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Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies
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Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 12696

Special Issue Editors

Dr. Christoffel Arnold Spek

E-Mail Website
Guest Editor
Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Interests: Pulmonary fibrosis, protease activated receptors (PARs), pulmonary inflammation, epithelial to mesencymal transition (EMT), blood coagulation, animal models, in vitro models, cell cultures, alveolar epithelial cells, smooth muscle cells, endothelial cells, fibroblasts, macrophages, pro-inflammatory and fibroproliferative cytokines and growth factors, proliferation, migration, transcription factors and biomarkers
Dr. Jan Willem Duitman

E-Mail Website
Guest Editor
Department of Respiratory Medicine and Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands
Interests: Pulmonary fibrosis, protease activated receptors (PARs), pulmonary inflammation, epithelial to mesencymal transition (EMT), blood coagulation, animal models, in vitro models, cell cultures, alveolar epithelial cells, smooth muscle cells, endothelial cells, fibroblasts, macrophages, pro-inflammatory and fibroproliferative cytokines and growth factors, proliferation, migration, transcription factors and biomarkers

Special Issue Information

Dear Colleagues,

Idiopathic pulmonary fibrosis (IPF), the most common form of pulmonary fibrosis (PF), is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. The prognosis of IPF is devastating, especially given that the median survival time lies between 3 and 5 years after diagnosis. Furthermore, only 15% of patients suffering from the disease show survival up to 10 years from the onset of symptoms, and the mortality rate of IPF exceeds many types of cancer. Despite the US Food and Drug Administration approval of nintedanib and pirfenidone for the treatment of IPF, pharmacological treatment options remain limited for IPF. Both drugs reduce the decline in lung function and (modestly) improve the survival of IPF patients but they have serious side effects, show no benefit on the quality of life, and do not stop nor reverse the disease. Additional therapies to improve the prognosis and quality of life of IPF patients are, therefore, urgently needed. The pathogenesis of IPF is complex and only partly understood. According to the current paradigm, IPF results from a failure in alveolar epithelial regeneration and an aberrant wound-healing response following repetitive epithelial injury. Once initiated, epithelial injury leads to immune cell infiltration and fibroblast activation, leading to extracellular matrix deposition within the alveolar interstitium and consequent destruction of the alveolar architecture. Detailed knowledge on cellular and molecular processes underlying the initiation and progression of IPF remains elusive, however, and a better understanding of pathogenic processes driving disease progression is essential in order to identify alternative therapeutic targets and improve the quality of life among IPF patients. 

The aim of this Special Issue, entitled “Idiopathic Pulmonary Fibrosis: pathogenic pathways and treatment strategies”, is to provide a detailed and up-to-date overview of IPF. We welcome both original papers and comprehensive reviews which cover important developments in the pathogenesis of IPF, as well as treatment strategies that hold promise for this dismal disease. In addition, we welcome papers on (novel) experimental models that accurately reflect disease progression in patients in order to improve the translation of basic scientific work into clinical efficacy.

We look forward to receiving your contributions. Dr JanWillem Duitman and Dr C. Arnold SpekGuest Editors.

Dr. Christoffel Arnold Spek
Dr. Jan Willem Duitman
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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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
  • interstitial lung disease
  • nintedanib
  • pirfenidone
  • extracellular matrix
  • alveolar epithelial injury
  • bleomycin

Published Papers (6 papers)

