American journal of physiology. Lung cellular and molecular physiology最新文献

{"title":"Microbiome modifications by steroids during viral exacerbation of asthma and in healthy mice.","authors":"Kazuma Yagi, Alexander D Ethridge, Nicole R Falkowski, Yvonne J Huang, Srikanth Elesela, Gary B Huffnagle, Nicholas W Lukacs, Wendy Fonseca, Nobuhiro Asai","doi":"10.1152/ajplung.00040.2024","DOIUrl":"10.1152/ajplung.00040.2024","url":null,"abstract":"<p><p>In the present studies, the assessment of how viral exacerbation of asthmatic responses with and without pulmonary steroid treatment alters the microbiome in conjunction with immune responses presents striking data. The overall findings identify that although steroid treatment of allergic animals diminished the severity of the respiratory syncytial virus (RSV)-induced exacerbation of airway function and mucus hypersecretion, there were local increases in IL-17 expression. Analysis of the lung and gut microbiome suggested that there are differences in RSV exacerbation that are further altered by fluticasone (FLUT) treatment. Using metagenomic inference software, PICRUSt2, we were able to predict that the metabolite profile produced by the changed gut microbiome was significantly different with multiple metabolic pathways and associated with specific treatments with or without FLUT. Importantly, measuring plasma metabolites in an unbiased manner, our data indicate that there are significant changes associated with chronic allergen exposure, RSV exacerbation, and FLUT treatment that are reflective of responses to the disease and treatment. In addition, the changes in metabolites appeared to have contributions from both host and microbial pathways. To understand if airway steroids on their own altered lung and gut microbiome along with host responses to RSV infection, naïve animals were treated with lung FLUT before RSV infection. The naïve animals treated with FLUT before RSV infection demonstrated enhanced disease that corresponded to an altered microbiome and the related PICRUSt2 metagenomic inference analysis. Altogether, these findings set the foundation for identifying important correlations of severe viral exacerbated allergic disease with microbiome changes and the relationship of host metabolome with a potential for early life pulmonary steroid influence on subsequent viral-induced disease.<b>NEW & NOTEWORTHY</b> These studies outline a novel finding that airway treatment with fluticasone, a commonly used inhaled steroid, has significant effects on not only the local lung environment but also on the mucosal microbiome, which may have significant disease implications. The findings further provide data to support that pulmonary viral exacerbations of asthma with or without steroid treatment alter the lung and gut microbiome, which have an impact on the circulating metabolome that likely alters the trajectory of disease progression.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L646-L660"},"PeriodicalIF":4.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11560076/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The pontine Kölliker-Fuse nucleus is important for reduced postinspiratory airflow elicited by stimulation of the ventral respiratory parafacial region.","authors":"Karine C Flor, Octavio A C Maia, Ana C Takakura, Thiago S Moreira","doi":"10.1152/ajplung.00155.2024","DOIUrl":"10.1152/ajplung.00155.2024","url":null,"abstract":"<p><p>Considering that the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) would be an important center in the central nervous system involved in the maintenance and modulation of respiratory activity, we hypothesized that neurons in this nucleus would also be involved in the postinspiratory (post-I) phase of the respiratory cycle through a connection with the pontine Kölliker-Fuse (KF) region. Here, we performed pharmacogenetic manipulation (AAV-hM3D(Gq)-mCherry or AAV-hM4D(Gi)-mCherry) in VGlut2-cre, Ai6 conscious mice to evaluate breathing parameters through whole body plethysmography under baseline conditions (normoxia: [Formula: see text] = 0.21) or under hypercapnia or hypoxia challenges ([Formula: see text] = 0.07 or [Formula: see text] = 0.08). Under normoxia, selective stimulation of RTN/pFRG resulted in a smaller increase in V̇e (1,272 ± 102.5, vs. RTN/pFRG stimulation: 1,878 ± 122.1 mL/kg/min), due to a smaller increase in V_T (5.4 ± 0.35, vs. RTN/pFRG stimulation: 7.77 ± 0.21 mL/kg) without changing <i>f</i>_R in a condition of KF inhibition. However, inhibition of the VGlut2 neurons in the KF did affect the <i>T</i>_E1 produced by selective activation of RTN/pFRG (119.9 ± 2.53, vs. RTN/pFRG stimulation: 104 ± 2.46 ms). Both the hypercapnia and hypoxia ventilatory response were reduced after inhibition of VGlut2-expressing KF neurons. Therefore, consistent with anatomical projections RTN/pFRG neurons regulate lung ventilation by controlling all aspects of breathing, i.e., breathing frequency, inspiration, postinspiration, and active expiration. All the modulation seems to be dependent on the integrity of the glutamatergic neurons in the KF region.