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Alveolar type 2 progenitor cells (AT2) seem closest to clinical translation, specifying the evidence that AT2 may satisfactorily control the immune response to decrease lung injury by stabilizing host immune-competence and a classic and crucial resource for lung regeneration and repair. AT2 establish potential in benefiting injured lungs. However,...
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... many of the lung injury diseases are related to aging 11 (Fig. 1). Chronic obstructive pulmonary disease (COPD) has elevated to become the fourth prominent reason for morbidity globally. There is an emergent dis- covery that aging is associated with the pathogenesis of a number of chronic lung diseases; really, most lung dis- eases are either mostly limited to the elderly. The occurrence of COPD was ...
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A new coronavirus respiratory disease (COVID-19) caused by the SARS-CoV-2 virus, surprised the entire world, producing social, economic, and health problems. The COVID-19 triggers a lung infection with a multiple proinflammatory cytokine storm in severe patients. Without effective and safe treatments, COVID-19 has killed thousands of people, becomi...
Citations
... Studies have demonstrated that MSCs effectively modulate host immune responses and facilitate tissue repair following lung injuries 6 . Type II alveolar epithelial cells (ATII) function as local unipotent stem cells responsible for repairing the alveolar epithelium during both steady-state replacement and after injury 7 . Notably, experiments involving the transplantation of embryonic stem cell-derived ATII cells into ALI-affected mice have yielded promising results, leading to improved lung injury outcomes, including body weight recovery, enhanced arterial blood oxygen saturation, reduced collagen deposition, and increased survival rates 8 . ...
Acute lung injury (ALI) is characterized by respiratory failure resulting from the disruption of the epithelial and endothelial barriers as well as immune system. In this study, we evaluated the therapeutic potential of airway epithelial cell-derived extracellular vesicles (EVs) in maintaining lung homeostasis. We isolated human bronchial epithelial cell-derived EVs (HBEC-EVs), which endogenously express various immune-related surface markers and investigated their immunomodulatory potential in ALI. In ALI cellular models, HBEC-EVs demonstrated immunosuppressive effects by reducing the secretion of proinflammatory cytokines in both THP-1 macrophages and HBECs. Mechanistically, these effects were partially ascribed to nine of the top 10 miRNAs enriched in HBEC-EVs, governing toll-like receptor-NF-κB signaling pathways. Proteomic analysis revealed the presence of proteins in HBEC-EVs involved in WNT and NF-κB signaling pathways, pivotal in inflammation regulation. ANXA1, a constituent of HBEC-EVs, interacts with formyl peptide receptor (FPR)2, eliciting anti-inflammatory responses by suppressing NF-κB signaling in inflamed epithelium, including type II alveolar epithelial cells. In a mouse model of ALI, intratracheal administration of HBEC-EVs reduced lung injury, inflammatory cell infiltration, and cytokine levels. Collectively, these findings suggest the therapeutic potential of HBEC-EVs, through their miRNAs and ANXA1 cargo, in mitigating lung injury and inflammation in ALI patients.
... However, when type I pneumocytes are injured, type II cells differentiate into type I pneumocytes. Therefore, type II pneumocytes are also called progenitor cells that work by proliferating or multiplying to maintain damage [6]. ...
Objective: This research aims to assess the preventive effect of ethanol extract of red galangal (Alpinia Galanga) on type I pneumocyte cell necrosis and proliferation of type II pulmonary pneumocytes in male mice (Mus musculus) exposed to lead acetate-induced damage. Method: A total of 25 male mice aged 2.5-3 months and weighing 25-30 g were divided into five groups. The negative control group (K-) received oral water without lead acetate exposure, while the positive control group (K+) received 20 mg/kg BW of lead acetate. The treatment groups P1, P2, and P3 were exposed to lead acetate at a dose of 20 mg/kg BW/day and received red galangal extract at doses of 200 mg/kg BW, 400 mg/kg BW, and 800 mg/kg BW, respectively. All treatment groups were administered lead and ethanol extract of galangal orally from days 4 to 24 at a rate of 0.2 ml/head. Results: The Mann-Whitney U statistical test revealed a significant increase in type I pneumocyte cell necrosis and type II pneumocyte cell proliferation in the lungs of male mice (Mus musculus) exposed to lead acetate (p<0.05). Administration of ethanol extract of galangal after exposure to lead acetate significantly reduced type I pneumocyte cell necrosis and type II pneumocyte cell proliferation (p<0.05). The highest dose of galangal ethanol extract, 800 mg/kg BW, showed a significant decrease in type II pneumocyte cell proliferation (p<0.05). Conclusion: This study concludes that red galangal extract has a preventive effect in reducing the damage to type I and type II pneumocytes in the lungs of male mice (Mus musculus) exposed to lead acetate.
