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Open accessJournal ArticleDOI: 10.3390/IJMS22052566

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

04 Mar 2021-International Journal of Molecular Sciences (MDPI AG)-Vol. 22, Iss: 5, pp 2566
Abstract: Alveolar type II (ATII) cells are a key structure of the distal lung epithelium, where they exert their innate immune response and serve as progenitors of alveolar type I (ATI) cells, contributing to alveolar epithelial repair and regeneration. In the healthy lung, ATII cells coordinate the host defense mechanisms, not only generating a restrictive alveolar epithelial barrier, but also orchestrating host defense mechanisms and secreting surfactant proteins, which are important in lung protection against pathogen exposure. Moreover, surfactant proteins help to maintain homeostasis in the distal lung and reduce surface tension at the pulmonary air-liquid interface, thereby preventing atelectasis and reducing the work of breathing. ATII cells may also contribute to the fibroproliferative reaction by secreting growth factors and proinflammatory molecules after damage. Indeed, various acute and chronic diseases are associated with intensive inflammation. These include oedema, acute respiratory distress syndrome, fibrosis and numerous interstitial lung diseases, and are characterized by hyperplastic ATII cells which are considered an essential part of the epithelialization process and, consequently, wound healing. The aim of this review is that of revising the physiologic and pathologic role ATII cells play in pulmonary diseases, as, despite what has been learnt in the last few decades of research, the origin, phenotypic regulation and crosstalk of these cells still remain, in part, a mystery.

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Topics: Lung (55%), Idiopathic pulmonary fibrosis (52%), Innate immune system (51%) ... show more
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19 results found


Open accessJournal ArticleDOI: 10.1038/S41435-021-00140-W
17 Jun 2021-Genes and Immunity
Abstract: When surveying the current literature on COVID-19, the "cytokine storm" is considered to be pathogenetically involved in its severe outcomes such as acute respiratory distress syndrome, systemic inflammatory response syndrome, and eventually multiple organ failure. In this review, the similar role of DAMPs is addressed, that is, of those molecules, which operate upstream of the inflammatory pathway by activating those cells, which ultimately release the cytokines. Given the still limited reports on their role in COVID-19, the emerging topic is extended to respiratory viral infections with focus on influenza. At first, a brief introduction is given on the function of various classes of activating DAMPs and counterbalancing suppressing DAMPs (SAMPs) in initiating controlled inflammation-promoting and inflammation-resolving defense responses upon infectious and sterile insults. It is stressed that the excessive emission of DAMPs upon severe injury uncovers their fateful property in triggering dysregulated life-threatening hyperinflammatory responses. Such a scenario may happen when the viral load is too high, for example, in the respiratory tract, "forcing" many virus-infected host cells to decide to commit "suicidal" regulated cell death (e.g., necroptosis, pyroptosis) associated with release of large amounts of DAMPs: an important topic of this review. Ironically, although the aim of this "suicidal" cell death is to save and restore organismal homeostasis, the intrinsic release of excessive amounts of DAMPs leads to those dysregulated hyperinflammatory responses-as typically involved in the pathogenesis of acute respiratory distress syndrome and systemic inflammatory response syndrome in respiratory viral infections. Consequently, as briefly outlined in this review, these molecules can be considered valuable diagnostic and prognostic biomarkers to monitor and evaluate the course of the viral disorder, in particular, to grasp the eventual transition precociously from a controlled defense response as observed in mild/moderate cases to a dysregulated life-threatening hyperinflammatory response as seen, for example, in severe/fatal COVID-19. Moreover, the pathogenetic involvement of these molecules qualifies them as relevant future therapeutic targets to prevent severe/ fatal outcomes. Finally, a theory is presented proposing that the superimposition of coronavirus-induced DAMPs with non-virus-induced DAMPs from other origins such as air pollution or high age may contribute to severe and fatal courses of coronavirus pneumonia.

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6 Citations


Open accessJournal ArticleDOI: 10.3390/CELLS10081897
Shu Yuan1, Si-Cong Jiang, Zhong-Wei Zhang1, Yu-Fan Fu1  +2 moreInstitutions (2)
26 Jul 2021-Cells
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 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.

