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Advances in Lung Injury, Regeneration, and 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 (25 November 2023) | Viewed by 15652

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Prof. Dr. Satish K. Madala

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Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, The University of Cincinnati, Cincinnati, OH 45229, USA
Interests: Idiopathic pulmonary fibrosis; scleroderma; cystic fibrosis; lung injury; allergic asthma
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Dear Colleagues,

Pulmonary fibrosis, characterized by a progressive loss of lung function, impaired gas exchange, and high mortality, is a pathological endpoint of many pediatric and adult chronic lung diseases. Idiopathic pulmonary fibrosis (IPF) and several autoimmune diseases, including rheumatoid arthritis and systemic sclerosis, are the most commonly occurring types. The molecular mechanisms underlying the early fibrotic response to acute injury and the dysfunctional regeneration in response to chronic injury are poorly understood. In general, the injury response is known to be triggered in part by dysregulated signaling networks within multiple lung cell types, including those of epithelial cells, endothelial, fibroblast, and immune origin. In addition, the disruption of paracrine communication networks between lung cells and their respective extracellular matrix (ECM) proteins further sustains fibrosis and, in severe cases, results in organ destruction. This Special Issue focuses on recent advances in the mechanistic understanding of the dysregulated molecular pathways and cellular networks involved in fibrogenesis. Authors are encouraged to submit both original research articles and reviews on all aspects of the molecular mechanisms underlying lung injury, regeneration, and the progression of pulmonary fibrosis. All submitted articles will undergo peer review.

Prof. Dr. Satish K. Madala
Guest Editor

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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
myofibroblast
extracellular matrix
infections
acute respiratory distress syndrome

Related Special Issue

Advances in Lung Injury, Regeneration, and Fibrosis 2.0 in International Journal of Molecular Sciences

Published Papers (9 papers)

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Research

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14 pages, 2220 KiB

Open AccessArticle

Nε-Carboxymethyl-Lysine Modification of Extracellular Matrix Proteins Augments Fibroblast Activation

by Harshavardhana H. Ediga, Patrick Hester, Adithi Yepuri, Geereddy Bhanuprakash Reddy and Satish K. Madala

Int. J. Mol. Sci. 2023, 24(21), 15811; https://doi.org/10.3390/ijms242115811 - 31 Oct 2023

Viewed by 1593

Abstract

The extracellular matrix (ECM) is a dynamic complex protein network that provides structural integrity and plays an active role in shaping fibroblast behavior both in health and disease. Despite its essential functions, the impact of age-associated post-translational modifications on ECM-driven fibroblast activities such as proliferation, survival, fibroblast-to-myofibroblast transformation (FMT), and extracellular matrix production remains largely unknown. Nε-carboxymethyl-lysine (CML) is one of the well-characterized advanced glycation end-products (AGEs) that can occur on lysine residues within ECM proteins through non-enzymatic glycation. In this study, we determined the accumulation and the effects of the CML-modified ECM (CML-ECM) on fibroblast activation. Immunostainings and immunoblot analysis demonstrated significant increases in CML-AGE content in idiopathic pulmonary fibrosis (IPF) compared to age-matched healthy lungs. Gene expression analysis and fibroblast activation assays collectively implicate the ECM as a negative regulator of fibroblast activation. Notably, the CML modification of the ECM resulted in a significant decrease in its anti-fibrotic effects including proliferation, FMT, apoptosis, and ECM production. Together, the results of this study revealed an unexplored pathological role played by the CML-ECM on fibroblast activation, which has wide implications in IPF and other fibrotic diseases. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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13 pages, 2827 KiB

Open AccessArticle

Prostaglandin E2 (PGE2) and Roflumilast Involvement in IPF Progression

by Noa Moshkovitz, Gali Epstein Shochet and David Shitrit

Int. J. Mol. Sci. 2023, 24(15), 12393; https://doi.org/10.3390/ijms241512393 - 03 Aug 2023

Viewed by 1721

Abstract

The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a platform for testing drug candidates. Here, we tested the involvement of a PGE2 and PDE4 inhibitor, Roflumilast, in the IPF-CM system. Primary normal/IPF tissue-derived human lung fibroblasts (N/IPF-HLFs) were cultured on Matrigel and then removed to create the IPF-CM. N-HLFs were exposed to the IPF-CM/N-CM with/without PGE2 (1 nM) and Roflumilast (1 µM) for 24 h. The effect of the IPF-CM on cell phenotype and pro-fibrotic gene expression was tested. In addition, electronic records of 107 patients with up to 15-year follow-up were retrospectively reviewed. Patients were defined as slow/rapid progressors using forced vital capacity (FVC) annual decline. Medication exposure was examined. N-HLFs cultured on IPF-CM were arranged in large aggregates as a result of increased proliferation, migration and differentiation. A PGE2 and Roflumilast combination blocked the large aggregate formation induced by the IPF-CM (p < 0.001) as well as cell migration, proliferation, and pro-fibrotic gene expression. A review of patient records showed that significantly more slow-progressing patients were exposed to NSAIDs (p = 0.003). PGE2/PDE4 signaling may be involved in IPF progression. These findings should be further studied. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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22 pages, 8808 KiB