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Research

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19 pages, 8950 KiB  
Article
Insights into Disease Progression of Translational Preclinical Rat Model of Interstitial Pulmonary Fibrosis through Endpoint Analysis
by Anil H. Kadam and Jan E. Schnitzer
Cells 2024, 13(6), 515; https://doi.org/10.3390/cells13060515 - 15 Mar 2024
Viewed by 946
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease characterized by the relentless deposition of extracellular matrix (ECM), causing lung distortions and dysfunction. Animal models of human IPF can provide great insight into the mechanistic pathways underlying disease progression and a means for evaluating novel therapeutic approaches. In this study, we describe the effect of bleomycin concentration on disease progression in the classical rat bleomycin model. In a dose–response study (1.5, 2, 2.5 U/kg i.t), we characterized lung fibrosis at day 14 after bleomycin challenge using endpoints including clinical signs, inflammatory cell infiltration, collagen content, and bronchoalveolar lavage fluid-soluble profibrotic mediators. Furthermore, we investigated fibrotic disease progression after 2 U/kg i.t. bleomycin administration at days 3, 7, and 14 by quantifying the expression of clinically relevant signaling molecules and pathways, epithelial mesenchymal transition (EMT) biomarkers, ECM components, and histopathology of the lung. A single bleomycin challenge resulted in a progressive fibrotic response in rat lung tissue over 14 days based on lung collagen content, histopathological changes, and modified Ashcroft score. The early fibrogenesis phase (days 3 to 7) is associated with an increase in profibrotic mediators including TGFβ1, IL6, TNFα, IL1β, CINC1, WISP1, VEGF, and TIMP1. In the mid and late fibrotic stages, the TGFβ/Smad and PDGF/AKT signaling pathways are involved, and clinically relevant proteins targeting galectin-3, LPA1, transglutaminase-2, and lysyl oxidase 2 are upregulated on days 7 and 14. Between days 7 and 14, the expressions of vimentin and α-SMA proteins increase, which is a sign of EMT activation. We confirmed ECM formation by increased expressions of procollagen-1Aα, procollagen-3Aα, fibronectin, and CTGF in the lung on days 7 and 14. Our data provide insights on a complex network of several soluble mediators, clinically relevant signaling pathways, and target proteins that contribute to drive the progressive fibrotic phenotype from the early to late phase (active) in the rat bleomycin model. The framework of endpoints of our study highlights the translational value for pharmacological interventions and mechanistic studies using this model. Full article
(This article belongs to the Special Issue Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies)
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19 pages, 1798 KiB  
Article
Pro-Fibrotic Effects of CCL18 on Human Lung Fibroblasts Are Mediated via CCR6
by Kerstin Höhne, Annett Wagenknecht, Corinna Maier, Peggy Engelhard, Torsten Goldmann, Stephan J. Schließmann, Till Plönes, Martin Trepel, Hermann Eibel, Joachim Müller-Quernheim and Gernot Zissel
Cells 2024, 13(3), 238; https://doi.org/10.3390/cells13030238 - 26 Jan 2024
Viewed by 976
Abstract
Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts [...] Read more.
Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities. Methods: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines. Results: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression. Conclusion: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis. Full article
(This article belongs to the Special Issue Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies)
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18 pages, 12144 KiB  
Article
Zingiber officinale-Derived Extracellular Vesicles Attenuate Bleomycin-Induced Pulmonary Fibrosis Trough Antioxidant, Anti-Inflammatory and Protease Activity in a Mouse Model
by Alma Aurora Ramírez-Hernández, Edilburga Reyes-Jiménez, Juan Manuel Velázquez-Enríquez, Jovito Cesar Santos-Álvarez, Adriana Soto-Guzmán, Luis Castro-Sánchez, Gabriela Tapia-Pastrana, Honorio Torres-Aguilar, Verónica Rocío Vásquez-Garzón and Rafael Baltiérrez-Hoyos
Cells 2023, 12(14), 1852; https://doi.org/10.3390/cells12141852 - 14 Jul 2023
Viewed by 2195
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe idiopathic interstitial pneumonia. It is a chronic and progressive disease with a poor prognosis and is a major cause of morbidity and mortality. This disease has no cure; therefore, there is a clinical [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe idiopathic interstitial pneumonia. It is a chronic and progressive disease with a poor prognosis and is a major cause of morbidity and mortality. This disease has no cure; therefore, there is a clinical need to search for alternative treatments with greater efficacy. In this study, we aimed to evaluate the effect of extracellular vesicles (EVs) from Zingiber officinale (EVZO) in a murine model of bleomycin (BLM)-induced IPF administered through an osmotic minipump. EVZO had an average size of 373 nm and a spherical morphology, as identified by scanning electron microscopy. Label-free proteomic analysis of EVZOs was performed by liquid chromatography coupled to mass spectrometry, and 20 proteins were identified. In addition, we demonstrated the protease activity of EVZO by gelatin-degrading zymography assay and the superoxide dismutase (SOD) activity of EVZO by an enzymatic assay. In the BLM-induced IPF mouse model, nasal administration of 50 μg of EVZO induced recovery of alveolar space size and decreased cellular infiltrate, collagen deposition, and expression of α-SMA-positive cells. Additionally, EVZO inhibited inflammatory markers such as iNOS and COX-2, lipid peroxidation, and apoptotic cells. These results show that EVZO may represent a novel natural delivery mechanism to treat IPF. Full article
(This article belongs to the Special Issue Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies)
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Graphical abstract

