Experimental Lung Research最新文献

{"title":"Animal models of infection-induced acute lung injury.","authors":"Wanying Tan, Lingjun Qi, Zhenghuai Tan","doi":"10.1080/01902148.2024.2428939","DOIUrl":"10.1080/01902148.2024.2428939","url":null,"abstract":"<p><p><b>Aim:</b> Acute lung injury (ALI) is characterized by severe hypoxemia, reduced lung elasticity, and notable pulmonary edema, often caused by infections and potentially progressing to ARDS. This article explores animal models of ALI and clarifies its main pathogenic mechanisms.</p><p><p><b>Materials and Methods:</b> we reviewed 20 years of ALI animal model advancements via PubMed, assessing clinical symptoms, histopathology, and reproducibility, and provided guidance on selecting models aligned with ALI pathogenesis.</p><p><p><b>Results:</b> key proinflammatory mediators and interleukins play a significant role in ALI development, though their interactions are not fully understood. Preclinical models are essential for investigating ALI causes and testing treatments. Animal models mimic ALI from sources such as infections, drugs, and I/R events, but differences between mouse and human lungs necessitate careful validation of these findings.</p><p><p><b>Conclusions:</b> A comprehensive strategy is essential to address clinical treatment and drug R&D challenges to prevent severe complications and reduce mortality rates.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"50 1","pages":"221-241"},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the role of oral microbiome dysbiosis in cardiometabolic syndrome and smoking.","authors":"Layla I Mohammed, Zain Zaki Zakaria, Fatiha M Benslimane, Maha Al-Asmakh","doi":"10.1080/01902148.2024.2331185","DOIUrl":"10.1080/01902148.2024.2331185","url":null,"abstract":"<p><p>Oral microbiome research has gained significant interest in recent years due to its potential impact on overall health. Smoking has been identified as a significant modulator of the oral microbiome composition, leading to dysbiosis and possible health consequences. Research has primarily focused on the association between smoking and oral microbiome, as well as smoking's association with cardiometabolic syndrome (CMS). This narrative review presents an overview of the recent findings and current knowledge on the oral microbiome and its role in CMS, including the effects of smoking and ethnicity. We discussed the development and composition of the oral microbiome and the association of periodontitis with diabetes and cardiovascular diseases. Furthermore, we highlighted the correlations between oral microbiome and CMS factors, such as diabetes, hypertension, dyslipidemia, and obesity. There is a need for further research in this area to better understand the mechanisms underlying the impact of smoking on oral microbiome dysbiosis and the development of CMS. Interestingly, geographic location and ethnicity have been shown to impact the oral microbiome profiles across populations. This knowledge will help develop personalized disease prevention and treatment approaches considering individual differences in oral microbiome composition. Understanding the complex interplay between oral microbiome, smoking, and CMS is essential for developing effective prevention and treatment strategies for a wide range of diseases.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"50 1","pages":"65-84"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCL6 attenuates hyperoxia-induced lung injury by inhibiting NLRP3-mediated inflammation in fetal mouse.","authors":"Dan Chen, Hui-Min Zhao, Xian-Hui Deng, Sheng-Peng Li, Mei-Hui Zhou, Ya-Xian Wu, Ying Tong, Ren-Qiang Yu, Qing-Feng Pang","doi":"10.1080/01902148.2024.2320665","DOIUrl":"10.1080/01902148.2024.2320665","url":null,"abstract":"<p><strong>Background: </strong>The transcriptional repressor B-cell lymphoma 6 (BCL6) has been reported to inhibit inflammation. So far, experimental evidence for the role of BCL6 in bronchopulmonary dysplasia (BPD) is lacking. Our study investigated the roles of BCL6 in the progression of BPD and its downstream mechanisms.</p><p><strong>Methods: </strong>Hyperoxia or lipopolysaccharide (LPS) was used to mimic the BPD mouse model. To investigate the effects of BCL6 on BPD, recombination adeno-associated virus serotype 9 expressing BCL6 (rAAV9-BCL6) and BCL6 inhibitor FX1 were administered in mice. The pulmonary pathological changes, inflammatory chemokines and NLRP3-related protein were observed. Meanwhile, BCL6 overexpression plasmid was used in human pulmonary microvascular endothelial cells (HPMECs). Cell proliferation, apoptosis, and NLRP3-related protein were detected.