... Normally, the bulk of AT2 cells remain quiescent, exhibiting limited regenerative potential [9]. However, in response to injury signals, AT2 stem cells undergo differentiation and proliferation, ultimately transitioning into AT1 cells to restore the damaged alveolar epithelium [10]. Previous research revealed that in a bleomycin-induced lung injury model, 12-month-old mice exhibited more severe damage to the alveolar epithelium compared to 3-month-old mice, and during a 63-day observation period, their capacity for alveolar self-repair was weaker than that of the 3-month-old mice [11]. ...
Lung aging triggers the onset of various chronic lung diseases, with alveolar repair being a key focus for alleviating pulmonary conditions. The regeneration of epithelial structures, particularly the differentiation from type II alveolar epithelial (AT2) cells to type I alveolar epithelial (AT1) cells, serves as a prominent indicator of alveolar repair. Nonetheless, the precise role of aging in impeding alveolar regeneration and its underlying mechanism remain to be fully elucidated. Our study employed histological methods to examine lung aging effects on structural integrity and pathology. Lung aging led to alveolar collapse, disrupted epithelial structures, and inflammation. Additionally, a relative quantification analysis revealed age-related decline in AT1 and AT2 cells, along with reduced proliferation and differentiation capacities of AT2 cells. To elucidate the mechanisms underlying AT2 cell functional decline, we employed transcriptomic techniques and revealed a correlation between inflammatory factors and genes regulating proliferation and differentiation. Furthermore, a D-galactose-induced senescence model in A549 cells corroborated our omics experiments and confirmed inflammation-induced cell cycle arrest and a >30% reduction in proliferation/differentiation. Physiological aging-induced chronic inflammation impairs AT2 cell functions, hindering tissue repair and promoting lung disease progression. This study offers novel insights into chronic inflammation’s impact on stem cell-mediated alveolar regeneration.
... PECAM-1 = platelet-endothelial cell adhesion molecule-1, VEGF = vascular endothelial growth factor, PAF-AH = platelet-activating factor acetyl hydrolase After the initial lung injury, a self-repair machinery may be activated. AEC II pneumocytes can proliferate and differentiate into AEC I pneumocytes, allowing edema fluids to drain into the interstitium and calling macrophages to purge cell debris [2,8]. Through this, the ACM integrity may be restored to some extent, improving oxygenation; or it may be unable to remove alveolar fluid, leading to hypoxemia and hypercapnic acidosis, and ALI progresses to acute respiratory distress syndrome (ARDS) [9]. ...
Acute lung injury (ALI) is a complex disease with numerous causes. This review begins with a discussion of disease development from direct or indirect pulmonary insults, as well as varied pathogenesis. The heterogeneous nature of ALI is then elaborated upon, including its epidemiology, clinical manifestations, potential biomarkers, and genetic contributions. Although no medication is currently approved for this devastating illness, supportive care and pharmacological intervention for ALI treatment are summarized, followed by an assessment of the pathophysiological gap between human ALI and animal models. Lastly, current research progress on advanced nanomedicines for ALI therapeutics in preclinical and clinical settings is reviewed, demonstrating new opportunities towards developing an effective treatment for ALI.
... Alveolar type 2 (AT2) cells have been shown to be a promising cell type for lung regeneration and repair [11]. They are also believed to be distal lung progenitor cells, thus undergoing selfrenewal to generate AT2 cells and differentiating to alveolar type 1 (AT1) cells [12]. ...
... They are also believed to be distal lung progenitor cells, thus undergoing selfrenewal to generate AT2 cells and differentiating to alveolar type 1 (AT1) cells [12]. There are however, inherent limitations with respect to their usability for tissue engineering applications including limited survival and growth in 2D ex vivo culture conditions, slow mitotic rate [13], rapid loss of phenotype, and an incomplete understanding of the mechanisms controlling AT2 cell function [7,11]. Therefore, to use AT2 cells for tissue engineering application and especially for recellularization of lung scaffolds, these limitations have to be addressed. ...
... We utilized freshly isolated primary mouse AT2 cells together with bone-marrow-derived mesenchymal cells for reepithelialization of lung scaffolds. AT2 cells are critical for alveolar regeneration in both mice and humans, serving as regional progenitors in the alveoli, capable of differentiation into AT1 cells, and self-renewal to replenish the alveolar epithelium [11,19,26]. While theoretically an ideal source, AT2 cells are difficult to work with ex vivo due to their limited capacity for survival and expansion [11,27]. ...