24 pages, 16438 KiB  
Article
Cellular Distribution of Secreted Phospholipase A2 in Lungs of IPF Patients and Its Inhibition in Bleomycin-Induced Pulmonary Fibrosis in Mice
by Ashish Jaiswal, Rakhshinda Rehman, Joytri Dutta, Sabita Singh, Archita Ray, Malathy Shridhar, Jaswant Jaisankar, Manas Bhatt, Dikshit Khandelwal, Bandya Sahoo, Arjun Ram and Ulaganathan Mabalirajan
Cells 2023, 12(7), 1044; https://doi.org/10.3390/cells12071044 - 30 Mar 2023
Cited by 2 | Viewed by 2084
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a very poor prognosis as it has a 2.5 to 5 years mean survival after proper diagnosis. Even nintedanib and pirfenidone cannot halt the progression, though they slow the progression of IPF. Hence, [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease with a very poor prognosis as it has a 2.5 to 5 years mean survival after proper diagnosis. Even nintedanib and pirfenidone cannot halt the progression, though they slow the progression of IPF. Hence, there is a need to understand the novel pathophysiology. Phospholipase A2 (PLA2) could be the ideal candidate to study in IPF, as they have a role in both inflammation and fibrosis. In the present study, we have shown the expression profile of various secretory Phospholipase A2 (PLA2) isoforms by analyzing publicly available transcriptome data of single cells from the lungs of healthy individuals and IPF patients. Among 11 members of sPLA2, PLA2G2A is found to be increased in the fibroblasts and mesothelial cells while PLA2G5 is found to be increased in the fibroblasts of IPF patients. We identified a subset of fibroblasts expressing high PLA2G2A with moderate expression of PLA2G5 and which are specific to IPF only; we named it as PLA2G2A+ IPF fibroblast. Pathway analysis revealed that these PLA2G2A+ IPF fibroblast have upregulation of both inflammatory and fibrosis-related pathways like the TGF-β signaling pathway, IL-17 signaling, the arachidonic acid metabolism pathway and ECM-receptor interaction. In addition to this, we found elevated levels of sPLA2-IIA in plasma samples of IPF patients in our cohort. PLA2G3, PLA2G10 and PLA2G12B are found in to be increased in certain epithelial cells of IPF patients. Thus, these findings indicate that these five isoforms have a disease-dominant role along with innate immune roles as these isoforms are found predominantly in structural cells of IPF patients. Further, we have targeted sPLA2 in mice model of bleomycin-induced lung fibrosis by pBPB, a known sPLA2 inhibitor. pBPB treatment attenuated lung fibrosis induced by bleomycin along with a reduction in TGF-β and deposition of extracellular matrix in lung. Thus, these findings indicate that these sPLA2 isoforms especially PLA2G2A may serve as a therapeutic target in lung fibrosis. Full article
(This article belongs to the Special Issue Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies)
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Review

