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Epithelial Cells Role in Lung Diseases
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Epithelial Cells Role in Lung Diseases

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

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 25163

Special Issue Editors

Dr. Barbara Ruaro

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Guest Editor
Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
Interests: interstitial lung disease; idiopathic pulmonary fibrosis; rheumatic diseases; pulmonary arterial hypertension (PAH)
Special Issues, Collections and Topics in MDPI journals
Dr. Francesco Salton

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Guest Editor
Department of Pulmonology, University Hospital of Cattinara, Trieste, Italy
Interests: non-invasive ventilation (NIV); COVID-19 disease; lung cancer; acute respiratory distress syndrome (ARDS); idiopathic pulmonary fibrosis
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Marco Confalonieri

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Guest Editor
Pulmonology Unit, Department of Medical Surgical and Health Sciences, University Hospital of Cattinara, University of Trieste, 34149 Trieste, Italy
Interests: non-invasive ventilation (NIV); acute respiratory distress syndrome (ARDS); idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; lung cancer; COVID-19 disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The alveolar epithelium is made up of alveolar type I (ATI) and alveolar type II (ATII) cell types. ATI cells cover the majority of the alveolar surface due to their thin, elongated shape and are largely responsible for barrier function and gas exchange. ATII cells have four main functions, i.e., (a) the production and secretion of surfactant; (b) the transepithelial movement of water and ions regulating the volume of the alveolar surface liquid, preventing alveoli flooding; (c) the expression of immunomodulatory proteins necessary for host defense and the regulation of innate immunity; (d) the regeneration of alveolar epithelium after injury. ATII cells play a crucial role in lung repair/regeneration after injury. During lung injury, ATI cells are susceptible to injury, including cell death. Under some circumstances, ATII cells also die. To regenerate lost epithelial cells, ATII cells serve as progenitor cells. They proliferate to create new ATII cells and then differentiate into ATI cells.

Dysfunctional alveolar epithelium is implicated to such an extent in almost every instance of lung disease that, of late, it has been considered a therapeutic target. Therefore, studying this role from a cellular perspective could well provide a novel understanding of lung disease. ATII dysfunction or dropout has been implicated in the pathogenesis of a variety of parenchymal lung diseases, such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). ATII cells may also contribute to fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include edema, 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 Special Issue is to underline the physiologic and pathologic role that alveolar type I and type II cells play in pulmonary diseases. Our major focus is on experimental cytology (in vitro and in vivo studies).

Dr. Barbara Ruaro
Dr. Francesco Salton
Prof. Marco Confalonieri
Guest Editors

Manuscript Submission Information

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Keywords

  • Alveolar type I (ATI)
  • Alveolar type II (ATII)
  • Acute Respiratory Distress Syndrome (ARDS)
  • idiopathic pulmonary fibrosis (IPF)
  • chronic obstructive pulmonary disease (COPD)

Published Papers (5 papers)