<b>NEW & NOTEWORTHY</b> Our research reveals specific roles and interactions between the retrotrapezoid nucleus/respiratory parafacial region (RTN/pFRG) and the pontine Kölliker-Fuse (KF) region in controlling respiratory phases. RTN/pFRG neurons are key in regulating all aspects of breathing, including frequency, inspiration, postinspiration, and active expiration. This regulation depends on the functional integrity of glutamatergic neurons in the KF region, aligning with anatomical projections.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L452-L463"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucociliary clearance is impaired in small airways of cystic fibrosis pigs.","authors":"Carley G Stewart, Brieanna M Hilkin, Nicholas D Gansemer, Ryan J Adam, David W Dick, John J Sunderland, David A Stoltz, Joseph Zabner, Mahmoud H Abou Alaiwa","doi":"10.1152/ajplung.00010.2024","DOIUrl":"10.1152/ajplung.00010.2024","url":null,"abstract":"<p><p>Cystic fibrosis (CF) is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance, and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to the limited accessibility of the small airways with the current single-photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [⁶⁸Ga]-tagged macroaggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down a few minutes after delivery. Cystic fibrosis pigs' small airways cleared significantly less than non-CF pigs' small airways (non-CF 25.1 ± 3.1% vs. CF 14.6 ± 0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue uridine-5'-triphosphate (UTP) further impaired clearance (non-CF with UTP 20.9 ± 0.3% vs. CF with UTP 13.0 ± 1.8%). None of the cystic fibrosis pigs treated with UTP (<i>n</i> = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.<b>NEW & NOTEWORTHY</b> We developed a novel positron emission tomography scan assay with unprecedented temporal and spatial resolution to measure mucociliary clearance in the small airways. We proved a long-standing but unproven assertion that mucociliary clearance is inherently abnormal in the small airways of newborn cystic fibrosis piglets that are otherwise free of infection or inflammation. This technique can be easily extended to other airway diseases such as asthma, idiopathic pulmonary fibrosis, or chronic obstructive pulmonary disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L415-L422"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482522/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of physical activity in lymphocytes senescence burden in patients with COPD.","authors":"Enrique Alfaro, Elena Díaz-García, Sara García-Tovar, Raúl Galera, Raquel Casitas, Elisabet Martínez-Cerón, María Torres-Vargas, José M Padilla, Cristina López-Fernández, Paula Pérez-Moreno, Francisco García-Río, Carolina Cubillos-Zapata","doi":"10.1152/ajplung.00151.2024","DOIUrl":"10.1152/ajplung.00151.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is regarded as an accelerated-age disease in which chronic inflammation, maladaptive immune responses, and senescence cell burden coexist. Accordingly, cellular senescence has emerged as a potential mechanism involved in COPD pathophysiology. In this study, 25 stable patients with COPD underwent a daily physical activity promotion program for 6 mo. We reported that increase of physical activity was related to a reduction of the senescent cell burden in circulating lymphocytes of patients with COPD. Senescent T-lymphocyte population, characterized by absence of surface expression of CD28, was reduced after physical activity intervention, and the reduction was associated to the increase of physical activity level. In addition, the mRNA expression of cyclin-dependent kinase inhibitors, a hallmark of cell senescence, was reduced and, in accordance, the proliferative capacity of lymphocytes was improved postintervention. Moreover, we observed an increase in functionality in T cells from patients after intervention, including improved markers of activation, enhanced cytotoxicity, and altered cytokine secretions in response to viral challenge. Lastly, physical activity intervention reduced the potential of lymphocytes' secretome to induce senescence in human primary fibroblasts. In conclusion, our study provides, for the first time, evidence of the potential of physical activity intervention in patients with COPD to reduce the senescent burden in circulating immune cells.