Alveolar Type 2 Epithelial Cells as Potential Therapeutics for Acute Lung Injury/Acute Respiratory Distress Syndrome.
TL;DR: The recent progress on the mechanisms of alveolar type 2 epithelial cells involved in the damaged lung repairment are reviewed, aiming to explore the possible therapeutic targets in acute lung injury/acute respiratory distress syndrome.
Abstract: Acute lung injury/acute respiratory distress syndrome is a common clinical illness with high morbidity and mortality, which is still one of the medical problems urgently needed to be solved. Alveolar type 2 epithelial cells are an important component of lung epithelial cells and as a kind of stem cells, they can proliferate and differentiate into alveolar type 1 epithelial cells, thus contributing to lung epithelial repairment. In addition, they synthesize and secrete all components of the surfactant that regulates alveolar surface tension in the lungs. Moreover, alveolar type 2 epithelial cells play an active role in enhancing alveolar fluid clearance and reducing lung inflammation. In recent years, as more advanced approaches appear in the field of stem and progenitor cells in the lung, many preclinical studies have shown that the cell therapy of alveolar type 2 epithelial cells has great potential effects for acute lung injury/acute respiratory distress syndrome. We reviewed the recent progress on the mechanisms of alveolar type 2 epithelial cells involved in the damaged lung repairment, aiming to explore the possible therapeutic targets in acute lung injury/acute respiratory distress syndrome.
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TL;DR: A review of the role of alveolar type II (ATII) cells in pulmonary diseases can be found in this paper, where the origin, phenotypic regulation and crosstalk of these cells still remain a mystery.
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.
94 citations
TL;DR: Both cell therapies are successful for the treatment of ALI, with similar beneficial results, and understanding direct cell crosstalk and the factors released from each cell will open the door to more accurate drugs being able to target specific pathways and offer new curative options for ARDS.
Abstract: The use of cell therapies has recently increased for the treatment of pulmonary diseases. Mesenchymal stem/stromal cells (MSCs) and alveolar type II cells (ATII) are the main cell-based therapies used for the treatment of acute respiratory distress syndrome (ARDS). Many pre-clinical studies have shown that both therapies generate positive outcomes; however, the differences in the efficiency of MSCs or ATII for reducing lung damage remains to be studied. We compared the potential of both cell therapies, administering them using the same route and dose and equal time points in a sustained acute lung injury (ALI) model. We found that the MSCs and ATII cells have similar therapeutic effects when we tested them in a hydrochloric acid and lipopolysaccharide (HCl-LPS) two-hit ALI model. Both therapies were able to reduce proinflammatory cytokines, decrease neutrophil infiltration, reduce permeability, and moderate hemorrhage and interstitial edema. Although MSCs and ATII cells have been described as targeting different cellular and molecular mechanisms, our data indicates that both cell therapies are successful for the treatment of ALI, with similar beneficial results. Understanding direct cell crosstalk and the factors released from each cell will open the door to more accurate drugs being able to target specific pathways and offer new curative options for ARDS.
14 citations
Cites background or methods from "Alveolar Type 2 Epithelial Cells as..."
...ATII cells have also been used as a cell therapy in acute and chronic diseases [17–23], and they share some of the MSCs’ properties, such as their ability to secrete growth factors and cytokines that reduce inflammation and enhance tissue repair [19,20,24]....
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...ATII cells synthesize surfactant and other proteins and lipids with anti-inflammatory and antimicrobial effects [18,24,25]....
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...We, among others, have published the potential use of ATII cells in lung regeneration due to their ability to differentiate to alveolar type I cells and due to their abilities to secrete surfactant, which has immune-modulatory and biomechanical functions [18,24,57]....
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...Additionally, our group and others have tested ATII for the treatment of lung injury, showing a decrease in pro-inflammatory cytokines, the modulation of macrophage activation, and a reduction of edema [19,20,24]....
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TL;DR: In this article, the authors identify 17 miRNAs with both the capacity to bind viral RNA and which expression can be modulated by polyphenols in the cells of interest.
Abstract: Coronaviruses (CoVs) are single-stranded RNA viruses which following virus attachment and entry into the host cell, particularly type 2 pneumocytes but also endothelial cells, release RNA into cytosol where it serves as a matrix for the host translation machinery to produce viral proteins. The viral RNA in cytoplasm can interact with host cell microRNAs which can degrade viral RNA and/or prevent viral replication. As such host cellular miRNAs represent key cellular mediators of antiviral defense. Polyphenols, plant food bioactives, exert antiviral properties, which is partially due to their capacity to modulate the expression of miRNAs. The objective of this work was to assess if polyphenols can play a role in prevention of SARS-CoV-2 associated complications by modulating the expression of host miRNAs. To test this hypothesis, we performed literature search to identify miRNAs that could bind SARS-CoV-2 RNA as well as miRNAs which expression can be modulated by polyphenols in lung, type 2 pneumocytes or endothelial cells. We identified over 600 miRNAs that have capacity to bind viral RNA and 125 miRNAs which expression can be modulated by polyphenols in the cells of interest. We identified that there are 17 miRNAs with both the capacity to bind viral RNA and which expression can be modulated by polyphenols. Some of these miRNAs have been identified as having antiviral properties or can target genes involved in regulation of processes of viral replication, apoptosis or viral infection. Taken together this analysis suggests that polyphenols could modulate expression of miRNAs in alveolar and endothelial cells and exert antiviral capacity.