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Research

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17 pages, 2893 KiB  
Article
iNOS Deletion in Alveolar Epithelium Cannot Reverse the Elastase-Induced Emphysema in Mice
by Marija Gredic, Vinita Sharma, Stefan Hadzic, Cheng-Yu Wu, Oleg Pak, Baktybek Kojonazarov, Julia Duerr, Marcus A. Mall, Andreas Guenther, Ralph T. Schermuly, Friedrich Grimminger, Werner Seeger, Simone Kraut, Natascha Sommer and Norbert Weissmann
Cells 2023, 12(1), 125; https://doi.org/10.3390/cells12010125 - 28 Dec 2022
Cited by 1 | Viewed by 1967
Abstract
Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and [...] Read more.
Background: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. In addition to chronic bronchitis and emphysema, patients often develop at least mild pulmonary hypertension (PH). We previously demonstrated that inhibition of inducible nitric oxide synthase (iNOS) prevents and reverses emphysema and PH in mice. Interestingly, strong iNOS upregulation was found in alveolar epithelial type II cells (AECII) in emphysematous murine lungs, and peroxynitrite, which can be formed from iNOS-derived NO, was shown to induce AECII apoptosis in vitro. However, the specific cell type(s) that drive(s) iNOS-dependent lung regeneration in emphysema/PH has (have) not been identified yet. Aim: we tested whether iNOS knockout in AECII affects established elastase-induced emphysema in mice. Methods: four weeks after a single intratracheal instillation of porcine pancreatic elastase for the induction of emphysema and PH, we induced iNOS knockout in AECII in mice, and gave an additional twelve weeks for the potential recovery. Results: iNOS knockout in AECII did not reduce elastase-induced functional and structural lung changes such as increased lung compliance, decreased mean linear intercept and increased airspace, decreased right ventricular function, increased right ventricular systolic pressure and increased pulmonary vascular muscularization. In vitro, iNOS inhibition did not reduce apoptosis of AECII following exposure to a noxious stimulus. Conclusion: taken together, our data demonstrate that iNOS deletion in AECII is not sufficient for the regeneration of emphysematous murine lungs, and suggest that iNOS expression in pulmonary vascular or stromal cells might be critically important in this regard. Full article
(This article belongs to the Special Issue Epithelial Cells Role in Lung Diseases)
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16 pages, 1663 KiB  
Article
Cell-Surface Programmed Death Ligand-1 Expression Identifies a Sub-Population of Distal Epithelial Cells Enriched in Idiopathic Pulmonary Fibrosis
by Negah Ahmadvand, Gianni Carraro, Matthew R. Jones, Irina Shalashova, Afshin Noori, Jochen Wilhelm, Nelli Baal, Farhad Khosravi, Chengshui Chen, Jin-San Zhang, Clemens Ruppert, Andreas Guenther, Roxana M. Wasnick and Saverio Bellusci
Cells 2022, 11(10), 1593; https://doi.org/10.3390/cells11101593 - 10 May 2022
Cited by 10 | Viewed by 3068
Abstract
Idiopathic lung fibrosis (IPF) is a fatal lung disease characterized by chronic epithelial injury and exhausted repair capacity of the alveolar compartment, associated with the expansion of cells with intermediate alveolar epithelial cell (AT2) characteristics. Using SftpcCreERT2/+: tdTomatoflox/flox mice, we [...] Read more.
Idiopathic lung fibrosis (IPF) is a fatal lung disease characterized by chronic epithelial injury and exhausted repair capacity of the alveolar compartment, associated with the expansion of cells with intermediate alveolar epithelial cell (AT2) characteristics. Using SftpcCreERT2/+: tdTomatoflox/flox mice, we previously identified a lung population of quiescent injury-activated alveolar epithelial progenitors (IAAPs), marked by low expression of the AT2 lineage trace marker tdTomato (Tomlow) and characterized by high levels of Pd-l1 (Cd274) expression. This led us to hypothesize that a population with similar properties exists in the human lung. To that end, we used flow cytometry to characterize the CD274 cell-surface expression in lung epithelial cells isolated from donor and end-stage IPF lungs. The identity and functional behavior of these cells were further characterized by qPCR analysis, in vitro organoid formation, and ex vivo precision-cut lung slices (PCLSs). Our analysis led to the identification of a population of CD274pos cells expressing intermediate levels of SFTPC, which was expanded in IPF lungs. While donor CD274pos cells initiated clone formation, they did not expand significantly in 3D organoids in AT2-supportive conditions. However, an increased number of CD274pos cells was found in cultured PCLS. In conclusion, we demonstrate that, similar to IAAPs in the mouse lung, a population of CD274-expressing cells exists in the normal human lung, and this population is expanded in the IPF lung and in an ex vivo PCLS assay, suggestive of progenitor cell behavior. CD274 function in these cells as a checkpoint inhibitor may be crucial for their progenitor function, suggesting that CD274 inhibition, unless specifically targeted, might further injure the already precarious lung epithelial compartment in IPF. Full article
(This article belongs to the Special Issue Epithelial Cells Role in Lung Diseases)
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Review

