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Molecular Research on Fibrotic Interstitial Lung Diseases

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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 (31 December 2021) | Viewed by 70716

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Special Issue Editors

Dr. Alessandro Marchioni

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Guest Editor

Azienda Ospedaliero - Universitaria di Modena Policlinico, Modena, Italy
Interests: respiratory physiology; mechanical ventilation; interstitial lung diseases; interventional pneumology; stem cells in pulmonary disease; airway repair and regeneration
Special Issues, Collections and Topics in MDPI journals

Dr. Roberto Tonelli

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Azienda Ospedaliero - Universitaria di Modena Policlinico, Modena, Italy
Interests: interstitial lung diseases; stem cells in pulmonary disease; laboratory of experimental pneumology; respiratory failure; mechanical ventilation; idiopathic pulmonary fibrosis

Special Issue Information

Dear Colleagues,

We are delighted to announce a call for submissions to a Special Issue of the International Journal of Molecular Sciences on the topic of Molecular Research on Fibrotic Interstitial Lung Diseases. Fibrotic disorders of the lung are a spectrum of clinical entities with different underlying etiology ranging from occupational exposures (e.g., beryllium, silica), immunological diseases (e.g., rheumatoid arthritis, scleroderma), and drug exposures to idiopathic etiology (e.g., idiopathic pulmonary fibrosis). Furthermore, vigorous inflammatory stimuli due to infections (e.g., SARS-CoV, SARS-CoV-2) or acute respiratory distress syndrome could result in dysregulated lung repair and pulmonary fibrosis. Idiopathic pulmonary fibrosis (IPF) is the most common fibrosing lung disease and is associated with progressive loss of pulmonary function and high mortality. Although pirfenidone and nintedanib, two drugs recently approved by the FDA, have shown an ability to reduce the progression of the disease, prognosis remains poor. Knowledge on the molecular mechanisms underlying pulmonary fibrogenesis is essential to support the efficient translation of new targeted therapy from bench to clinic. We encourage the submission of both original research articles and reviews on all aspects of the molecular mechanisms behind the development and the progression of fibrotic lung diseases. All submitted articles will undergo peer review.

Dr. Alessandro Marchioni
Dr. Roberto Tonelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

idiopathic pulmonary fibrosis
rheumatoid arthritis
myofibroblast
transforming growth factor beta
extracellular matrix
infections
acute respiratory distress syndrome
severe acute respiratory syndrome coronavirus 2

Published Papers (13 papers)

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Research

Jump to: Review

27 pages, 2975 KiB

Open AccessArticle

Distal Lung Microenvironment Triggers Release of Mediators Recognized as Potential Systemic Biomarkers for Idiopathic Pulmonary Fibrosis

by Dimitrios Kalafatis, Anna Löfdahl, Per Näsman, Göran Dellgren, Åsa M. Wheelock, Linda Elowsson Rendin, Magnus Sköld and Gunilla Westergren-Thorsson

Int. J. Mol. Sci. 2021, 22(24), 13421; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413421 - 14 Dec 2021

Cited by 10 | Viewed by 3591

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model’s applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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20 pages, 4431 KiB

Open AccessArticle

Linking Fibrotic Remodeling and Ultrastructural Alterations of Alveolar Epithelial Cells after Deletion of Nedd4-2

by Theresa A. Engelmann, Lars Knudsen, Dominik H. W. Leitz, Julia Duerr, Michael F. Beers, Marcus A. Mall and Matthias Ochs

Int. J. Mol. Sci. 2021, 22(14), 7607; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147607 - 16 Jul 2021

