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Molecular Pathology of Idiopathic Pulmonary Fibrosis

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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 (29 April 2021) | Viewed by 54057

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Prof. Dr. Elena Bargagli

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Guest Editor

Respiratory Diseases and Lung Transplant Unit, Department of Medical and Surgical Sciences and Neurosciences, University of Siena, 53100 Siena, Italy
Interests: interstitial lung diseases; biomarkers; bronchoalveolar lavage; pathogenesis
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Dr. Paolo Cameli

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Co-Guest Editor

Respiratory Diseases and Lung Transplantation Unit, Department of Medicine, Surgery and Neurosciences, University Hospital of Siena, 53100 Siena, Italy
Interests: interstitial lung disease; KL-6; lung transplant; vasculitis; myositis
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Special Issue Information

Dear Colleagues,

This is a novel era in idiopathic pulmonary fibrosis research. In the last decade, we have experienced great advances of our knowledge and comprehension on the pathogenetic pathways involved in fibrotic lung diseases.

These novel findings have led to the approval of specific antifibrotic drugs that are currently the milestones of clinical management of these patients.

However, many questions remain unsolved: We still need to identify reliable biomarkers that could help in differential diagnosis, prognosis, and in patient stratification, as well as in the definition of the response to treatment. Other unmet needs include the definition of the etiology and risk factors for idiopathic pulmonary fibrosis development, as well as genetic definition of susceptibility. OMIC sciences are contributing greatly to this field, and this Special Issue aims to provide some answers to the unresolved questions on the Molecular Pathology of Idiopathic Pulmonary Fibrosis.

Prof. Dr. Elena Bargagli
Dr. Paolo Cameli
Guest Editors

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Keywords

Idiopathic pulmonary fibrosis
Pathology
Molecular biomarkers
Pathogenesis
Interstitial lung diseases
Omics
Prognosis
Pathogenesis
Proteomics
Genetic

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Published Papers (9 papers)

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Research

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17 pages, 15999 KiB

Open AccessArticle

MUC16 Is Overexpressed in Idiopathic Pulmonary Fibrosis and Induces Fibrotic Responses Mediated by Transforming Growth Factor-β1 Canonical Pathway

by Beatriz Ballester, Javier Milara, Paula Montero and Julio Cortijo

Int. J. Mol. Sci. 2021, 22(12), 6502; https://doi.org/10.3390/ijms22126502 - 17 Jun 2021

Cited by 10 | Viewed by 2992

Abstract

Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients (n = 20) compared with healthy subjects (n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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14 pages, 3670 KiB

Open AccessArticle

Loss of MT1-MMP in Alveolar Epithelial Cells Exacerbates Pulmonary Fibrosis

by Luis Placido, Yair Romero, Mariel Maldonado, Fernanda Toscano-Marquez, Remedios Ramírez, Jazmín Calyeca, Ana L. Mora, Moisés Selman and Annie Pardo

Int. J. Mol. Sci. 2021, 22(6), 2923; https://doi.org/10.3390/ijms22062923 - 13 Mar 2021

Cited by 17 | Viewed by 4155

Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal age-related lung disease whose pathogenesis involves an aberrant response of alveolar epithelial cells (AEC). Activated epithelial cells secrete mediators that participate in the activation of fibroblasts and the excessive deposition of extracellular matrix proteins. Previous studies indicate that matrix metalloproteinase 14 (MMP14) is increased in the lung epithelium in patients with IPF, however, the role of this membrane-type matrix metalloproteinase has not been elucidated. In this study, the role of Mmp14 was explored in experimental lung fibrosis induced with bleomycin in a conditional mouse model of lung epithelial MMP14-specific genetic deletion. Our results show that epithelial Mmp14 deficiency in mice increases the severity and extension of fibrotic injury and affects the resolution of the lesions. Gain-and loss-of-function experiments with human epithelial cell line A549 demonstrated that cells with a deficiency of MMP14 exhibited increased senescence-associated markers. Moreover, conditioned medium from these cells increased fibroblast expression of fibrotic molecules. These findings suggest a new anti-fibrotic mechanism of MMP14 associated with anti-senescent activity, and consequently, its absence results in impaired lung repair. Increased MMP14 in IPF may represent an anti-fibrotic mechanism that is overwhelmed by the strong profibrotic microenvironment that characterizes this disease. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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Review

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15 pages, 621 KiB

Open AccessReview

Cellular Senescence in Lung Fibrosis

by Fernanda Hernandez-Gonzalez, Rosa Faner, Mauricio Rojas, Alvar Agustí, Manuel Serrano and Jacobo Sellarés

Int. J. Mol. Sci. 2021, 22(13), 7012; https://doi.org/10.3390/ijms22137012 - 29 Jun 2021

