International Journal of Molecular Sciences

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19 pages, 8193 KiB

Open AccessArticle

Regeneration of Pulmonary Tissue in a Calf Model of Fibrinonecrotic Bronchopneumonia Induced by Experimental Infection with Chlamydia psittaci

by Elisabeth M. Liebler-Tenorio, Jacqueline Lambertz, Carola Ostermann, Konrad Sachse and Petra Reinhold

Int. J. Mol. Sci. 2020, 21(8), 2817; https://doi.org/10.3390/ijms21082817 - 17 Apr 2020

Cited by 2 | Viewed by 3254

Abstract

Pneumonia is a cause of high morbidity and mortality in humans. Animal models are indispensable to investigate the complex cellular interactions during lung injury and repair in vivo. The time sequence of lesion development and regeneration is described after endobronchial inoculation of calves [...] Read more.

Pneumonia is a cause of high morbidity and mortality in humans. Animal models are indispensable to investigate the complex cellular interactions during lung injury and repair in vivo. The time sequence of lesion development and regeneration is described after endobronchial inoculation of calves with Chlamydia psittaci. Calves were necropsied 2–37 days after inoculation (dpi). Lesions and presence of Chlamydia psittaci were investigated using histology and immunohistochemistry. Calves developed bronchopneumonia at the sites of inoculation. Initially, Chlamydia psittaci replicated in type 1 alveolar epithelial cells followed by an influx of neutrophils, vascular leakage, fibrinous exudation, thrombosis and lobular pulmonary necrosis. Lesions were most extensive at 4 dpi. Beginning at 7 dpi, the number of chlamydial inclusions declined and proliferation of cuboidal alveolar epithelial cells and sprouting of capillaries were seen at the periphery of necrotic tissue. At 14 dpi, most of the necrosis had been replaced with alveoli lined with cuboidal epithelial cells resembling type 2 alveolar epithelial cells and mild fibrosis, and hyperplasia of organized lymphoid tissue were observed. At 37 dpi, regeneration of pulmonary tissue was nearly complete and only small foci of remodeling remained. The well-defined time course of development and regeneration of necrotizing pneumonia allows correlation of morphological findings with clinical data or treatment regimen. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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18 pages, 3394 KiB

Open AccessArticle

Hypercapnia Impairs Na,K-ATPase Function by Inducing Endoplasmic Reticulum Retention of the β-Subunit of the Enzyme in Alveolar Epithelial Cells

by Vitalii Kryvenko, Miriam Wessendorf, Rory E. Morty, Susanne Herold, Werner Seeger, Olga Vagin, Laura A. Dada, Jacob I. Sznajder and István Vadász

Int. J. Mol. Sci. 2020, 21(4), 1467; https://doi.org/10.3390/ijms21041467 - 21 Feb 2020

Cited by 14 | Viewed by 3781

Abstract

Alveolar edema, impaired alveolar fluid clearance, and elevated CO₂ levels (hypercapnia) are hallmarks of the acute respiratory distress syndrome (ARDS). This study investigated how hypercapnia affects maturation of the Na,K-ATPase (NKA), a key membrane transporter, and a cell adhesion molecule involved in [...] Read more.

Alveolar edema, impaired alveolar fluid clearance, and elevated CO₂ levels (hypercapnia) are hallmarks of the acute respiratory distress syndrome (ARDS). This study investigated how hypercapnia affects maturation of the Na,K-ATPase (NKA), a key membrane transporter, and a cell adhesion molecule involved in the resolution of alveolar edema in the endoplasmic reticulum (ER). Exposure of human alveolar epithelial cells to elevated CO₂ concentrations caused a significant retention of NKA-β in the ER and, thus, decreased levels of the transporter in the Golgi apparatus. These effects were associated with a marked reduction of the plasma membrane (PM) abundance of the NKA-α/β complex as well as a decreased total and ouabain-sensitive ATPase activity. Furthermore, our study revealed that the ER-retained NKA-β subunits were only partially assembled with NKA α-subunits, which suggests that hypercapnia modifies the ER folding environment. Moreover, we observed that elevated CO₂ levels decreased intracellular ATP production and increased ER protein and, particularly, NKA-β oxidation. Treatment with α-ketoglutaric acid (α-KG), which is a metabolite that has been shown to increase ATP levels and rescue mitochondrial function in hypercapnia-exposed cells, attenuated the deleterious effects of elevated CO₂ concentrations and restored NKA PM abundance and function. Taken together, our findings provide new insights into the regulation of NKA in alveolar epithelial cells by elevated CO₂ levels, which may lead to the development of new therapeutic approaches for patients with ARDS and hypercapnia. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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19 pages, 82319 KiB