Open AccessArticle

Repetitive Low-Level Blast Exposure via Akt/NF-κB Signaling Pathway Mediates the M1 Polarization of Mouse Alveolar Macrophage MH-S Cells

by Chenhao Geng, Xinyue Wang, Jiale Chen, Na Sun, Yuru Wang, Zizheng Li, Lu Han, Shike Hou, Haojun Fan, Ning Li and Yanhua Gong

Int. J. Mol. Sci. 2023, 24(13), 10596; https://doi.org/10.3390/ijms241310596 - 25 Jun 2023

Viewed by 1121

Abstract

Repetitive low-level blast (rLLB) exposure is a potential risk factor for the health of soldiers or workers who are exposed to it as an occupational characteristic. Alveolar macrophages (AMs) are susceptible to external blast waves and produce pro-inflammatory or anti-inflammatory effects. However, the effect of rLLB exposure on AMs is still unclear. Here, we generated rLLB waves through a miniature manual Reddy-tube and explored their effects on MH-S cell morphology, phenotype transformation, oxidative stress status, and apoptosis by immunofluorescence, real-time quantitative PCR (qPCR), western blotting (WB) and flow cytometry. Ipatasertib (GDC-0068) or PDTC was used to verify the role of the Akt/NF-κB signaling pathway in these processes. Results showed that rLLB treatment could cause morphological irregularities and cytoskeletal disorders in MH-S cells and promote their polarization to the M1 phenotype by increasing iNOS, CD86 and IL-6 expression. The molecular mechanism is through the Akt/NF-κB signaling pathway. Moreover, we found reactive oxygen species (ROS) burst, Ca²⁺ accumulation, mitochondrial membrane potential reduction, and early apoptosis of MH-S cells. Taken together, our findings suggest rLLB exposure may cause M1 polarization and early apoptosis of AMs. Fortunately, it is blocked by specific inhibitors GDC-0068 or PDTC. This study provides a new treatment strategy for preventing and alleviating health damage in the occupational population caused by rLLB exposure. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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12 pages, 3043 KiB

Open AccessArticle

The Effects of Interstitial Lung Diseases on Alveolar Extracellular Vesicles Profile: A Multicenter Study

by Miriana d’Alessandro, Sara Gangi, Piera Soccio, Elisabet Cantó, Rubén Osuna-Gómez, Laura Bergantini, Paolo Cameli, Gaia Fabbri, Sara Croce, Giulia Scioscia, Giusy Montuori, Matteo Fanetti, Giorgia Moriondo, Fabrizio Mezzasalma, Diego Castillo, Donato Lacedonia, Silvia Vidal and Elena Bargagli

Int. J. Mol. Sci. 2023, 24(4), 4071; https://doi.org/10.3390/ijms24044071 - 17 Feb 2023

Cited by 2 | Viewed by 1848

Abstract

Diagnosis of interstitial lung diseases (ILD) is difficult to perform. Extracellular vesicles (EVs) facilitate cell-to-cell communication, and they are released by a variety of cells. Our goal aimed to investigate EV markers in bronchoalveolar lavage (BAL) from idiopathic pulmonary fibrosis (IPF), sarcoidosis and hypersensitivity pneumonitis (HP) cohorts. ILD patients followed at Siena, Barcelona and Foggia University Hospitals were enrolled. BAL supernatants were used to isolate the EVs. They were characterized by flow cytometry assay through MACSPlex Exsome KIT. The majority of alveolar EV markers were related to the fibrotic damage. CD56, CD105, CD142, CD31 and CD49e were exclusively expressed by alveolar samples from IPF patients, while HP showed only CD86 and CD24. Some EV markers were common between HP and sarcoidosis (CD11c, CD1c, CD209, CD4, CD40, CD44, CD8). Principal component analysis distinguished the three groups based on EV markers with total variance of 60.08%. This study has demonstrated the validity of the flow cytometric method to phenotype and characterize EV surface markers in BAL samples. The two granulomatous diseases, sarcoidosis and HP, cohorts shared alveolar EV markers not revealed in IPF patients. Our findings demonstrated the viability of the alveolar compartment allowing identification of lung-specific markers for IPF and HP. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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21 pages, 2384 KiB