Cited by 44 | Viewed by 6202

Abstract

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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18 pages, 1434 KiB

Open AccessReview

Molecular Pathogenesis of Pulmonary Fibrosis, with Focus on Pathways Related to TGF-β and the Ubiquitin-Proteasome Pathway

by Naoki Inui, Satoshi Sakai and Masatoshi Kitagawa

Int. J. Mol. Sci. 2021, 22(11), 6107; https://doi.org/10.3390/ijms22116107 - 5 Jun 2021

Cited by 85 | Viewed by 8530

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease. During the past decade, novel pathogenic mechanisms of IPF have been elucidated that have shifted the concept of IPF from an inflammatory-driven to an epithelial-driven disease. Dysregulated repair responses induced by recurrent epithelial cell damage and excessive extracellular matrix accumulation result in pulmonary fibrosis. Although there is currently no curative therapy for IPF, two medications, pirfenidone and nintedanib, have been introduced based on understanding the pathogenesis of the disease. In this review, we discuss advances in understanding IPF pathogenesis, highlighting epithelial–mesenchymal transition (EMT), the ubiquitin-proteasome system, and endothelial cells. TGF-β is a central regulator involved in EMT and pulmonary fibrosis. HECT-, RING finger-, and U-box-type E3 ubiquitin ligases regulate TGF-β-Smad pathway-mediated EMT via the ubiquitin-proteasome pathway. p27 degradation mediated by the SCF-type E3 ligase, Skp2, contributes to the progression of pulmonary fibrosis by promotion of either mesenchymal fibroblast proliferation, EMT, or both. In addition to fibroblasts as key effector cells in myofibroblast differentiation and extracellular matrix deposition, endothelial cells also play a role in the processes of IPF. Endothelial cells can transform into myofibroblasts; therefore, endothelial–mesenchymal transition can be another source of myofibroblasts. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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19 pages, 1567 KiB

Open AccessReview

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

by Yoshitoshi Kasuya, Jun-Dal Kim, Masahiko Hatano, Koichiro Tatsumi and Shuichi Matsuda

Int. J. Mol. Sci. 2021, 22(11), 6041; https://doi.org/10.3390/ijms22116041 - 3 Jun 2021

Cited by 24 | Viewed by 6371

Abstract

Idiopathic pulmonary fibrosis (IPF) is one of the most symptomatic progressive fibrotic lung diseases, in which patients have an extremely poor prognosis. Therefore, understanding the precise molecular mechanisms underlying pulmonary fibrosis is necessary for the development of new therapeutic options. Stress-activated protein kinases (SAPKs), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38) are ubiquitously expressed in various types of cells and activated in response to cellular environmental stresses, including inflammatory and apoptotic stimuli. Type II alveolar epithelial cells, fibroblasts, and macrophages are known to participate in the progression of pulmonary fibrosis. SAPKs can control fibrogenesis by regulating the cellular processes and molecular functions in various types of lung cells (including cells of the epithelium, interstitial connective tissue, blood vessels, and hematopoietic and lymphoid tissue), all aspects of which remain to be elucidated. We recently reported that the stepwise elevation of intrinsic p38 signaling in the lungs is correlated with a worsening severity of bleomycin-induced fibrosis, indicating an importance of this pathway in the progression of pulmonary fibrosis. In addition, a transcriptome analysis of RNA-sequencing data from this unique model demonstrated that several lines of mechanisms are involved in the pathogenesis of pulmonary fibrosis, which provides a basis for further studies. Here, we review the accumulating evidence for the spatial and temporal roles of SAPKs in pulmonary fibrosis. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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16 pages, 2120 KiB

Open AccessReview

The History and Mystery of Alveolar Epithelial Type II Cells: Focus on Their Physiologic and Pathologic Role in Lung

by Barbara Ruaro, Francesco Salton, Luca Braga, Barbara Wade, Paola Confalonieri, Maria Concetta Volpe, Elisa Baratella, Serena Maiocchi and Marco Confalonieri

Int. J. Mol. Sci. 2021, 22(5), 2566; https://doi.org/10.3390/ijms22052566 - 4 Mar 2021

Cited by 156 | Viewed by 11280

Abstract

Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air–liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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11 pages, 8612 KiB

Open AccessReview

sFasL—The Key to a Riddle: Immune Responses in Aging Lung and Disease

by Shulamit B. Wallach-Dayan, Dmytro Petukhov, Ronit Ahdut-HaCohen, Mark Richter-Dayan and Raphael Breuer

Int. J. Mol. Sci. 2021, 22(4), 2177; https://doi.org/10.3390/ijms22042177 - 22 Feb 2021