9 citations
TL;DR: The present study suggests that FA attenuates LPS-induced adhesion and migration of monocytes to type II alveolar epithelial cells though upregulating miR-124, thereby inhibiting the expression of CCL2.
8 citations
TL;DR: ROS may be a common activating mechanism of apoptosis and EMT in alveolar epithelial cells, during which the degree of apoptotic rate is positively related to EMT.
6 citations
References
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TL;DR: An overview of the definitions, clinical features, and epidemiology of the acute respiratory distress syndrome is provided and advances in the areas of pathogenesis, resolution, and treatment are discussed.
Abstract: The acute respiratory distress syndrome is a common, devastating clinical syndrome of acute lung injury that affects both medical and surgical patients. Since the last review of this syndrome appeared in the Journal, 1 more uniform definitions have been devised and important advances have occurred in the understanding of the epidemiology, natural history, and pathogenesis of the disease, leading to the design and testing of new treatment strategies. This article provides an overview of the definitions, clinical features, and epidemiology of the acute respiratory distress syndrome and discusses advances in the areas of pathogenesis, resolution, and treatment. Historical Perspective and Definitions . . .
5,002 citations
TL;DR: Although bronchiolar cells and alveolar cells are proposed to be the precursor cells of adenocarcinoma, this work points to bronchioalveolar stem cells as the putative cells of origin for this subtype of lung cancer.
2,087 citations
TL;DR: Progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors, and on developing novel therapeutics that can facilitate and enhance lung repair.
Abstract: The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.
1,506 citations
TL;DR: A combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations is used to obtain new information about the contribution of AEC2s to alveolar maintenance and repair.
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.
1,249 citations
TL;DR: The Berlin definition of acute respiratory distress syndrome addressed limitations of the American-European Consensus Conference definition, but poor reliability of some criteria may contribute to underrecognition by clinicians.
Abstract: Importance Acute respiratory distress syndrome (ARDS) is a life-threatening form of respiratory failure that affects approximately 200 000 patients each year in the United States, resulting in nearly 75 000 deaths annually. Globally, ARDS accounts for 10% of intensive care unit admissions, representing more than 3 million patients with ARDS annually. Objective To review advances in diagnosis and treatment of ARDS over the last 5 years. Evidence Review We searched MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews from 2012 to 2017 focusing on randomized clinical trials, meta-analyses, systematic reviews, and clinical practice guidelines. Articles were identified for full text review with manual review of bibliographies generating additional references. Findings After screening 1662 citations, 31 articles detailing major advances in the diagnosis or treatment of ARDS were selected. The Berlin definition proposed 3 categories of ARDS based on the severity of hypoxemia: mild (200 mm Hg 2 /Fio 2 ≤300 mm Hg), moderate (100 mm Hg 2 /Fio 2 ≤200 mm Hg), and severe (Pao 2 /Fio 2 ≤100 mm Hg), along with explicit criteria related to timing of the syndrome’s onset, origin of edema, and the chest radiograph findings. The Berlin definition has significantly greater predictive validity for mortality than the prior American-European Consensus Conference definition. Clinician interpretation of the origin of edema and chest radiograph criteria may be less reliable in making a diagnosis of ARDS. The cornerstone of management remains mechanical ventilation, with a goal to minimize ventilator-induced lung injury (VILI). Aspirin was not effective in preventing ARDS in patients at high-risk for the syndrome. Adjunctive interventions to further minimize VILI, such as prone positioning in patients with a Pao 2 /Fio 2 ratio less than 150 mm Hg, were associated with a significant mortality benefit whereas others (eg, extracorporeal carbon dioxide removal) remain experimental. Pharmacologic therapies such as β 2 agonists, statins, and keratinocyte growth factor, which targeted pathophysiologic alterations in ARDS, were not beneficial and demonstrated possible harm. Recent guidelines on mechanical ventilation in ARDS provide evidence-based recommendations related to 6 interventions, including low tidal volume and inspiratory pressure ventilation, prone positioning, high-frequency oscillatory ventilation, higher vs lower positive end-expiratory pressure, lung recruitment maneuvers, and extracorporeal membrane oxygenation. Conclusions and Relevance The Berlin definition of acute respiratory distress syndrome addressed limitations of the American-European Consensus Conference definition, but poor reliability of some criteria may contribute to underrecognition by clinicians. No pharmacologic treatments aimed at the underlying pathology have been shown to be effective, and management remains supportive with lung-protective mechanical ventilation. Guidelines on mechanical ventilation in patients with acute respiratory distress syndrome can assist clinicians in delivering evidence-based interventions that may lead to improved outcomes.
873 citations