Cited by 4 | Viewed by 2121

Abstract

Our previous study showed that in adult mice, conditional Nedd4-2-deficiency in club and alveolar epithelial type II (AE2) cells results in impaired mucociliary clearance, accumulation of Muc5b and progressive, terminal pulmonary fibrosis within 16 weeks. In the present study, we investigated ultrastructural alterations of the alveolar epithelium in relation to interstitial remodeling in alveolar septa as a function of disease progression. Two, eight and twelve weeks after induction of Nedd4-2 knockout, lungs were fixed and subjected to design-based stereological investigation at the light and electron microscopic level. Quantitative data did not show any abnormalities until 8 weeks compared to controls. At 12 weeks, however, volume of septal wall tissue increased while volume of acinar airspace and alveolar surface area significantly decreased. Volume and surface area of alveolar epithelial type I cells were reduced, which could not be compensated by a corresponding increase of AE2 cells. The volume of collagen fibrils in septal walls increased and was linked with an increase in blood–gas barrier thickness. A high correlation between parameters reflecting interstitial remodeling and abnormal AE2 cell ultrastructure could be established. Taken together, abnormal regeneration of the alveolar epithelium is correlated with interstitial septal wall remodeling. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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13 pages, 3061 KiB

Open AccessArticle

Extension of Collagen Deposition in COVID-19 Post Mortem Lung Samples and Computed Tomography Analysis Findings

by Lorenzo Ball, Emanuela Barisione, Luca Mastracci, Michela Campora, Delfina Costa, Chiara Robba, Denise Battaglini, Marco Micali, Federico Costantino, Giuseppe Cittadini, Nicolò Patroniti, Paolo Pelosi, Roberto Fiocca and Federica Grillo

Int. J. Mol. Sci. 2021, 22(14), 7498; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147498 - 13 Jul 2021

Cited by 14 | Viewed by 5356

Abstract

Lung fibrosis has specific computed tomography (CT) findings and represents a common finding in advanced COVID-19 pneumonia whose reversibility has been poorly investigated. The aim of this study was to quantify the extension of collagen deposition and aeration in postmortem cryobiopsies of critically ill COVID-19 patients and to describe the correlations with qualitative and quantitative analyses of lung CT. Postmortem transbronchial cryobiopsy samples were obtained, formalin fixed, paraffin embedded and stained with Sirius red to quantify collagen deposition, defining fibrotic samples as those with collagen deposition above 10%. Lung CT images were analyzed qualitatively with a radiographic score and quantitatively with computer-based analysis at the lobe level. Thirty samples from 10 patients with COVID-19 pneumonia deceased during invasive mechanical ventilation were included in this study. The median [interquartile range] percent collagen extension was 6.8% (4.6–16.2%). In fibrotic compared to nonfibrotic samples, the qualitative score was higher (260 (250–290) vs. 190 (120–270), p = 0.036) while the gas fraction was lower (0.46 (0.32–0.47) vs. 0.59 (0.37–0.68), p = 0.047). A radiographic score above 230 had 100% sensitivity (95% confidence interval, CI: 66.4% to 100%) and 66.7% specificity (95% CI: 41.0% to 92.3%) to detect fibrotic samples, while a gas fraction below 0.57 had 100% sensitivity (95% CI: 66.4% to 100%) and 57.1% specificity (95% CI: 26.3% to 88.0%). In COVID-19 pneumonia, qualitative and quantitative analyses of lung CT images have high sensitivity but moderate to low specificity to detect histopathological fibrosis. Pseudofibrotic CT findings do not always correspond to increased collagen deposition. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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18 pages, 2387 KiB

Open AccessArticle

Congenital Deletion of Nedd4-2 in Lung Epithelial Cells Causes Progressive Alveolitis and Pulmonary Fibrosis in Neonatal Mice

by Dominik H. W. Leitz, Julia Duerr, Surafel Mulugeta, Ayça Seyhan Agircan, Stefan Zimmermann, Hiroshi Kawabe, Alexander H. Dalpke, Michael F. Beers and Marcus A. Mall

Int. J. Mol. Sci. 2021, 22(11), 6146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116146 - 07 Jun 2021