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18 pages, 1829 KiB  
Review
Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF)
by Paola Confalonieri, Maria Concetta Volpe, Justin Jacob, Serena Maiocchi, Francesco Salton, Barbara Ruaro, Marco Confalonieri and Luca Braga
Cells 2022, 11(13), 2095; https://doi.org/10.3390/cells11132095 - 30 Jun 2022
Cited by 59 | Viewed by 8990
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease (ILD) with unknown etiology in which gradual fibrotic scarring of the lungs leads to usual interstitial pneumonia (UIP) and, ultimately, to death. IPF affects three million people worldwide, and the only currently available treatments include the antifibrotic drugs nintedanib and pirfenidone, which effectively reduce fibrosis progression are, unfortunately, not effective in curing the disease. In recent years, the paradigm of IPF pathogenesis has shifted from a fibroblast-driven disease to an epithelium-driven disease, wherein, upon recurrent microinjuries, dysfunctional alveolar type II epithelial cells (ATII) are not only unable to sustain physiological lung regeneration but also promote aberrant epithelial–mesenchymal crosstalk. This creates a drift towards fibrosis rather than regeneration. In the context of this review article, we discuss the most relevant mechanisms involved in IPF pathogenesis with a specific focus on the role of dysfunctional ATII cells in promoting disease progression. In particular, we summarize the main causes of ATII cell dysfunction, such as aging, environmental factors, and genetic determinants. Next, we describe the known mechanisms of physiological lung regeneration by drawing a parallel between embryonic lung development and the known pathways involved in ATII-driven alveolar re-epithelization after injury. Finally, we review the most relevant interventional clinical trials performed in the last 20 years with the aim of underlining the urgency of developing new therapies against IPF that are not only aimed at reducing disease progression by hampering ECM deposition but also boost the physiological processes of ATII-driven alveolar regeneration. Full article
(This article belongs to the Special Issue Epithelial Cells Role in Lung Diseases)
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26 pages, 812 KiB  
Review
The Role of Airway Epithelial Cell Alarmins in Asthma
by Christiane E. Whetstone, Maral Ranjbar, Hafsa Omer, Ruth P. Cusack and Gail M. Gauvreau
Cells 2022, 11(7), 1105; https://doi.org/10.3390/cells11071105 - 24 Mar 2022
Cited by 27 | Viewed by 6580
Abstract
The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important [...] Read more.
The airway epithelium is the first line of defense for the lungs, detecting inhaled environmental threats through pattern recognition receptors expressed transmembrane or intracellularly. Activation of pattern recognition receptors triggers the release of alarmin cytokines IL-25, IL-33, and TSLP. These alarmins are important mediators of inflammation, with receptors widely expressed in structural cells as well as innate and adaptive immune cells. Many of the key effector cells in the allergic cascade also produce alarmins, thereby contributing to the airways disease by driving downstream type 2 inflammatory processes. Randomized controlled clinical trials have demonstrated benefit when blockade of TSLP and IL-33 were added to standard of care medications, suggesting these are important new targets for treatment of asthma. With genome-wide association studies demonstrating associations between single-nucleotide polymorphisms of the TSLP and IL-33 gene and risk of asthma, it will be important to understand which subsets of asthma patients will benefit most from anti-alarmin therapy. Full article
(This article belongs to the Special Issue Epithelial Cells Role in Lung Diseases)
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15 pages, 5995 KiB  
Review
The Role of Alveolar Edema in COVID-19
by Shu Yuan, Si-Cong Jiang, Zhong-Wei Zhang, Yu-Fan Fu, Jing Hu and Zi-Lin Li
Cells 2021, 10(8), 1897; https://doi.org/10.3390/cells10081897 - 26 Jul 2021
Cited by 15 | Viewed by 3455
Abstract
The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threatening hypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation-perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar [...] Read more.
The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threatening hypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation-perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar edema in the disease progression has not been discussed comprehensively. Since the exudation of pulmonary edema fluid was extremely serious in COVID-19 patients, we bring out a hypothesis that severity of alveolar edema may determine the size of poorly-ventilated area and the blood oxygen content. Treatments to pulmonary edema (conservative fluid management, exogenous surfactant replacements and ethanol–oxygen vapor therapy hypothetically) may be greatly helpful for reducing the occurrences of severe cases. Given that late mechanical ventilation may cause mucus (edema fluid) to be blown deep into the small airways, oxygen therapy should be given at the early stages. The optimal time and blood oxygen saturation (SpO2) threshold for oxygen therapy are also discussed. Full article
(This article belongs to the Special Issue Epithelial Cells Role in Lung Diseases)
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