Open AccessArticle

The Three-Dimensional Ultrastructure of the Human Alveolar Epithelium Revealed by Focused Ion Beam Electron Microscopy

by Jan Philipp Schneider, Christoph Wrede and Christian Mühlfeld

Int. J. Mol. Sci. 2020, 21(3), 1089; https://doi.org/10.3390/ijms21031089 - 6 Feb 2020

Cited by 6 | Viewed by 4397

Abstract

Thin type 1 alveolar epithelial (AE1) and surfactant producing type 2 alveolar epithelial (AE2) cells line the alveoli in the lung and are essential for normal lung function. Function is intimately interrelated to structure, so that detailed knowledge of the epithelial ultrastructure can [...] Read more.

Thin type 1 alveolar epithelial (AE1) and surfactant producing type 2 alveolar epithelial (AE2) cells line the alveoli in the lung and are essential for normal lung function. Function is intimately interrelated to structure, so that detailed knowledge of the epithelial ultrastructure can significantly enhance our understanding of its function. The basolateral surface of the cells or the epithelial contact sites are of special interest, because they play an important role in intercellular communication or stabilizing the epithelium. The latter is in particular important for the lung with its variable volume. The aim of the present study was to investigate the three-dimensional (3D) ultrastructure of the human alveolar epithelium focusing on contact sites and the basolateral cell membrane of AE2 cells using focused ion beam electron microscopy and subsequent 3D reconstructions. The study provides detailed surface reconstructions of two AE1 cell domains and two AE2 cells, showing AE1/AE1, AE1/AE2 and AE2/AE2 contact sites, basolateral microvilli pits at AE2 cells and small AE1 processes beneath AE2 cells. Furthermore, we show reconstructions of a surfactant secretion pore, enlargements of the apical AE1 cell surface and long folds bordering grooves on the basal AE1 cell surface. The functional implications of our findings are discussed. These findings may lay the structural basis for further molecular investigations. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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16 pages, 4076 KiB

Open AccessArticle

miR-21-KO Alleviates Alveolar Structural Remodeling and Inflammatory Signaling in Acute Lung Injury

by Johanna Christine Jansing, Jan Fiedler, Andreas Pich, Janika Viereck, Thomas Thum, Christian Mühlfeld and Christina Brandenberger

Int. J. Mol. Sci. 2020, 21(3), 822; https://doi.org/10.3390/ijms21030822 - 27 Jan 2020

Cited by 11 | Viewed by 3284

Abstract

Acute lung injury (ALI) is characterized by enhanced permeability of the air–blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling [...] Read more.

Acute lung injury (ALI) is characterized by enhanced permeability of the air–blood barrier, pulmonary edema, and hypoxemia. MicroRNA-21 (miR-21) was shown to be involved in pulmonary remodeling and the pathology of ALI, and we hypothesized that miR-21 knock-out (KO) reduces injury and remodeling in ALI. ALI was induced in miR-21 KO and C57BL/6N (wildtype, WT) mice by an intranasal administration of 75 µg lipopolysaccharide (LPS) in saline (n = 10 per group). The control mice received saline alone (n = 7 per group). After 24 h, lung function was measured. The lungs were then excised for proteomics, cytokine, and stereological analysis to address inflammatory signaling and structural damage. LPS exposure induced ALI in both strains, however, only WT mice showed increased tissue resistance and septal thickening upon LPS treatment. Septal alterations due to LPS exposure in WT mice consisted of an increase in extracellular matrix (ECM), including collagen fibrils, elastic fibers, and amorphous ECM. Proteomics analysis revealed that the inflammatory response was dampened in miR-21 KO mice with reduced platelet and neutrophil activation compared with WT mice. The WT mice showed more functional and structural changes and inflammatory signaling in ALI than miR-21 KO mice, confirming the hypothesis that miR-21 KO reduces the development of pathological changes in ALI. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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16 pages, 4955 KiB