Cited by 10 | Viewed by 2710

Abstract

Recent studies found that expression of NEDD4-2 is reduced in lung tissue from patients with idiopathic pulmonary fibrosis (IPF) and that the conditional deletion of Nedd4-2 in lung epithelial cells causes IPF-like disease in adult mice via multiple defects, including dysregulation of the epithelial Na⁺ channel (ENaC), TGFβ signaling and the biosynthesis of surfactant protein-C proprotein (proSP-C). However, knowledge of the impact of congenital deletion of Nedd4-2 on the lung phenotype remains limited. In this study, we therefore determined the effects of congenital deletion of Nedd4-2 in the lung epithelial cells of neonatal doxycycline-induced triple transgenic Nedd4-2^fl/fl/CCSP-rtTA2^S-M2/LC1 mice, with a focus on clinical phenotype, survival, lung morphology, inflammation markers in BAL, mucin expression, ENaC function and proSP-C trafficking. We found that the congenital deletion of Nedd4-2 caused a rapidly progressive lung disease in neonatal mice that shares key features with interstitial lung diseases in children (chILD), including hypoxemia, growth failure, sterile pneumonitis, fibrotic lung remodeling and high mortality. The congenital deletion of Nedd4-2 in lung epithelial cells caused increased expression of Muc5b and mucus plugging of distal airways, increased ENaC activity and proSP-C mistrafficking. This model of congenital deletion of Nedd4-2 may support studies of the pathogenesis and preclinical development of therapies for chILD. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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16 pages, 3048 KiB

Open AccessArticle

by Pavel Solopov, Ruben Manuel Luciano Colunga Biancatelli, Christiana Dimitropoulou and John D. Catravas

Int. J. Mol. Sci. 2021, 22(11), 5909; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115909 - 31 May 2021

Cited by 15 | Viewed by 5245

Abstract

We developed two models of chemically induced chronic lung injury and pulmonary fibrosis in mice (intratracheally administered hydrochloric acid (HCl) and intratracheally administered nitrogen mustard (NM)) and investigated male–female differences. Female mice exhibited higher 30-day survival and less weight loss than male mice. Thirty days after the instillation of either HCl or NM, bronchoalveolar lavage fluid displayed a persistent, mild inflammatory response, but with higher white blood cell numbers and total protein content in males vs. females. Furthermore, females exhibited less collagen deposition, milder pulmonary fibrosis, and lower Ashcroft scores. After instillation of either HCl or NM, all animals displayed increased values of phosphorylated (activated) Heat Shock Protein 90, which plays a crucial role in the alveolar wound-healing processes; however, females presented lower activation of both transforming growth factor-β (TGF-β) signaling pathways: ERK and SMAD. We propose that female mice are protected from chronic complications of a single exposure to either HCl or NM through a lesser activation of TGF-β and downstream signaling. The understanding of the molecular mechanisms that confer a protective effect in females could help develop new, gender-specific therapeutics for IPF. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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22 pages, 44484 KiB

Open AccessArticle

Micellar Hyaluronidase and Spiperone as a Potential Treatment for Pulmonary Fibrosis

by Evgenii Skurikhin, Pavel Madonov, Olga Pershina, Natalia Ermakova, Angelina Pakhomova, Darius Widera, Edgar Pan, Mariia Zhukova, Lubov Sandrikina, Andrey Artamonov and Alexander Dygai

Int. J. Mol. Sci. 2021, 22(11), 5599; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115599 - 25 May 2021