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Topics: Edema (61%), Pulmonary edema (60%), Hypoxemia (57%) ... show more

3 Citations


Open accessJournal ArticleDOI: 10.3390/JCM10173985
Abstract: Background: The purpose of this study was to evaluate High-Resolution CT (HRCT) findings in SARS-CoV-2-related ARDS survivors treated with prolonged low-dose methylprednisolone after hospital discharge. Methods: A total of 44 consecutive patients (M: 32, F: 12, average age: 64), hospitalised in our department from April to September 2020 for SARS-CoV-2-related ARDS, who had a postdischarge CT scan, were enrolled into this retrospective study. We reviewed the electronic medical charts to collect laboratory, clinical, and demographic data. The CT findings were evaluated and classified according to lung segmental distribution. The imaging findings were correlated with spirometry results and included ground glass opacities (GGOs), consolidations, reticulations, bronchiectasis/bronchiolectasis, linear bands, and loss of pulmonary volume. Results: Alterations in the pulmonary parenchyma were observed in 97.7% of patients at HRCT (median time lapse between ARDS diagnosis and HRCT: 2.8 months, range 0.9 to 6.7). The most common findings were linear bands (84%), followed by GGOs (75%), reticulations (34%), bronchiolectasis (32%), consolidations (30%), bronchiectasis (30%) and volume loss (25%). They had a symmetric distribution, and both lower lobes were the most affected areas. Conclusions: A reticular pattern with a posterior distribution was observed 3 months after discharge from severe COVID-19 pneumonia, and this differs from previously described postCOVID-19 fibrotic-like changes. We hypothesized that the systematic use of prolonged low-dose of corticosteroid could be the main reason of this different CT scan appearance.

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Topics: High-resolution computed tomography (55%), ARDS (52%), Bronchiectasis (51%) ... show more

2 Citations


Open accessJournal ArticleDOI: 10.3390/JCM10112462
Abstract: Background. Some studies with inconclusive results have reported a link between sarcoidosis and an increased risk of pulmonary embolism (PE). This study aimed at assessing a possible correlation between potential risk factors and PE in sarcoidosis patients. Methods. A total of 256 sarcoidosis patients (84 males and 172 females; mean age at diagnosis 49 ± 13) were enrolled after giving written informed consent. Clinical evaluations, laboratory and radiology tests were performed to evaluate the presence of pulmonary embolism. Results. Fifteen sarcoidosis patients with PE (4 males and 11 females; mean age at diagnosis 50 ± 11), diagnosed by lung scintigraphy and 241 sarcoidosis patients without PE (80 males and 161 females; mean age at diagnosis 47 ± 13), were observed. There was a statistically significant increase of the presence of antiphospholipid antibodies in the sarcoidosis group with pulmonary embolism. There was no statistically significant difference between the two groups as to smoking habit, obesity or hereditary thrombophilia frequency (p > 0.05, respectively). Conclusions. This study demonstrates a significant correlation between the presence of antiphospholipid antibody positivity and the pulmonary embolism events in our sarcoidosis patients. Furthermore, we propose screening for these antibodies and monitoring, aimed at timely treatment.

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Topics: Pulmonary embolism (54%)

1 Citations


Open accessJournal ArticleDOI: 10.1080/21655979.2021.1982845
Hang Li1, Chang Yao1, Kaihu Shi1, Yang Zhao1  +3 moreInstitutions (1)
01 Jan 2021-Bioengineered bugs
Abstract: We aimed to explore the role of miR-21-5p in the inhibitory effects of astragaloside IV (As-IV) on hypoxia/reoxygenation injury-induced apoptosis of type II alveolar epithelial cells. Rat type II alveolar epithelial cells RLE-6TN were cultured in vitro and randomly divided into control (C), hypoxia/reoxygenation injury (H/R), As-IV and miR-21-5p-siRNA + As-IV groups (n = 6). H/R model was established by 24 h of hypoxia and 4 h of reoxygenation. As-IV group was given 1 nmol/L As-IV and incubated for 1 h before modeling. MiR-21-5p-siRNA + As-IV group was transfected with 50 nmol/L miR-21-5p-siRNA. After 48 h, they were incubated with 1 nmol/L As-IV for 1 h before modeling. Cell viability was detected by cell counting kit-8 assay, and apoptosis rate was detected by flow cytometry. The expression levels of TLR4 and NF-κB were measured by immunofluorescence assay. The targeting relationship between miR-21-5p and TLR4 was determined by luciferase assay. Compared with H/R group, the cell viability, miR-21-5p, bax and cleaved caspase-3 expressions of As-IV group increased, apoptosis rate and Bcl-2 expression decreased, and TLR4 and NF-κB expressions were down-regulated (P < 0.05). Compared with As-IV group, the cell viability, miR-21-5p, bax and cleaved caspase-3 expressions of miR-21-5p-siRNA + As-IV group decreased, apoptosis rate and Bcl-2 expression increased, and the expressions of TLR4 and NF-κB were up-regulated (P < 0.05). As-IV up-regulates miR-21-5p expression, inhibits the TLR4/NF-κB signaling pathway and suppresses the apoptosis of type II alveolar epithelial cells during hypoxia/reoxygenation injury.