Open AccessArticle

Evidence for Nanoparticle-Induced Lysosomal Dysfunction in Lung Adenocarcinoma (A549) Cells

by Arnold Sipos, Kwang-Jin Kim, Constantinos Sioutas and Edward D. Crandall

Int. J. Mol. Sci. 2019, 20(21), 5253; https://doi.org/10.3390/ijms20215253 - 23 Oct 2019

Cited by 25 | Viewed by 4120

Abstract

Background: Polystyrene nanoparticles (PNP) are taken up by primary rat alveolar epithelial cell monolayers (RAECM) in a time-, dose-, and size-dependent manner without involving endocytosis. Internalized PNP in RAECM activate autophagy, are delivered to lysosomes, and undergo [Ca²⁺]-dependent exocytosis. In this [...] Read more.

Background: Polystyrene nanoparticles (PNP) are taken up by primary rat alveolar epithelial cell monolayers (RAECM) in a time-, dose-, and size-dependent manner without involving endocytosis. Internalized PNP in RAECM activate autophagy, are delivered to lysosomes, and undergo [Ca²⁺]-dependent exocytosis. In this study, we explored nanoparticle (NP) interactions with A549 cells. Methods: After exposure to PNP or ambient pollution particles (PM0.2), live single A549 cells were studied using confocal laser scanning microscopy. PNP uptake and egress were investigated and activation of autophagy was confirmed by immunolabeling with LC3-II and LC3-GFP transduction/colocalization with PNP. Mitochondrial membrane potential, mitophagy, and lysosomal membrane permeability (LMP) were assessed in the presence/absence of apical nanoparticle (NP) exposure. Results: PNP uptake into A549 cells decreased in the presence of cytochalasin D, an inhibitor of macropinocytosis. PNP egress was not affected by increased cytosolic [Ca²⁺]. Autophagy activation was indicated by increased LC3 expression and LC3-GFP colocalization with PNP. Increased LMP was observed following PNP or PM0.2 exposure. Mitochondrial membrane potential was unchanged and mitophagy was not detected after NP exposure. Conclusions: Interactions between NP and A549 cells involve complex cellular processes leading to lysosomal dysfunction, which may provide opportunities for improved nanoparticle-based therapeutic approaches to lung cancer management. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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27 pages, 4605 KiB

Open AccessArticle

Surfactant Protein B Deficiency Induced High Surface Tension: Relationship between Alveolar Micromechanics, Alveolar Fluid Properties and Alveolar Epithelial Cell Injury

by Nina Rühl, Elena Lopez-Rodriguez, Karolin Albert, Bradford J Smith, Timothy E Weaver, Matthias Ochs and Lars Knudsen

Int. J. Mol. Sci. 2019, 20(17), 4243; https://doi.org/10.3390/ijms20174243 - 30 Aug 2019

Cited by 21 | Viewed by 4322

Abstract

High surface tension at the alveolar air-liquid interface is a typical feature of acute and chronic lung injury. However, the manner in which high surface tension contributes to lung injury is not well understood. This study investigated the relationship between abnormal alveolar micromechanics, [...] Read more.

High surface tension at the alveolar air-liquid interface is a typical feature of acute and chronic lung injury. However, the manner in which high surface tension contributes to lung injury is not well understood. This study investigated the relationship between abnormal alveolar micromechanics, alveolar epithelial injury, intra-alveolar fluid properties and remodeling in the conditional surfactant protein B (SP-B) knockout mouse model. Measurements of pulmonary mechanics, broncho-alveolar lavage fluid (BAL), and design-based stereology were performed as a function of time of SP-B deficiency. After one day of SP-B deficiency the volume of alveolar fluid V(alvfluid,par) as well as BAL protein and albumin levels were normal while the surface area of injured alveolar epithelium S(AEinjure,sep) was significantly increased. Alveoli and alveolar surface area could be recruited by increasing the air inflation pressure. Quasi-static pressure-volume loops were characterized by an increased hysteresis while the inspiratory capacity was reduced. After 3 days, an increase in V(alvfluid,par) as well as BAL protein and albumin levels were linked with a failure of both alveolar recruitment and airway pressure-dependent redistribution of alveolar fluid. Over time, V(alvfluid,par) increased exponentially with S(AEinjure,sep). In conclusion, high surface tension induces alveolar epithelial injury prior to edema formation. After passing a threshold, epithelial injury results in vascular leakage and exponential accumulation of alveolar fluid critically hampering alveolar recruitability. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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16 pages, 4260 KiB