Cited by 10 | Viewed by 3855

Abstract

By dint of the aging population and further deepened with the Covid-19 pandemic, lung disease has turned out to be a major cause of worldwide morbidity and mortality. The condition is exacerbated when the immune system further attacks the healthy, rather than the diseased, tissue within the lung. Governed by unremittingly proliferating mesenchymal cells and increased collagen deposition, if inflammation persists, as frequently occurs in aging lungs, the tissue develops tumors and/or turns into scars (fibrosis), with limited regenerative capacity and organ failure. Fas ligand (FasL, a ligand of the Fas cell death receptor) is a key factor in the regulation of these processes. FasL is primarily found in two forms: full length (membrane, or mFasL) and cleaved (soluble, or sFasL). We and others found that T-cells expressing the mFasL retain autoimmune surveillance that controls mesenchymal, as well as tumor cell accumulation following an inflammatory response. However, mesenchymal cells from fibrotic lungs, tumor cells, or cells from immune-privileged sites, resist FasL⁺ T-cell-induced cell death. The mechanisms involved are a counterattack of immune cells by FasL, by releasing a soluble form of FasL that competes with the membrane version, and inhibits their cell death, promoting cell survival. This review focuses on understanding the previously unrecognized role of FasL, and in particular its soluble form, sFasL, in the serum of aged subjects, and its association with the evolution of lung disease, paving the way to new methods of diagnosis and treatment. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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18 pages, 496 KiB

Open AccessReview

Extended Exhaled Nitric Oxide Analysis in Interstitial Lung Diseases: A Systematic Review

by Paolo Cameli, Elena Bargagli, Laura Bergantini, Miriana d’Alessandro, Maria Pieroni, Giovanni A. Fontana, Piersante Sestini and Rosa Metella Refini

Int. J. Mol. Sci. 2020, 21(17), 6187; https://doi.org/10.3390/ijms21176187 - 27 Aug 2020

Cited by 19 | Viewed by 3216

Abstract

Fractional exhaled nitric oxide (FeNO) is a well-known and widely accepted biomarker of airways inflammation that can be useful in the therapeutic management, and adherence to inhalation therapy control, in asthmatic patients. However, the multiple-flows assessment of FeNO can provide a reliable measurement of bronchial and alveolar production of NO, supporting its potential value as biomarker also in peripheral lung diseases, such as interstitial lung diseases (ILD). In this review, we first discuss the role of NO in the pathobiology of lung fibrosis and the technique currently approved for the measurement of maximum bronchial flux of NO (J’awNO) and alveolar concentration of NO (CaNO). We systematically report the published evidence regarding extended FeNO analysis in the management of patients with different ILDs, focusing on its potential role in differential diagnosis, prognostic evaluation and severity assessment of disease. The few available data concerning extended FeNO analysis, and the most common comorbidities of ILD, are explored too. In conclusion, multiple-flows FeNO analysis, and CaNO in particular, appears to be a promising tool to be implemented in the diagnostic and prognostic pathways of patients affected with ILDs. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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17 pages, 2080 KiB

Open AccessReview

Metabolic Dysregulation in Idiopathic Pulmonary Fibrosis

by Elena Bargagli, Rosa Metella Refini, Miriana d’Alessandro, Laura Bergantini, Paolo Cameli, Lorenza Vantaggiato, Luca Bini and Claudia Landi

Int. J. Mol. Sci. 2020, 21(16), 5663; https://doi.org/10.3390/ijms21165663 - 7 Aug 2020

Cited by 36 | Viewed by 6084

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative disorder limited to the lung. New findings, starting from our proteomics studies on IPF, suggest that systemic involvement with altered molecular mechanisms and metabolic disorder is an underlying cause of fibrosis. The role of metabolic dysregulation in the pathogenesis of IPF has not been extensively studied, despite a recent surge of interest. In particular, our studies on bronchoalveolar lavage fluid have shown that the renin–angiotensin–aldosterone system (RAAS), the hypoxia/oxidative stress response, and changes in iron and lipid metabolism are involved in onset of IPF. These processes appear to interact in an intricate manner and to be related to different fibrosing pathologies not directly linked to the lung environment. The disordered metabolism of carbohydrates, lipids, proteins and hormones has been documented in lung, liver, and kidney fibrosis. Correcting these metabolic alterations may offer a new strategy for treating fibrosis. This paper focuses on the role of metabolic dysregulation in the pathogenesis of IPF and is a continuation of our previous studies, investigating metabolic dysregulation as a new target for fibrosis therapy. Full article

(This article belongs to the Special Issue Molecular Pathology of Idiopathic Pulmonary Fibrosis)

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