</p><p><strong>Results: </strong>Either hyperoxia or LPS suppressed pulmonary BCL6 mRNA expression. rAAV9-BCL6 administration significantly inhibited hyperoxia-induced NLRP3 upregulation and inflammation, attenuated alveolar simplification and dysregulated angiogenesis in BPD mice, which were characterized by decreased mean linear intercept, increased radical alveolar count and alveoli numbers, and the upregulated CD31 expression. Meanwhile, BCL6 overexpression promoted proliferation and angiogenesis, inhibited apoptosis and inflammation in hyperoxia-stimulated HPMECs. Moreover, administration of BCL6 inhibitor FX1 arrested growth and development. FX1-treated BPD mice exhibited exacerbation of alveolar pathological changes and pulmonary vessel permeability, with upregulated mRNA levels of pro-inflammatory cytokines and pro-fibrogenic factors. Furthermore, both rAAV9-BCL6 and FX1 administration exerted a long-lasting effect on hyperoxia-induced lung injury (≥4 wk).</p><p><strong>Conclusions: </strong>BCL6 inhibits NLRP3-mediated inflammation, attenuates alveolar simplification and dysregulated pulmonary vessel development in hyperoxia-induced BPD mice. Hence, BCL6 may be a target in treating BPD and neonatal diseases.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"50 1","pages":"25-41"},"PeriodicalIF":1.7,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139989704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ErbB deletion effect on pulmonary intracellular surfactant distribution.","authors":"Veronika Nolting, Christiane E L Dammann, Katja Hönzke, Andreas Schmiedl","doi":"10.1080/01902148.2024.2430721","DOIUrl":"https://doi.org/10.1080/01902148.2024.2430721","url":null,"abstract":"<p><p><b>Background:</b> Alveolar epithelial type II cells (AEII) synthesize, store, and recycle surfactant. Lipids and primarily hydrophobic surfactant proteins (SPs) are stored in lamellar bodies (Lbs) while the hydrophilic SPs and the precursors of hydrophobic SPs are stored in multivesicular bodies (mvb). ErbB4-receptor and its ligand neuregulin (NRG) are important regulators of fetal lung development and fetal surfactant synthesis. ErbB4 deletion leads predominantly to an alveolar simplification. We hypothesized that ErbB4 deletion affects the ultrastructure of AEII, specifically Lb and the intracellular distribution of the immunomodulating hydrophilic SP-A and the hydrophobic SP-B. <b>Material and Methods:</b> Using a HER4 transgenic cardiac rescue mouse model, AEII were characterized stereologically in lungs of juvenile transgenic HER4^heart+/- and HER4^heart-/- mice. The ultrastructure of Lb and the intracellular distribution of SPs were evaluated by immune electron microscopy. A preferential nonrandom labeling of a compartment for SP is present, if the relative labeling index (RLI) > 1and the chi-quadrat test is significant. <b>Results:</b> HER4 deletion had no significant effects on size of AEII and volume fractions of subcellular organelles as well as on the volume weighted mean volume of Lb in HER4^heart-/- when compared to HER4^heart+/- mice. The cytoplasm was preferentially labeled for SP-A in the AEII of both genotypes. Lbs were preferential labeled for SP-A in the AEII of HER4^heart-/-, but not in the AEII of HER4^heart+/- mice. SP-B was preferentially distributed over Lbs in AEII independent of the genotype, however, the evaluated RLI was significantly higher in HER4^heart-/- mice. <b>Conclusion:</b> HER4 deletion does not affect the ultrastructure of AEII and influence the distribution of SP-A and SP-B only moderately. Responsible for this could be compensatory mechanisms caused by the redundancy of ErbB receptors.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"50 1","pages":"259-277"},"PeriodicalIF":1.5,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stevioside attenuates bleomycin-induced pulmonary fibrosis by activating the Nrf2 pathway and inhibiting the NF-κB and TGF-β1/Smad2/3 pathways.","authors":"Wei Hao, Ting-Ting Yu, Dong-Ze Zuo, Heng-Zhao Hu, Ping-Ping Zhou","doi":"10.1080/01902148.2023.2286465","DOIUrl":"10.1080/01902148.2023.2286465","url":null,"abstract":"<p><p><b>Objective:</b> This study aimed to investigate the effects of stevioside (STE) on pulmonary fibrosis (PF) and the potential mechanisms. <b>Methods:</b> In this study, a mouse model of PF was established by a single intratracheal injection of bleomycin (BLM, 3 mg/kg). The experiment consisted of four groups: control group, BLM group, and STE treatment groups (STE 50 and 100 mg/kg). ELISA and biochemical tests were conducted to determine the levels of TNF-α, IL-1β, IL-6, NO, hydroxyproline (HYP), SOD, GSH, and MDA. Histopathological changes and collagen deposition in lung tissues were observed by HE and Masson