Open AccessArticle

Mechanical Ventilation-Related High Stretch Mainly Induces Endoplasmic Reticulum Stress and Thus Mediates Inflammation Response in Cultured Human Primary Airway Smooth Muscle Cells

by Chongxin Yang, Jia Guo, Kai Ni, Kang Wen, Youyuan Qin, Rong Gu, Chunhong Wang, Lei Liu, Yan Pan, Jingjing Li, Mingzhi Luo and Linhong Deng

Int. J. Mol. Sci. 2023, 24(4), 3811; https://doi.org/10.3390/ijms24043811 - 14 Feb 2023

Cited by 3 | Viewed by 1457

Abstract

Ventilator-induced lung injury (VILI) occurs in mechanically ventilated patients of respiratory disease and is typically characterized by airway inflammation. However, recent studies increasingly indicate that a major cause of VILI may be the excessive mechanical loading such as high stretch (>10% strain) on airway smooth muscle cells (ASMCs) due to mechanical ventilation (MV). Although ASMCs are the primary mechanosensitive cells in airways and contribute to various airway inflammation diseases, it is still unclear how they respond to high stretch and what mediates such a response. Therefore, we used whole genome-wide mRNA-sequencing (mRNA-Seq), bioinformatics, and functional identification to systematically analyze the mRNA expression profiles and signaling pathway enrichment of cultured human ASMCs exposed to high stretch (13% strain), aiming to screen the susceptible signaling pathway through which cells respond to high stretch. The data revealed that in response to high stretch, 111 mRNAs with count ≥100 in ASMCs were significantly differentially expressed (defined as DE-mRNAs). These DE-mRNAs are mainly enriched in endoplasmic reticulum (ER) stress-related signaling pathways. ER stress inhibitor (TUDCA) abolished high-stretch-enhanced mRNA expression of genes associated with ER stress, downstream inflammation signaling, and major inflammatory cytokines. These results demonstrate in a data-driven approach that in ASMCs, high stretch mainly induced ER stress and activated ER stress-related signaling and downstream inflammation response. Therefore, it suggests that ER stress and related signaling pathways in ASMCs may be potential targets for timely diagnosis and intervention of MV-related pulmonary airway diseases such as VILI. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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Review

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27 pages, 1547 KiB

Open AccessReview

The Plastic Interplay between Lung Regeneration Phenomena and Fibrotic Evolution: Current Challenges and Novel Therapeutic Perspectives

by Sara Lettieri, Francesco R. Bertuccio, Lucia del Frate, Fabio Perrotta, Angelo G. Corsico and Giulia M. Stella

Int. J. Mol. Sci. 2024, 25(1), 547; https://doi.org/10.3390/ijms25010547 - 31 Dec 2023

Viewed by 1744

Abstract

Interstitial lung diseases (ILDs) are a heterogeneous group of pulmonary disorders characterized by variable degrees of inflammation, interstitial thickening, and fibrosis leading to distortion of the pulmonary architecture and gas exchange impairment. Among them, idiopathic pulmonary fibrosis (IPF) displays the worst prognosis. The only therapeutic options consist of the two antifibrotic drugs, pirfenidone and nintedanib, which limit fibrosis progression but do not reverse the lung damage. The shift of the pathogenetic paradigm from inflammatory disease to epithelium-derived disease has definitively established the primary role of type II alveolar cells, which lose their epithelial phenotype and acquire a mesenchymal phenotype with production of collagen and extracellular matrix (EMC) deposition. Some predisposing environmental and genetic factors (e.g., smoke, pollution, gastroesophageal reflux, variants of telomere and surfactant genes) leading to accelerated senescence set a pro-fibrogentic microenvironment and contribute to the loss of regenerative properties of type II epithelial cells in response to pathogenic noxae. This review provides a complete overview of the different pathogenetic mechanisms leading to the development of IPF. Then, we summarize the currently approved therapies and the main clinical trials ongoing. Finally, we explore the potentialities offered by agents not only interfering with the processes of fibrosis but also restoring the physiological properties of alveolar regeneration, with a particular focus on potentialities and concerns about cell therapies based on mesenchymal stem cells (MSCs), whose anti-inflammatory and immunomodulant properties have been exploited in other fibrotic diseases, such as graft versus host disease (GVHD) and COVID-19-related ARDS. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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15 pages, 882 KiB