Open AccessArticle

Voluntary Activity Modulates Sugar-Induced Elastic Fiber Remodeling in the Alveolar Region of the Mouse Lung

by Julia Hollenbach, Elena Lopez-Rodriguez, Christian Mühlfeld and Julia Schipke

Int. J. Mol. Sci. 2019, 20(10), 2438; https://doi.org/10.3390/ijms20102438 - 17 May 2019

Cited by 9 | Viewed by 3265

Abstract

Diabetes and respiratory diseases are frequently comorbid conditions. However, the mechanistic links between hyperglycemia and lung dysfunction are not entirely understood. This study examined the effects of high sucrose intake on lung mechanics and alveolar septal composition and tested voluntary activity as an [...] Read more.

Diabetes and respiratory diseases are frequently comorbid conditions. However, the mechanistic links between hyperglycemia and lung dysfunction are not entirely understood. This study examined the effects of high sucrose intake on lung mechanics and alveolar septal composition and tested voluntary activity as an intervention strategy. C57BL/6N mice were fed a control diet (CD, 7% sucrose) or a high sucrose diet (HSD, 35% sucrose). Some animals had access to running wheels (voluntary active; CD-A, HSD-A). After 30 weeks, lung mechanics were assessed, left lungs were used for stereological analysis and right lungs for protein expression measurement. HSD resulted in hyperglycemia and higher static compliance compared to CD. Lung and septal volumes were increased and the septal ratio of elastic-to-collagen fibers was decreased despite normal alveolar epithelial volumes. Elastic fibers appeared more loosely arranged accompanied by an increase in elastin protein expression. Voluntary activity prevented hyperglycemia in HSD-fed mice. The parenchymal airspace volume, but not the septal volume, was increased. The septal extracellular matrix (ECM) composition together with the protein expression of ECM components was similar to control levels in the HSD-A-group. In conclusion, HSD was associated with elastic fiber remodeling and reduced pulmonary elasticity. Voluntary activity alleviated HSD-induced ECM alterations, possibly by preventing hyperglycemia. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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14 pages, 3039 KiB

Open AccessArticle

P2X7 Receptor Indirectly Regulates the JAM-A Protein Content via Modulation of GSK-3β

by Karl-Philipp Wesslau, Anabel Stein, Michael Kasper and Kathrin Barth

Int. J. Mol. Sci. 2019, 20(9), 2298; https://doi.org/10.3390/ijms20092298 - 9 May 2019

Cited by 7 | Viewed by 3015

Abstract

The alveolar epithelial cells represent an important part of the alveolar barrier, which is maintained by tight junction proteins, particularly JAM-A, occludin, and claudin-18, which regulate paracellular permeability. In this study, we report on a strong increase in epithelial JAM-A expression in P2X7 [...] Read more.

The alveolar epithelial cells represent an important part of the alveolar barrier, which is maintained by tight junction proteins, particularly JAM-A, occludin, and claudin-18, which regulate paracellular permeability. In this study, we report on a strong increase in epithelial JAM-A expression in P2X7 receptor knockout mice when compared to the wildtype. Precision-cut lung slices of wildtype and knockout lungs and immortal epithelial lung E10 cells were treated with bleomycin, the P2X7 receptor inhibitor oxATP, and the agonist BzATP, respectively, to evaluate early changes in JAM-A expression. Biochemical and immunohistochemical data showed evidence for P2X7 receptor-dependent JAM-A expression in vitro. Inhibition of the P2X7 receptor using oxATP increased JAM-A, whereas activation of the receptor decreased the JAM-A protein level. In order to examine the role of GSK-3β in the expression of JAM-A in alveolar epithelial cells, we used lithium chloride for GSK-3β inhibiting experiments, which showed a modulating effect on bleomycin-induced alterations in JAM-A levels. Our data suggest that an increased constitutive JAM-A protein level in P2X7 receptor knockout mice may have a protective effect against bleomycin-induced lung injury. Bleomycin-treated precision-cut lung slices from P2X7 receptor knockout mice responded with a lower increase in mRNA expression of JAM-A than bleomycin-treated precision-cut lung slices from wildtype mice. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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Review

Jump to: Research

18 pages, 669 KiB

Open AccessReview

Treatment of Diffuse Alveolar Hemorrhage: Controlling Inflammation and Obtaining Rapid and Effective Hemostasis

by Jeong A. Park

Int. J. Mol. Sci. 2021, 22(2), 793; https://doi.org/10.3390/ijms22020793 - 14 Jan 2021

Cited by 28 | Viewed by 13399

Abstract

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or systemic autoimmune disorders. Pathologic findings show pulmonary capillaritis, bland hemorrhage, diffuse alveolar damage, and hemosiderin-laden macrophages, but in the majority of cases, pathogenesis remains unclear. Despite the severity [...] Read more.