staining. Immunohistochemistry was performed to determine the levels of collagen I-, collagen III-, TGF-β1- and p-Smad2/3-positive cells. Western blot analysis was used to measure the expression of epithelial-mesenchymal transition (EMT) markers, including α-SMA, vimentin, E-cadherin, and ZO-1, as well as proteins related to the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, nuclear transcription factor-κB (NF-κB) pathway, and TGF-β1/Smad2/3 pathway in lung tissues. <b>Results:</b> STE significantly alleviated BLM-induced body weight loss and lung injury in mice, decreased HYP levels, and reduced the levels of collagen I- and collagen III-positive cells, thereby decreasing extracellular matrix (ECM) deposition. Moreover, STE markedly improved oxidative stress (MDA levels were decreased, while SOD and GSH activity were enhanced), the inflammatory response (the levels of TNF-α, IL-1β, IL-6, and NO were reduced), and EMT (the expression of α-SMA and vimentin was downregulated, and the expression of E-cadherin and ZO-1 was upregulated). Further mechanistic analysis revealed that STE could activate the Nrf2 pathway and inhibit the NF-κB and TGF-β1/Smad2/3 pathways. <b>Conclusion:</b> STE may alleviate oxidative stress by activating the Nrf2 pathway, suppress the inflammatory response by downregulating the NF-κB pathway, and inhibit EMT progression by blocking the TGF-β1/Smad2/3 pathway, thereby improving BLM-induced PF.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"49 1","pages":"205-219"},"PeriodicalIF":1.7,"publicationDate":"2023-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138477173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ultrastructural analysis of the intracellular surfactant in lungs of healthy and ovalbumin sensitized and challenged <i>Brown Norway</i> rats.","authors":"Andreas Schmiedl,&nbsp;Stefanie Frank,&nbsp;Thomas Tschernig,&nbsp;Jens M Hohlfeld","doi":"10.1080/01902148.2023.2238232","DOIUrl":"https://doi.org/10.1080/01902148.2023.2238232","url":null,"abstract":"<p><p><b>Introduction:</b> In human and experimentally induced asthma, a dysfunction of the intra-alveolar-surface active agent (surfactant) has been demonstrated. Type II alveolar epithelial cells (AEII) synthesize, secrete and recycle surfactant. Prior to secretion, intracellular surfactant is stored in specific secretory organelles of AEII. The lamellar bodies (Lb) represent its ultrastructural correlate. The aim of this study was to investigate whether disturbances of the intra-alveolar surfactant are accompanied by alterations in the intracellular surfactant.<b>Material and Methods:</b> Brown-Norway rats were sensitized twice with ovalbumin (OVA) and heat killed Bordetella pertussis bacilli. During airway challenge, an aerosol of 5% ovalbumin/saline solution (0.25 l/min) was nebulized. 24 h after airway challenge, lungs were fixed by vascular perfusion. AEII and their Lb were characterized stereologically by light and electron microscopy.<b>Results:</b> In both groups, AEII were structurally intact. The number of AEII per lung and their number-weighted mean volume did not differ (controls: 49 × 10⁶, 393 µm³; asthmatics: 44 × 10⁶, 390 µm³). A mean of 90 Lb in AEII of asthmatics and of 93 Lb in AEII of controls were evaluated. The Lb mean total volume was 59 µm in asthmatics and 68 µm in controls. Values of both parameters did not reach significance. Also, the size distribution and mean volume of Lb was not influenced by asthma induction, because the volume weighted mean volume of Lb (2.18 µm in asthmatics compared to 1.87 µm in controls) and the numerical weighted mean volume (0.96 µm in asthmatics and 0.75 µm in controls) were comparable in both groups.<b>Conclusion:</b> The obtained results suggest that asthma-induced surfactant dysfunction is not related to disturbances in the intracellular surfactant´s ultrastructural correlates.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"49 1","pages":"142-151"},"PeriodicalIF":1.7,"publicationDate":"2023-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9883888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic exposure to ampicillin alters lung microbial composition in laboratory rat.","authors":"Ping Chen,&nbsp;Tingting Hu,&nbsp;Haonan Jiang,&nbsp;Bing Li,&nbsp;Guiying Li,&nbsp;Pixin Ran,&nbsp;Yumin Zhou","doi":"10.1080/01902148.2023.2219790","DOIUrl":"https://doi.org/10.1080/01902148.2023.2219790","url":null,"abstract":"<p><strong>Purpose: </strong>High-throughput sequencing technologies have revealed that the lungs contain a variety of low biomass microbiota associated with various lung diseases. Rat model is an important tool to understand the possible causal relationship between pulmonary microbiota and diseases. Antibiotic exposure can alter the microbiota, however, a direct influence of long-term ampicillin exposure on commensal bacteria of healthy lungs has not been investigated, which could be useful in the study of the relation between microbiome and long-term lung diseases, especially in animal model-making of lung diseases.