Cited by 6 | Viewed by 2887

Abstract

Concentration of hyaluronic acid (HA) in the lungs increases in idiopathic pulmonary fibrosis (IPF). HA is involved in the organization of fibrin, fibronectin, and collagen. HA has been proposed to be a biomarker of fibrosis and a potential target for antifibrotic therapy. Hyaluronidase (HD) breaks down HA into fragments, but is a subject of rapid hydrolysis. A conjugate of poloxamer hyaluronidase (pHD) was prepared using protein immobilization with ionizing radiation. In a model of bleomycin-induced pulmonary fibrosis, pHD decreased the level of tissue IL-1β and TGF-β, prevented the infiltration of the lung parenchyma by CD16⁺ cells, and reduced perivascular and peribronchial inflammation. Simultaneously, a decrease in the concentrations of HA, hydroxyproline, collagen 1, total soluble collagen, and the area of connective tissue in the lungs was observed. The effects of pHD were significantly stronger compared to native HD which can be attributed to the higher stability of pHD. Additional spiperone administration increased the anti-inflammatory and antifibrotic effects of pHD and accelerated the regeneration of the damaged lung. The potentiating effects of spiperone can be explained by the disruption of the dopamine-induced mobilization and migration of fibroblast progenitor cells into the lungs and differentiation of lung mesenchymal stem cells (MSC) into cells of stromal lines. Thus, a combination of pHD and spiperone may represent a promising approach for the treatment of IPF and lung regeneration. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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Review

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15 pages, 1004 KiB

Open AccessReview

Involvement of the ACE2/Ang-(1–7)/MasR Axis in Pulmonary Fibrosis: Implications for COVID-19

by Taylor Morganstein, Zahraa Haidar, Joshua Trivlidis, Ilan Azuelos, Megan Jiaxin Huang, David H. Eidelman and Carolyn J. Baglole

Int. J. Mol. Sci. 2021, 22(23), 12955; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312955 - 30 Nov 2021

Cited by 14 | Viewed by 4508

Abstract

Pulmonary fibrosis is a chronic, fibrotic lung disease affecting 3 million people worldwide. The ACE2/Ang-(1–7)/MasR axis is of interest in pulmonary fibrosis due to evidence of its anti-fibrotic action. Current scientific evidence supports that inhibition of ACE2 causes enhanced fibrosis. ACE2 is also the primary receptor that facilitates the entry of SARS-CoV-2, the virus responsible for the current COVID-19 pandemic. COVID-19 is associated with a myriad of symptoms ranging from asymptomatic to severe pneumonia and acute respiratory distress syndrome (ARDS) leading to respiratory failure, mechanical ventilation, and often death. One of the potential complications in people who recover from COVID-19 is pulmonary fibrosis. Cigarette smoking is a risk factor for fibrotic lung diseases, including the idiopathic form of this disease (idiopathic pulmonary fibrosis), which has a prevalence of 41% to 83%. Cigarette smoke increases the expression of pulmonary ACE2 and is thought to alter susceptibility to COVID-19. Cannabis is another popular combustible product that shares some similarities with cigarette smoke, however, cannabis contains cannabinoids that may reduce inflammation and/or ACE2 levels. The role of cannabis smoke in the pathogenesis of pulmonary fibrosis remains unknown. This review aimed to characterize the ACE2-Ang-(1–7)-MasR Axis in the context of pulmonary fibrosis with an emphasis on risk factors, including the SARS-CoV-2 virus and exposure to environmental toxicants. In the context of the pandemic, there is a dire need for an understanding of pulmonary fibrotic events. More research is needed to understand the interplay between ACE2, pulmonary fibrosis, and susceptibility to coronavirus infection. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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18 pages, 1110 KiB

Open AccessReview

COPD, Pulmonary Fibrosis and ILAs in Aging Smokers: The Paradox of Striking Different Responses to the Major Risk Factors

by Bianca Beghé, Stefania Cerri, Leonardo M. Fabbri and Alessandro Marchioni

Int. J. Mol. Sci. 2021, 22(17), 9292; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179292 - 27 Aug 2021