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication in patients with hematologic malignancies or systemic autoimmune disorders. Pathologic findings show pulmonary capillaritis, bland hemorrhage, diffuse alveolar damage, and hemosiderin-laden macrophages, but in the majority of cases, pathogenesis remains unclear. Despite the severity and high mortality, the current treatment options for DAH remain empirical. Systemic treatment to control inflammatory activity including high-dose corticosteroids, cyclophosphamide, and rituximab and supportive care have been applied, but largely unsuccessful in critical cases. Activated recombinant factor VII (FVIIa) can achieve rapid local hemostasis and has been administered either systemically or intrapulmonary for the treatment of DAH. However, there is no randomized controlled study to evaluate the efficacy and safety, and the use of FVIIa for DAH remains open to debate. This review discusses the pathogenesis, diverse etiologies causing DAH, diagnosis, and treatments focusing on hemostasis using FVIIa. In addition, the risks and benefits of the off-label use of FVIIa in pediatric patients will be discussed in detail. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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12 pages, 609 KiB

Open AccessReview

Mechanisms of ATII-to-ATI Cell Differentiation during Lung Regeneration

by Mohit Aspal and Rachel L. Zemans

Int. J. Mol. Sci. 2020, 21(9), 3188; https://doi.org/10.3390/ijms21093188 - 30 Apr 2020

Cited by 88 | Viewed by 10667

Abstract

The alveolar epithelium consists of (ATI) and type II (ATII) cells. 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. During lung injury, ATI cells are susceptible [...] Read more.

The alveolar epithelium consists of (ATI) and type II (ATII) cells. 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. 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. Regeneration of ATI cells is critical to restore normal barrier and gas exchange function. Although the signaling pathways by which ATII cells proliferate have been explored, the mechanisms of ATII-to-ATI cell differentiation have not been well studied until recently. New studies have uncovered signaling pathways that mediate ATII-to-ATI differentiation. Bone morphogenetic protein (BMP) signaling inhibits ATII proliferation and promotes differentiation. Wnt/β-catenin and ETS variant transcription factor 5 (Etv5) signaling promote proliferation and inhibit differentiation. Delta-like 1 homolog (Dlk1) leads to a precisely timed inhibition of Notch signaling in later stages of alveolar repair, activating differentiation. Yes-associated protein/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling appears to promote both proliferation and differentiation. We recently identified a novel transitional cell state through which ATII cells pass as they differentiate into ATI cells, and this has been validated by others in various models of lung injury. This intermediate cell state is characterized by the activation of Transforming growth factor beta (TGFβ) and other pathways, and some evidence suggests that TGFβ signaling induces and maintains this state. While the abovementioned signaling pathways have all been shown to be involved in ATII-to-ATI cell differentiation during lung regeneration, there is much that remains to be understood. The up- and down-stream signaling events by which these pathways are activated and by which they induce ATI cell differentiation are unknown. In addition, it is still unknown how the various mechanistic steps from each pathway interact with one another to control differentiation. Based on these recent studies that identified major signaling pathways driving ATII-to-ATI differentiation during alveolar regeneration, additional studies can be devised to understand the interaction between these pathways as they work in a coordinated manner to regulate differentiation. Moreover, the knowledge from these studies may eventually be used to develop new clinical treatments that accelerate epithelial cell regeneration in individuals with excessive lung damage, such as patients with the Acute Respiratory Distress Syndrome (ARDS), pulmonary fibrosis, and emphysema. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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14 pages, 3896 KiB

Open AccessReview

On Top of the Alveolar Epithelium: Surfactant and the Glycocalyx

by Matthias Ochs, Jan Hegermann, Elena Lopez-Rodriguez, Sara Timm, Geraldine Nouailles, Jasmin Matuszak, Szandor Simmons, Martin Witzenrath and Wolfgang M. Kuebler

Int. J. Mol. Sci. 2020, 21(9), 3075; https://doi.org/10.3390/ijms21093075 - 27 Apr 2020

Cited by 38 | Viewed by 8266

Abstract

Gas exchange in the lung takes place via the air-blood barrier in the septal walls of alveoli. The tissue elements that oxygen molecules have to cross are the alveolar epithelium, the interstitium and the capillary endothelium. The epithelium that lines the alveolar surface [...] Read more.