<b>NEW & NOTEWORTHY</b> For the first time, we identified in patients with COPD a relation between physical activity intervention with respiratory function improvement and cellular senescence burden in lymphocytes that improved the T cell functionality and proliferative capacity of patients. In addition, our experiments highlight the possible impact of T-cell senescence in other cell types which could be related to some of the clinical lung complications observed in COPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L464-L472"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Citrullination, a novel posttranslational modification of elastin, is involved in COPD pathogenesis.","authors":"Mark P Murphy, Marina Zieger, Michael Henry, Paula Meleady, Christian Mueller, Noel G McElvaney, Emer P Reeves","doi":"10.1152/ajplung.00185.2024","DOIUrl":"10.1152/ajplung.00185.2024","url":null,"abstract":"<p><p>Elastin is an extracellular matrix protein (ECM) that supports elasticity of the lung, and in patients with chronic obstructive pulmonary disease (COPD) and emphysema, the structural changes that reduce the amount of elastic recoil, lead to loss of pulmonary function. We recently demonstrated that elastin is a target of peptidyl arginine deiminase (PAD) enzyme-induced citrullination, thereby leading to enhanced susceptibility of this ECM protein to proteolysis. This study aimed to investigate the impact of PAD activity in vivo and furthermore assessed whether pharmacological inhibition of PAD activity protects against pulmonary emphysema. Using a <i>Serpina1a-e</i> knockout mouse model, previously shown to develop inflammation-mediated emphysema, we validated the involvement of PADs in airway disease. In line with emphysema development, intratracheal administration of lipopolysaccharide in combination with PADs provoked significant airspace enlargement (<i>P</i> < 0.001) and diminished lung function, including loss of lung tissue elastance (<i>P</i> = 0.0217) and increases in lung volumes (<i>P</i> = 0.0463). Intraperitoneal treatment of mice with the PAD inhibitor, BB-Cl-amidine, prevented PAD/LPS-mediated lung function decline and emphysema and reduced levels of citrullinated airway elastin (<i>P</i> = 0.0199). These results provide evidence for the impact of PADs on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.<b>NEW & NOTEWORTHY</b> This study provides evidence for the impact of peptidyl arginine deiminase (PAD) enzymes on lung function decline, indicating promising potential for the future development of PAD-based therapeutics for preserving lung function in patients with COPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L600-L606"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Faces: Introducing the newest Editorial Board Fellows of the <i>American Journal of Physiology-Lung Cellular and Molecular Physiology</i>.","authors":"Larissa A Shimoda, Cristina M Alvira, Julie A Bastarache, Rodney D Britt, Wolfgang M Kuebler, Thiago S Moreira, Eric P Schmidt","doi":"10.1152/ajplung.00304.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00304.2024","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic hyperglycemia aggravates lung function in a <i>Scnn1b</i>-Tg murine model.","authors":"Guiying Cui, Dina A Moustafa, Shilin Zhao, Analia Vazquez Cegla, James T Lyles, Joanna B Goldberg, Joshua D Chandler, Nael A McCarty","doi":"10.1152/ajplung.00279.2023","DOIUrl":"10.1152/ajplung.00279.2023","url":null,"abstract":"<p><p>Cystic fibrosis-related diabetes (CFRD), the most common comorbidity in cystic fibrosis (CF), leads to increased mortality by accelerating the decline in lung function. <i>Scnn1b-</i>Tg transgenic mice overexpressing the epithelial sodium channel β subunit exhibit spontaneous CF-like lung disease, including airway mucus obstruction and chronic inflammation. Here, we established a chronic CFRD-like model using <i>Scnn1b-</i>Tg mice made diabetic by injection of streptozotocin (STZ). In Ussing chamber recordings of the trachea, <i>Scnn1b-</i>Tg mice exhibited larger amiloride-sensitive currents and forskolin-activated currents, without a difference in adenosine triphosphate (ATP)-activated currents compared with wild-type (WT) littermates. Both diabetic WT (WT-D) and diabetic <i>Scnn1b-</i>Tg (<i>Scnn1b</i>-Tg-D) mice on the same genetic background exhibited substantially elevated blood glucose at 8 wk; glucose levels