Objectives
Tissue engineering approaches via repopulation of acellular biological grafts provide an exciting opportunity to generate lung grafts for transplantation. Alveolar type 2 (AT2) cells are a promising cell source for re-epithelialization. There are however inherent limitations with respect to their survival and growth, thus impeding their usability for tissue engineering applications. This study investigates the use of mesenchymal stromal cells to support primary AT2 cells for recellularization of mouse lung scaffolds.
Methods
AT2 cells and bone marrow-derived mesenchymal cells (BMC) were co-delivered to decellularized mouse lung scaffolds. Recellularized lungs were evaluated for cell surface coverage, viability, and differentiation at 1 and 4 days after cell seeding. Recellularization was evaluated via histological analysis and immunofluorescence.
Results
Simultaneous delivery of AT2 and BMC into acellular lung scaffolds resulted in enhanced cell surface coverage and reduced AT2 cell apoptosis in the recellularized scaffolds at Day 1 but not Day 4. AT2 cell number decreased after 4 days in both of AT2 only and codelivery groups suggesting limited expansion potential in the scaffold. After retention in the scaffold, AT2 cells differentiated into Aqp5-expressing cells.
Conclusions
Our results indicate that BMC support AT2 cell survival during the initial attachment and engraftment phase of recellularization. While our findings suggest only a short-term beneficial effect of BMC, our study demonstrates that AT2 cells can be delivered and retained in acellular lung scaffolds; thus with preconditioning and supporting cells, may be used for re-epithelialization. Selection and characterization of appropriate cell sources for use in recellularization, will be critical for ultimate clinical application.
... Interestingly, the use of exosomes such as the mesenchymal stem cell (MSCs)-derived exosomes was seen to inhibit many pro-inflammatory cytokines and differentiation of T cells into Th17 cells in endotoxin-induced mice. Further, it also promoted cell regeneration, including the proliferation of alveolar type 2 progenitor (AT 2) (Olajuyin et al., 2019) Generally, ALI and ARDS patients do not need surgery, but once massive hemoptysis occurs, the airway should be kept smooth, artificial airway and endotracheal intubation should be established immediately. Double lumen endotracheal intubation is preferred, and surgery should be performed when necessary (Goh and Kong, 2020). ...
Acute respiratory distress syndrome (ARDS) is a life-threatening pulmonary disease typically caused by microbial infections, trauma, inhalation of harmful gases, and other factors. It is characterized by an inflammation in the lungs and increased alveolar permeability, leading to pulmonary edema and consequently, a low oxygen supply or hypoxemia. ARDS is responsible for 1 in 10 admissions to intensive care units, and the mortality rate for patients with severe ARDS is as high as 46%. Extensive efforts have been devoted to investigating the pathological mechanisms of ARDS to develop new effective clinical strategies. Recent studies have reported that receptor-interacting serine/threonine kinase 1 (RIPK1) is involved in the pathogenesis of ARDS. RIPK1 is a critical mediator of programmed cell death and inflammation. Growing evidence suggests that RIPK1 plays a role in the pathogenesis of different inflammatory diseases and serves as a promising pharmaceutical target. This review summarizes and sheds some light on the recent findings regarding the role of RIPK1 and related molecules in the pathogenesis of ARDS.
... Indeed, many patients who do well do not progress to consolidation on computed tomographic (CT) scans. Thus, a potential deleterious effect of these foci of inflammation could be the obliteration of regenerative potential in type II alveolar epithelial cells, the purported stem cells for the alveolar unit 46 , and development of organising pneumonia (OP). ...
Single cell spatial interrogation of the immune-structural interactions in COVID −19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.
... AT2 cells are responsible for repairing processes and modulating immune responses upon lung injury [74]. AT2 cell apoptosis has been implicated in the pathogenesis of idiopathic pulmonary fibrosis [75]. In asthma, AT2 cells protect the lungs against allergen-induced airway inflammation by secreting TGFβ 1, which stimulates regulatory T cell (Treg) development [76]. ...
Background
Allergic asthma is a common respiratory disease that significantly impacts human health. Through in silico analysis of human lung RNASeq, we found that asthmatic lungs display lower levels of Isthmin-1 (ISM1) expression than healthy lungs. ISM1 is an endogenous anti-inflammatory protein that is highly expressed in mouse lungs and bronchial epithelial cells, playing a crucial role in maintaining lung homeostasis. However, how ISM1 influences asthma remains unclear. This study aims to investigate the potential involvement of ISM1 in allergic airway inflammation and uncover the underlying mechanisms.