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24 pages, 2552 KiB  
Review
Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways
by Deepak Pokhreal, Bruno Crestani and Doumet Georges Helou
Cells 2023, 12(17), 2193; https://doi.org/10.3390/cells12172193 - 01 Sep 2023
Cited by 4 | Viewed by 3138
Abstract
Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease of unknown etiology with a poor prognosis. It is a chronic and progressive disease that has a distinct radiological and pathological pattern from common interstitial pneumonia. The use of immunosuppressive medication was shown [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease of unknown etiology with a poor prognosis. It is a chronic and progressive disease that has a distinct radiological and pathological pattern from common interstitial pneumonia. The use of immunosuppressive medication was shown to be completely ineffective in clinical trials, resulting in years of neglect of the immune component. However, recent developments in fundamental and translational science demonstrate that immune cells play a significant regulatory role in IPF, and macrophages appear to be among the most crucial. These highly plastic cells generate multiple growth factors and mediators that highly affect the initiation and progression of IPF. In this review, we will provide an update on the role of macrophages in IPF through a systemic discussion of various regulatory mechanisms involving immune receptors, cytokines, metabolism, and epigenetics. Full article
(This article belongs to the Special Issue Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies)
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12 pages, 548 KiB  
Review
Caveolin-1-Related Intervention for Fibrotic Lung Diseases
by Sreerama Shetty and Steven Idell
Cells 2023, 12(4), 554; https://doi.org/10.3390/cells12040554 - 09 Feb 2023
Cited by 3 | Viewed by 2278
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD) for which there are no effective treatments. Lung transplantation is the only viable option for patients with end-stage PF but is only available to a minority of patients. Lung lesions in ILDs, including IPF, are characterized by alveolar epithelial cell (AEC) senescence and apoptosis and accumulation of activated myofibroblasts and/or fibrotic lung (fL) fibroblasts (fLfs). These composite populations of fLfs show a high rate of basal proliferation, resist apoptosis and senescence, and have increased migration and invasiveness. They also more readily deposit ECM proteins. These features eventuate in progressive destruction of alveolar architecture and loss of lung function in patients with PF. The identification of new, safer, and more effective therapy is therefore mandatory for patients with IPF or related ILDs. We found that increased caveolin-1 and tumor suppressor protein, p53 expression, and apoptosis in AECs occur prior to and then with the proliferation of fLfs in fibrotic lungs. AECs with elevated p53 typically undergo apoptosis. fLfs alternatively demonstrate strikingly low basal levels of caveolin-1 and p53, while mouse double minute 2 homolog (mdm2) levels and mdm2-mediated degradation of p53 protein are markedly increased. The disparities in the expression of p53 in injured AECs and fLfs appear to be due to increased basal expression of caveolin-1 in apoptotic AECs with a relative paucity of caveolin-1 and increased mdm2 in fLfs. Therefore, targeting caveolin-1 using a caveolin 1 scaffolding domain peptide, CSP7, represents a new and promising approach for patients with IPF, perhaps other forms of progressive ILD or even other forms of organ injury characterized by fibrotic repair. The mechanisms of action differ in the injured AECs and in fLfs, in which differential signaling enables the preservation of AEC viability with concurrent limitation of fLf expansion and collagen secretion. The findings in three models of PF indicate that lung scarring can be nearly abrogated by airway delivery of the peptide. Phase 1 clinical trial testing of this approach in healthy volunteers has been successfully completed; Phase 1b in IPF patients is soon to be initiated and, if successful, will be followed by phase 2 testing in short order. Apart from the treatment of IPF, this intervention may be applicable to other forms of tissue injury characterized by fibrotic repair. Full article
(This article belongs to the Special Issue Idiopathic Pulmonary Fibrosis: Pathogenic Pathways and Treatment Strategies)
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