Cited by 14 | Viewed by 3843

Abstract

Aging and smoking are associated with the progressive development of three main pulmonary diseases: chronic obstructive pulmonary disease (COPD), interstitial lung abnormalities (ILAs), and idiopathic pulmonary fibrosis (IPF). All three manifest mainly after the age of 60 years, but with different natural histories and prevalence: COPD prevalence increases with age to >40%, ILA prevalence is 8%, and IPF, a rare disease, is 0.0005–0.002%. While COPD and ILAs may be associated with gradual progression and mortality, the natural history of IPF remains obscure, with a worse prognosis and life expectancy of 2–5 years from diagnosis. Acute exacerbations are significant events in both COPD and IPF, with a much worse prognosis in IPF. This perspective discusses the paradox of the striking pathological and pathophysiologic responses on the background of the same main risk factors, aging and smoking, suggesting two distinct pathophysiologic processes for COPD and ILAs on one side and IPF on the other side. Pathologically, COPD is characterized by small airways fibrosis and remodeling, with the destruction of the lung parenchyma. By contrast, IPF almost exclusively affects the lung parenchyma and interstitium. ILAs are a heterogenous group of diseases, a minority of which present with the alveolar and interstitial abnormalities of interstitial lung disease. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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17 pages, 1190 KiB

Open AccessReview

Fibrotic Idiopathic Interstitial Lung Disease: The Molecular and Cellular Key Players

by Anna Valeria Samarelli, Roberto Tonelli, Alessandro Marchioni, Giulia Bruzzi, Filippo Gozzi, Dario Andrisani, Ivana Castaniere, Linda Manicardi, Antonio Moretti, Luca Tabbì, Stefania Cerri, Bianca Beghè, Massimo Dominici and Enrico Clini

Int. J. Mol. Sci. 2021, 22(16), 8952; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168952 - 19 Aug 2021

Cited by 24 | Viewed by 6696

Abstract

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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14 pages, 1520 KiB

Open AccessReview

Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung

by Alessandro Marchioni, Roberto Tonelli, Stefania Cerri, Ivana Castaniere, Dario Andrisani, Filippo Gozzi, Giulia Bruzzi, Linda Manicardi, Antonio Moretti, Jacopo Demurtas, Serena Baroncini, Alessandro Andreani, Gaia Francesca Cappiello, Stefano Busani, Riccardo Fantini, Luca Tabbì, Anna Valeria Samarelli and Enrico Clini

Int. J. Mol. Sci. 2021, 22(12), 6443; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126443 - 16 Jun 2021

Cited by 25 | Viewed by 5721

Abstract

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress–strain curve but follows the mechano-elastic models of “squishy balls”, where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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25 pages, 917 KiB

Open AccessReview

Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions

by Anna Stainer, Paola Faverio, Sara Busnelli, Martina Catalano, Matteo Della Zoppa, Almerico Marruchella, Alberto Pesci and Fabrizio Luppi

Int. J. Mol. Sci. 2021, 22(12), 6255; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126255 - 10 Jun 2021

Cited by 34 | Viewed by 7763

Abstract

Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called “usual interstitial pneumonia” pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5–10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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22 pages, 828 KiB

Open AccessReview

Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

by Tanyalak Parimon, Miriam S. Hohmann and Changfu Yao

Int. J. Mol. Sci. 2021, 22(12), 6214; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126214 - 09 Jun 2021

Cited by 45 | Viewed by 7201

Abstract

Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate limited efficacies. Advancing our understanding of the pathogenic mechanisms of lung fibrosis will provide a future path for the cure. Cellular senescence has gained substantial interest in recent decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence-targeted signaling molecules and specific therapies to target senescent cells, known collectively as “senolytic” or “senotherapeutic” agents. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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22 pages, 1529 KiB

Open AccessReview

Role of JAK/STAT in Interstitial Lung Diseases; Molecular and Cellular Mechanisms

by Paula Montero, Javier Milara, Inés Roger and Julio Cortijo

Int. J. Mol. Sci. 2021, 22(12), 6211; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126211 - 09 Jun 2021

Cited by 112 | Viewed by 11752

Abstract

Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor β1 (TGF-β1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders. Full article

(This article belongs to the Special Issue Molecular Research on Fibrotic Interstitial Lung Diseases)

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