</p><p><strong>Methods: </strong>The rats were aerosolized ampicillin of different concentrations for five months, and then the effect on the lung microbiota was investigated using 16S rRNA gene sequencing.</p><p><strong>Results: </strong>The ampicillin treatment by a certain concentration (LA5, 0.2 ml of 5 mg/ml ampicillin) administration leads to profound changes in the rat lung microbiota but not in the low critical ampicillin concentration (LA01 and LA1, 0.1 and 1 mg/ml ampicillin), when compared to the untreated group (LC). The genus <i>Acidobacteria_Gp16</i> dominated the ampicillin treated lung microbiota while the genera <i>Brucella</i>, <i>Acinetobacter</i>, <i>Acidobacteria_Gp14</i>, <i>Sphingomonas</i>, and <i>Tumebacillus</i> dominated the untreated lung microbiota. The predicted KEGG pathway analysis profile revealed some difference in the ampicillin treated group.</p><p><strong>Conclusions: </strong>The study demonstrated the effects of different concentrations of ampicillin treatment on lung microbiota of rats in a relatively long term. It could serve as a basis for the clinical use of antibiotic and the use of ampicillin to control certain bacteria in the animal model-making of respiratory diseases such as chronic obstructive pulmonary disease.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"49 1","pages":"116-130"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9651652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Force adaptation through the intravenous route in naïve mice.","authors":"Magali Boucher,&nbsp;Cyndi Henry,&nbsp;Ynuk Bossé","doi":"10.1080/01902148.2023.2237127","DOIUrl":"10.1080/01902148.2023.2237127","url":null,"abstract":"<p><p><b>Aim of the study:</b> Force adaptation is a process whereby the contractile capacity of the airway smooth muscle increases during a sustained contraction (aka tone). Tone also increases the response to a nebulized challenge with methacholine <i>in vivo</i>, presumably through force adaptation. Yet, due to its patchy pattern of deposition, nebulized methacholine often spurs small airway narrowing heterogeneity and closure, two important enhancers of the methacholine response. This raises the possibility that the potentiating effect of tone on the methacholine response is not due to force adaptation but by furthering heterogeneity and closure. Herein, methacholine was delivered homogenously through the intravenous (i.v.) route. <b>Materials and Methods:</b> Female and male BALB/c mice were subjected to one of two i.v. methacholine challenges, each of the same cumulative dose but starting by a 20-min period either with or without tone induced by serial i.v. boluses. Changes in respiratory mechanics were monitored throughout by oscillometry, and the response after the final dose was compared between the two challenges to assess the effect of tone. <b>Results:</b> For the elastance of the respiratory system (E_rs), tone potentiated the methacholine response by 64 and 405% in females (37.4 ± 10.7 <i>vs.</i> 61.5 ± 15.1 cmH₂O/mL; <i>p</i> = 0.01) and males (33.0 ± 14.3 <i>vs.</i> 166.7 ± 60.6 cmH₂O/mL; <i>p</i> = 0.0004), respectively. For the resistance of the respiratory system (R_rs), tone potentiated the methacholine response by 129 and 225% in females (9.7 ± 3.5 <i>vs.</i> 22.2 ± 4.3 cmH₂O·s/mL; <i>p</i> = 0.0003) and males (10.7 ± 3.1 <i>vs.</i> 34.7 ± 7.9 cmH₂O·s/mL; <i>p</i> < 0.0001), respectively. <b>Conclusions:</b> As previously reported with nebulized challenges, tone increases the response to i.v. methacholine in both sexes; albeit sexual dimorphisms were obvious regarding the relative resistive <i>versus</i> elastic nature of this potentiation. This represents further support that tone increases the lung response to methacholine through force adaptation.