Open AccessReview

Oxidative Stress and Lung Fibrosis: Towards an Adverse Outcome Pathway

by Patrudu Makena, Tatiana Kikalova, Gaddamanugu L. Prasad and Sarah A. Baxter

Int. J. Mol. Sci. 2023, 24(15), 12490; https://doi.org/10.3390/ijms241512490 - 06 Aug 2023

Cited by 4 | Viewed by 1778

Abstract

Lung fibrosis is a progressive fatal disease in which deregulated wound healing of lung epithelial cells drives progressive fibrotic changes. Persistent lung injury due to oxidative stress and chronic inflammation are central features of lung fibrosis. Chronic cigarette smoking causes oxidative stress and is a major risk factor for lung fibrosis. The objective of this manuscript is to develop an adverse outcome pathway (AOP) that serves as a framework for investigation of the mechanisms of lung fibrosis due to lung injury caused by inhaled toxicants, including cigarette smoke. Based on the weight of evidence, oxidative stress is proposed as a molecular initiating event (MIE) which leads to increased secretion of proinflammatory and profibrotic mediators (key event 1 (KE1)). At the cellular level, these proinflammatory signals induce the recruitment of inflammatory cells (KE2), which in turn, increase fibroblast proliferation and myofibroblast differentiation (KE3). At the tissue level, an increase in extracellular matrix deposition (KE4) subsequently culminates in lung fibrosis, the adverse outcome. We have also defined a new KE relationship between the MIE and KE3. This AOP provides a mechanistic platform to understand and evaluate how persistent oxidative stress from lung injury may develop into lung fibrosis. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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15 pages, 2952 KiB

Open AccessReview

Regulatory Cues in Pulmonary Fibrosis—With Emphasis on the AIM2 Inflammasome

by Yu-Hsin Tseng, I-Chen Chen, Wan-Chun Li and Jong-Hau Hsu

Int. J. Mol. Sci. 2023, 24(13), 10876; https://doi.org/10.3390/ijms241310876 - 29 Jun 2023

Viewed by 1434

Abstract

Pulmonary fibrosis (PF) is a chronic lung disorder characterized by the presence of scarred and thickened lung tissues. Although the Food and Drug Administration approved two antifibrotic drugs, pirfenidone, and nintedanib, that are currently utilized for treating idiopathic PF (IPF), the clinical therapeutic efficacy remains unsatisfactory. It is crucial to develop new drugs or treatment schemes that combine pirfenidone or nintedanib to achieve more effective outcomes for PF patients. Understanding the complex mechanisms underlying PF could potentially facilitate drug discovery. Previous studies have found that the activation of inflammasomes, including nucleotide-binding and oligomerization domain (NOD)-like receptor protein (NLRP)1, NLRP3, NOD-like receptor C4, and absent in melanoma (AIM)2, contributes to lung inflammation and fibrosis. This article aims to summarize the cellular and molecular regulatory cues that contribute to PF with a particular emphasis on the role of AIM2 inflammasome in mediating pathophysiologic events during PF development. The insights gained from this research may pave the way for the development of more effective strategies for the prevention and treatment of PF. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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17 pages, 4843 KiB

Open AccessReview

Modeling of Respiratory Diseases Evolving with Fibrosis from Organoids Derived from Human Pluripotent Stem Cells

by Irene Chamorro-Herrero and Alberto Zambrano

Int. J. Mol. Sci. 2023, 24(5), 4413; https://doi.org/10.3390/ijms24054413 - 23 Feb 2023

Cited by 1 | Viewed by 2235

Abstract

Respiratory disease is one of the leading causes of morbidity and mortality worldwide. There is no cure for most diseases, which are treated symptomatically. Hence, new strategies are required to deepen the understanding of the disease and development of therapeutic strategies. The advent of stem cell and organoid technology has enabled the development of human pluripotent stem cell lines and adequate differentiation protocols for developing both airways and lung organoids in different formats. These novel human-pluripotent-stem-cell-derived organoids have enabled relatively accurate disease modeling. Idiopathic pulmonary fibrosis is a fatal and debilitating disease that exhibits prototypical fibrotic features that may be, to some extent, extrapolated to other conditions. Thus, respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or the one caused by SARS-CoV-2 may reflect some fibrotic aspects reminiscent of those present in idiopathic pulmonary fibrosis. Modeling of fibrosis of the airways and the lung is a real challenge due to the large number of epithelial cells involved and interaction with other cell types of mesenchymal origin. This review will focus on the status of respiratory disease modeling from human-pluripotent-stem-cell-derived organoids, which are being used to model several representative respiratory diseases, such as idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, and COVID-19. Full article

(This article belongs to the Special Issue Advances in Lung Injury, Regeneration, and Fibrosis)

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