable biomarkers for the diagnosis and prognosis of lung fibrosis post-COVID-19 and promising molecular targets for the development of new and original therapeutic tools to treat the disease. Full article
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