Gas exchange in the lung takes place via the air-blood barrier in the septal walls of alveoli. The tissue elements that oxygen molecules have to cross are the alveolar epithelium, the interstitium and the capillary endothelium. The epithelium that lines the alveolar surface is covered by a thin and continuous liquid lining layer. Pulmonary surfactant acts at this air-liquid interface. By virtue of its biophysical and immunomodulatory functions, surfactant keeps alveoli open, dry and clean. What needs to be added to this picture is the glycocalyx of the alveolar epithelium. Here, we briefly review what is known about this glycocalyx and how it can be visualized using electron microscopy. The application of colloidal thorium dioxide as a staining agent reveals differences in the staining pattern between type I and type II alveolar epithelial cells and shows close associations of the glycocalyx with intraalveolar surfactant subtypes such as tubular myelin. These morphological findings indicate that specific spatial interactions between components of the surfactant system and those of the alveolar epithelial glycocalyx exist which may contribute to the maintenance of alveolar homeostasis, in particular to alveolar micromechanics, to the functional integrity of the air-blood barrier, to the regulation of the thickness and viscosity of the alveolar lining layer, and to the defence against inhaled pathogens. Exploring the alveolar epithelial glycocalyx in conjunction with the surfactant system opens novel physiological perspectives of potential clinical relevance for future research. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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22 pages, 1538 KiB

Open AccessReview

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

by Tanyalak Parimon, Changfu Yao, Barry R Stripp, Paul W Noble and Peter Chen

Int. J. Mol. Sci. 2020, 21(7), 2269; https://doi.org/10.3390/ijms21072269 - 25 Mar 2020

Cited by 216 | Viewed by 15781

Abstract

: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute [...] Read more.

: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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13 pages, 1577 KiB

Open AccessReview

The Hen or the Egg: Impaired Alveolar Oxygen Diffusion and Acute High-altitude Illness?

by Heimo Mairbäurl, Christoph Dehnert, Franziska Macholz, Daniel Dankl, Mahdi Sareban and Marc M. Berger

Int. J. Mol. Sci. 2019, 20(17), 4105; https://doi.org/10.3390/ijms20174105 - 22 Aug 2019

Cited by 11 | Viewed by 3758

Abstract

Individuals ascending rapidly to altitudes >2500 m may develop symptoms of acute mountain sickness (AMS) within a few hours of arrival and/or high-altitude pulmonary edema (HAPE), which occurs typically during the first three days after reaching altitudes above 3000–3500 m. Both diseases have [...] Read more.

Individuals ascending rapidly to altitudes >2500 m may develop symptoms of acute mountain sickness (AMS) within a few hours of arrival and/or high-altitude pulmonary edema (HAPE), which occurs typically during the first three days after reaching altitudes above 3000–3500 m. Both diseases have distinct pathologies, but both present with a pronounced decrease in oxygen saturation of hemoglobin in arterial blood (SO₂). This raises the question of mechanisms impairing the diffusion of oxygen (O₂) across the alveolar wall and whether the higher degree of hypoxemia is in causal relationship with developing the respective symptoms. In an attempt to answer these questions this article will review factors affecting alveolar gas diffusion, such as alveolar ventilation, the alveolar-to-arterial O₂-gradient, and balance between filtration of fluid into the alveolar space and its clearance, and relate them to the respective disease. The resultant analysis reveals that in both AMS and HAPE the main pathophysiologic mechanisms are activated before aggravated decrease in SO₂ occurs, indicating that impaired alveolar epithelial function and the resultant diffusion limitation for oxygen may rather be a consequence, not the primary cause, of these altitude-related illnesses. Full article

(This article belongs to the Special Issue The Alveolar Epithelium: Mechanisms of Injury and Repair)

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