also were elevated in bronchoalveolar lavage fluid (BALF). Bulk lung RNA-seq data showed significant differences between WT-D and <i>Scnn1b</i>-Tg-D mice. Neutrophil counts in BALF were substantially increased in <i>Scnn1b-</i>Tg-D lungs compared with controls (<i>Scnn1b</i>-Tg-con) and compared with WT-D lungs. Lung histology data showed enhanced parenchymal destruction, alveolar wall thickening, and neutrophilic infiltration in <i>Scnn1b-</i>Tg-D mice compared with WT-D mice, consistent with the development of a spontaneous lung infection. We intranasally administered <i>Pseudomonas aeruginosa</i> to induce lung infection in these mice for 24 h, which led to severe lung leukocytic infiltration and an increase in pro-inflammatory cytokine levels in the BALF. In summary, we established a chronic CFRD-like lung mouse model using the <i>Scnn1b</i>-Tg mice. The model can be used for future studies toward understanding the mechanisms underlying the lung pathophysiology associated with CFRD and developing novel therapeutics.<b>NEW & NOTEWORTHY</b> We established a chronic CFRD-like mouse model using the <i>Scnn1b</i>-Tg transgenic mice overexpressing the epithelial sodium channel β subunit made diabetic by injection of streptozotocin. The results underscore the urgent need to develop novel therapeutics for CF lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L473-L486"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Developing a mouse model of human coronavirus NL63 infection: comparison with rhinovirus-A1B and effects of prior rhinovirus infection.","authors":"J Kelley Bentley, Jordan E Kreger, Haley A Breckenridge, Shilpi Singh, Jing Lei, Yiran Li, Susan C Baker, Carey N Lumeng, Marc B Hershenson","doi":"10.1152/ajplung.00149.2023","DOIUrl":"10.1152/ajplung.00149.2023","url":null,"abstract":"<p><p>Human coronavirus (HCoV)-NL63 causes respiratory tract infections in humans and uses angiotensin-converting enzyme 2 (ACE2) as a receptor. We sought to establish a mouse model of HCoV-NL63 and determine whether prior rhinovirus (RV)-A1B infection affected HCoV-NL63 replication. HCoV-NL63 was propagated in LLC-MK2 cells expressing human ACE2. RV-A1B was grown in HeLa-H1 cells. C57BL6/J or transgenic mice expressing human ACE2 were infected intranasally with sham LLC-MK2 cell supernatant or 1 × 10⁵ tissue culture infectious dose (TCID₅₀) units HCoV-NL63. Wild-type mice were infected with 1 × 10⁶ plaque-forming units (PFU) RV-A1B. Lungs were assessed for vRNA, bronchoalveolar lavage (BAL) cells, histology, HCoV-NL63 nonstructural protein 3 (nsp3), and host gene expression by next-generation sequencing and qPCR. To evaluate sequential infections, mice were infected with RV-A1B followed by HCoV-NL63 infection 4 days later. We report that hACE2 mice infected with HCoV-NL63 showed evidence of replicative infection with increased levels of vRNA, BAL neutrophils and lymphocytes, peribronchial and perivascular infiltrates, and expression of nsp3. Viral replication peaked 3 days after infection and inflammation persisted 6 days after infection. HCoV-NL63-infected hACE2 mice showed increased mRNA expression of IFNs, IFN-stimulated proteins, and proinflammatory cytokines. Infection with RV-A1B 4 days before HCoV-NL63 significantly decreased both HCoV-NL63 vRNA levels and airway inflammation. Mice infected with RV-A1B prior to HCoV-NL63 showed increased expression of antiviral proteins compared with sham-treated mice. In conclusion, we established a mouse model of HCoV-NL63 replicative infection characterized by relatively persistent viral replication and inflammation. Prior infection with RV-A1B reduced HCoV-NL63 replication and airway inflammation, indicative of viral interference.<b>NEW & NOTEWORTHY</b> We describe a mouse model of human coronavirus (HCoV) infection. Infection of transgenic mice expressing human angiotensin-converting enzyme 2 (ACE2) with HCoV-NL63 produced a replicative infection with peribronchial inflammation and nonstructural protein 3 expression. Mice infected with RV-A1B 4 days before HCoV-NL63 showed decreased HCoV-NL63 replication and airway inflammation and increased expression of antiviral proteins compared with sham-treated mice. This research may shed light on human coronavirus infections, viral interference, and viral-induced asthma exacerbations.