Methods
We investigated the pivotal role of ISM1 in airway inflammation using an ISM1 knockout mouse line (ISM1−/−) and challenged them with house dust mite (HDM) extract to induce allergic-like airway/lung inflammation. To examine the impact of ISM1 deficiency, we analyzed the infiltration of immune cells into the lungs and cytokine levels in bronchoalveolar lavage fluid (BALF) using flow cytometry and multiplex ELISA, respectively. Furthermore, we examined the therapeutic potential of ISM1 by administering recombinant ISM1 (rISM1) via the intratracheal route to rescue the effects of ISM1 reduction in HDM-challenged mice. RNA-Seq, western blot, and fluorescence microscopy techniques were subsequently used to elucidate the underlying mechanisms.
Results
ISM1−/− mice showed a pronounced worsening of allergic airway inflammation and hyperresponsiveness upon HDM challenge. The heightened inflammation in ISM1−/− mice correlated with enhanced lung cell necroptosis, as indicated by higher pMLKL expression. Intratracheal delivery of rISM1 significantly reduced the number of eosinophils in BALF and goblet cell hyperplasia. Mechanistically, ISM1 stimulates adiponectin secretion by type 2 alveolar epithelial cells partially through the GRP78 receptor and enhances adiponectin-facilitated apoptotic cell clearance via alveolar macrophage efferocytosis. Reduced adiponectin expression under ISM1 deficiency also contributed to intensified necroptosis, prolonged inflammation, and heightened severity of airway hyperresponsiveness.
Conclusions
This study revealed for the first time that ISM1 functions to restrain airway hyperresponsiveness to HDM-triggered allergic-like airway/lung inflammation in mice, consistent with its persistent downregulation in human asthma. Direct administration of rISM1 into the airway alleviates airway inflammation and promotes immune cell clearance, likely by stimulating airway adiponectin production. These findings suggest that ISM1 has therapeutic potential for allergic asthma.
Graphical abstract
... In normal lungs, epithelial cells provide surface areas, thus serve as mediators of gas exchange, with AT2 cells to produce surfactant and replace injured Q. Li et al. AT1 cells through cell differentiation [38]. In lung diseases like IPF, abnormal epithelial cell differentiation was usually observed, with the inability of AT2 cells to repair injured AT1 cells or AT2 cells to differentiate to other cell types [5,39]. ...
The bleomycin-induced pulmonary fibrosis mouse model is commonly used in idiopathic pulmonary fibrosis research, but its cellular and molecular changes and efficiency as a model at the molecular level are not fully understood. In this study, we used spatial transcriptome technology to investigate the cellular and molecular changes in the lungs of bleomycin-induced pulmonary fibrosis mouse models. Our analyses revealed cell dynamics during fibrosis in epithelial cells, mesenchymal cells, immunocytes, and erythrocytes with their spatial distribution available. We confirmed the differentiation of the alveolar type II (AT2) cell type expressing Krt8, and we inferred their trajectories from both the AT2 cells and club cells. In addition to the fibrosis process, we also noticed evidence of self-resolving, especially to identify possible self-resolving related genes, including Prkca. Our findings provide insights into the cellular and molecular mechanisms underlying fibrosis resolution and represent the first spatiotemporal transcriptome dataset of the bleomycin-induced fibrosis mouse model.
... Type 2 alveolar (AT2) cells are resident lung progenitor cells (31). AT2 cells in neonatal lungs are more susceptible to HOX than AT2 cells in adult lungs, because AT2 cell counts drop precipitously after short exposure to 100% O 2 , which explains the poor growth potential of BPD lungs (32). ...
Oxidative stress (OS), inflammation, and endoplasmic reticulum (ER) stress sequentially occur in bronchopulmonary dysplasia (BPD), and all result in DNA damage. When DNA damage becomes irreparable, tumor suppressors increase, followed by apoptosis or senescence. Although cellular senescence contributes to wound healing, its persistence inhibits growth. Therefore, we hypothesized that cellular senescence contributes to BPD progression. Human autopsy lungs were obtained. Sprague-Dawley rat pups exposed to 95% oxygen between postnatal day 1 (P1) to P10 were used as the BPD phenotype. N-acetyl-lysyltyrosylcysteine-amide (KYC), tauroursodeoxycholic acid (TUDCA), and Foxo4dri were given i.p. to mitigate myeloperoxidase (MPO)-oxidant generation, ER stress, and cellular senescence, respectively. Lungs were examined by histology, transcriptomics, and immunoblots. Cellular senescence increased in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression. Cellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P21. Single-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells (AT2). In addition, Foxo4-p53 binding increased in BPD rat lungs. Daily TUDCA or KYC, i.p., effectively decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of AT2. Foxo4dri given at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC. Our data suggest that cellular senescence plays an essential role in BPD after initial inducement by hyperoxia. Reducing MPO toxic oxidant production, ER stress, and attenuating cellular senescence are potential therapeutic strategies for halting BPD progression.