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"49 1","pages":"131-141"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10204552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of lipopolysaccharide-induced acute lung injury in aged mice.","authors":"Sukjin Bae, In Kyoung Kim, Jeonghyeon Im, Heayon Lee, Sang Haak Lee, Sei Won Kim","doi":"10.1080/01902148.2023.2285061","DOIUrl":"10.1080/01902148.2023.2285061","url":null,"abstract":"<p><p><b>Study Aim:</b> As the geriatric population rapidly expands, there has been a concurrent increase in elderly admissions to intensive care units (ICUs). Acute lung injury (ALI) is a prevalent reason for these admissions and carries poorer survival rates for the aged population compared to younger counterparts. The aging lung is subject to physiological, cellular, and immunological changes. However, our understanding of how aging impacts the clinical progression of ALI is limited. This study explored the effect of aging using a murine model of ALI. <b>Methods:</b> Female C57BL/6J mice, aged 7-8 wk (young) and 18 months (aged), were divided into four groups: young controls, aged controls, young with ALI (YL), and aged with ALI (AL). ALI was induced <i>via</i> intratracheal administration of lipopolysaccharide (LPS, 0.5 mg/kg). The animals were euthanized 72 h after LPS exposure. <b>Results:</b> The AL group exhibited a significantly increased wet/dry ratio compared to the other three groups, including the YL group. The bronchoalveolar lavage (BAL) fluid in the AL group had more cells overall, including more neutrophils, than the other groups. Inflammatory cytokines in BAL fluid showed similar trends. Histological analyses demonstrated more severe lung injury and fibrosis in the AL group than in the other groups. Increased transcription of senescence-associated secretory phenotype markers, including PAI-1 and MUC5B, was more prominent in the AL group than in the other groups. This trend was also observed in BAL samples from humans with pneumonia. <b>Conclusions:</b> Aging may amplify lung damage and inflammatory responses in ALI. This suggests that physicians should exercise increased caution in the clinical management of aged patients with ALI.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"49 1","pages":"193-204"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138440489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxic conditions promote a proliferative, poorly differentiated phenotype in COPD lung tissue progenitor cells in vitro.","authors":"Tina P Dale,&nbsp;Michael D Santer,&nbsp;Mohammed Haris,&nbsp;Wei Zuo,&nbsp;Nicholas R Forsyth","doi":"10.1080/01902148.2022.2158404","DOIUrl":"https://doi.org/10.1080/01902148.2022.2158404","url":null,"abstract":"<p><strong>Purpose: </strong>Chronic obstructive pulmonary disease (COPD) patients experience hypoxemia and lung tissue hypoxia, causing vasoconstriction, and at its most severe Cor pulmonale. However, minimal attention has been given to the effects of hypoxia at the cellular level. We hypothesize that a persistent progenitor cell population undergoes an aberrant differentiation process, influenced by changes in oxygen.</p><p><strong>Methods: </strong>Distal lung progenitor cells from two emphysematous donors were cultured in 21% and 2% oxygen. Proliferation was determined on collagen-coated plastic and in 3T3-J2 co-culture. Epithelial (E-cadherin, pan-cytokeratin) and progenitor (TP63, cytokeratin 5) marker expressions were examined. Cells were differentiated at air-liquid interface, and ciliated, mucus-producing, and club cell populations identified by immunofluorescence. <i>MUC5AC, MUC5B, CC10</i>, and <i>TP63</i> expression were determined using qRT-PCR, mucin5AC, and mucin5B protein levels by ELISA, and secreted mucin by periodic acid biotin hydrazide assay.</p><p><strong>Results: </strong>Cells were positive for epithelial and progenitor markers at isolation and passage 5. Passage 5 cells in hypoxia increased the proportion of TP63 by 10% from 51.6 ± 1.2% to 62.6 ± 2.3% (p ≤ 0.01). Proliferative capacity was greater on 3T3J2 cells and in 2% oxygen, supporting the emergence of a proliferation unrestricted population with limited differentiation capacity. Differentiation resulted in βIV tubulin positive-ciliated cells, mucin5AC, mucin5B, and CC10 positive secretory cells. Epithelial barrier formation was reduced (p ≤ 0.0001) in hypoxia-expanded cells. qRT-PCR showed higher mucin expression in 2% cells, significantly so with <i>MUC5B</i> (p ≤ 0.05). Although overall mucin5AC and mucin5B content was greater in 21% cells, normalization of secreted mucin to DNA showed a trend for increased mucin by low oxygen cells.</p><p><strong>Conclusions: </strong>These results demonstrate that hypoxia promotes a proliferative phenotype while affecting subsequent progenitor cell differentiation capacity. Furthermore, the retained differentiation potential becomes skewed to a more secretory phenotype, demonstrating that hypoxia may be contributing to disease symptoms and severity in COPD patients.</p>","PeriodicalId":12206,"journal":{"name":"Experimental Lung Research","volume":"49 1","pages":"12-26"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9969533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}