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Topics: Viability assay (56%), Apoptosis (52%)

1 Citations


References
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89 results found


Journal ArticleDOI: 10.1016/S0140-6736(67)90168-7
12 Aug 1967-The Lancet
Abstract: The respiratory-distress syndrome in 12 patients was manifested by acute onset of tachypnœa, hypoxaemia, and loss of compliance after a variety of stimuli; the syndrome did not respond to usual and ordinary methods of respiratory therapy. The clinical and pathological features closely resembled those seen in infants with respiratory distress and to conditions in congestive atelectasis and postperfusion lung. The theoretical relationship of this syndrome to alveolar surface active agent is postulated. Positive end-expiratory pressure was most helpful in combating atelectasis and hypoxaemia. Corticosteroids appeared to have value in the treatment of patients with fat-embolism and possibly viral pneumonia.

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Topics: Respiratory distress (64%), Atelectasis (57%), Lung (52%)

3,479 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1188302
25 Jun 2010-Science
Abstract: Here, we describe a biomimetic microsystem that reconstitutes the critical functional alveolar-capillary interface of the human lung. This bioinspired microdevice reproduces complex integrated organ-level responses to bacteria and inflammatory cytokines introduced into the alveolar space. In nanotoxicology studies, this lung mimic revealed that cyclic mechanical strain accentuates toxic and inflammatory responses of the lung to silica nanoparticles. Mechanical strain also enhances epithelial and endothelial uptake of nanoparticulates and stimulates their transport into the underlying microvascular channel. Similar effects of physiological breathing on nanoparticle absorption are observed in whole mouse lung. Mechanically active "organ-on-a-chip" microdevices that reconstitute tissue-tissue interfaces critical to organ function may therefore expand the capabilities of cell culture models and provide low-cost alternatives to animal and clinical studies for drug screening and toxicology applications.

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Topics: Organ-on-a-chip (51%)

2,468 Citations


Open accessJournal ArticleDOI: 10.1172/JCI68782
Abstract: Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.

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Topics: Alveolar cells (66%), Lung injury (62%), Stem cell (61%) ... show more

945 Citations


Open accessJournal ArticleDOI: 10.1186/RR36
Heinz Fehrenbach1Institutions (1)
Abstract: In 1977, Mason and Williams developed the concept of the alveolar epithelial type II (AE2) cell as a defender of the alveolus. It is well known that AE2 cells synthesise, secrete, and recycle all components of the surfactant that regulates alveolar surface tension in mammalian lungs. AE2 cells influence extracellular surfactant transformation by regulating, for example, pH and [Ca2+] of the hypophase. AE2 cells play various roles in alveolar fluid balance, coagulation/fibrinolysis, and host defence. AE2 cells proliferate, differentiate into AE1 cells, and remove apoptotic AE2 cells by phagocytosis, thus contributing to epithelial repair. AE2 cells may act as immunoregulatory cells. AE2 cells interact with resident and mobile cells, either directly by membrane contact or indirectly via cytokines/growth factors and their receptors, thus representing an integrative unit within the alveolus. Although most data support the concept, the controversy about the character of hyperplastic AE2 cells, reported to synthesise profibrotic factors, proscribes drawing a definite conclusion today.

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Topics: A549 cell (60%), Stem cell (54%), Alveolar Epithelium (53%)

627 Citations


Open accessJournal ArticleDOI: 10.1164/ARRD.1986.134.1.141
Abstract: A method has been developed for isolating alveolar type II cells by digesting lung tissue with elastase and “panning” the resultant cell suspension on plates coated with IgG. This method provides both high yield and purity of type II cells. In 50 experiments with rats, we obtained 35 ± 11 × 106cells/rat, 89 ± 4% of which were type II cells (mean ± SD). Type II cells isolated by “panning” adhered more rapidly and completely in tissue culture than did cells isolated by centrifugation over discontinuous density gradients of metrizamide. The “panning” method is superior to other methods for isolating type II cells in that it provides a population of type II cells of both high yield and high purity. The method is fast, reproducible, and easily adaptable to isolating type II cells from species other than rats.

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Topics: Population (51%)

594 Citations


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202119