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L557-L573"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071779","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo channels modulate human lung fibroblast function.","authors":"Mengning Zheng, Yang Yao, Niyati A Borkar, Michael A Thompson, Emily Zhang, Li Y Drake, Xianwei Ye, Elizabeth R Vogel, Christina M Pabelick, Y S Prakash","doi":"10.1152/ajplung.00356.2023","DOIUrl":"10.1152/ajplung.00356.2023","url":null,"abstract":"<p><p>Bronchial airways and lung parenchyma undergo both static and dynamic stretch in response to normal breathing as well as in the context of insults such as mechanical ventilation (MV) or in diseases such as asthma and chronic obstructive pulmonary disease (COPD) which lead to airway remodeling involving increased extracellular matrix (ECM) production. Here, the role of fibroblasts is critical, but the relationship between stretch- and fibroblast-induced ECM remodeling under these conditions is not well-explored. Piezo (PZ) channels play a role in mechanotransduction in many cell and organ systems, but their role in mechanical stretch-induced airway remodeling is not known. To explore this, we exposed human lung fibroblasts to 10% static stretch on a background of 5% oscillations for 48 h, with no static stretch considered controls. Collagen I, fibronectin, alpha-smooth muscle actin (α-SMA), and Piezo 1 (PZ1) expression was determined in the presence or absence of Yoda1 (PZ1 agonist) or GsMTx4 (PZ1 inhibitor). Collagen I, fibronectin, and α-SMA expression was increased by stretch and Yoda1, whereas pretreatment with GsMTx4 or knockdown of PZ1 by siRNA blunted this effect. Acute stretch in the presence and absence of Yoda1 demonstrated activation of the ERK pathway but not Smad. Measurement of [Ca²⁺]_i responses to histamine showed significantly greater responses following stretch, effects that were blunted by knockdown of PZ1. Our findings identify an essential role for PZ1 in mechanical stretch-induced production of ECM mediated by ERK phosphorylation and Ca²⁺ influx in lung fibroblasts. Targeting PZ channels in fibroblasts may constitute a novel approach to ameliorate airway remodeling by decreasing ECM deposition.<b>NEW & NOTEWORTHY</b> The lung is an inherently mechanosensitive organ that can respond to mechanical forces in adaptive or maladaptive ways, including via remodeling resulting in increased fibrosis. We explored the mechanisms that link mechanical forces to remodeling using human lung fibroblasts. We found that mechanosensitive Piezo channels increase with stretch and mediate extracellular matrix formation and the fibroblast-to-myofibroblast transition that occurs with stretch. Our data highlight the importance of Piezo channels in lung mechanotransduction toward remodeling.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L547-L556"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adiponectin suppresses stiffness-dependent, profibrotic activation of lung fibroblasts.","authors":"Julia Nemeth, Wioletta Skronska-Wasek, Sophie Keppler, Annika Schundner, Alexander Groß, Tanja Schoenberger, Karsten Quast, Karim C El Kasmi, Clemens Ruppert, Andreas Günther, Manfred Frick","doi":"10.1152/ajplung.00037.2024","DOIUrl":"10.1152/ajplung.00037.2024","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible respiratory disease with limited therapeutic options. A hallmark of IPF is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We performed an unbiased, next-generation sequencing (NGS) screen to identify signaling pathways involved in stiffness-dependent lung fibroblast activation. Adipocytokine signaling was downregulated in primary lung fibroblasts (PFs) cultured on stiff matrices. Re-activating adipocytokine signaling with adiponectin suppressed stiffness-dependent activation of human PFs. Adiponectin signaling depended on CDH13 expression and p38 mitogen-activated protein kinase gamma (p38MAPKγ) activation. CDH13 expression and p38MAPKγ activation were strongly reduced in lungs from IPF donors. Our data suggest that adiponectin-signaling via CDH13 and p38MAPKγ activation suppresses profibrotic activation of fibroblasts in the lung. Targeting of the adiponectin signaling cascade may provide therapeutic benefits in IPF.<b>NEW & NOTEWORTHY</b> A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive fibroblast activation and extracellular matrix (ECM) deposition. The resulting increase in tissue stiffness amplifies fibroblast activation and drives disease progression. Dampening stiffness-dependent activation of fibroblasts could slow disease progression. We found that activation of the adipocytokine signaling pathway halts and reverses stiffness-induced, profibrotic fibroblast activation. Specific targeting of this signaling cascade may therefore provide therapeutic benefits in IPF.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L487-L502"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}