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

{"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":"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":"","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":"","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":"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":"","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":"","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}

{"title":"Enhanced glycolysis causes extracellular acidification and activates acid-sensing ion channel 1a in hypoxic pulmonary hypertension.","authors":"Megan N Tuineau, Lindsay M Herbert, Selina M Garcia, Thomas C Resta, Nikki L Jernigan","doi":"10.1152/ajplung.00083.2024","DOIUrl":"10.1152/ajplung.00083.2024","url":null,"abstract":"<p><p>In pulmonary hypertension (PHTN), a metabolic shift to aerobic glycolysis promotes a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells (PASMCs). Enhanced glycolysis induces extracellular acidosis, which can activate proton-sensing membrane receptors and ion channels. We previously reported that activation of the proton-gated cation channel acid-sensing ion channel 1a (ASIC1a) contributes to the development of hypoxic PHTN. Therefore, we hypothesize that enhanced glycolysis and subsequent acidification of the PASMC extracellular microenvironment activate ASIC1a in hypoxic PHTN. We observed decreased oxygen consumption rate and increased extracellular acidification rate in PASMCs from chronic hypoxia (CH)-induced PHTN rats, indicating a shift to aerobic glycolysis. In addition, we found that intracellular alkalization and extracellular acidification occur in PASMCs following CH and in vitro hypoxia, which were prevented by the inhibition of glycolysis with 2-deoxy-d-glucose (2-DG). Inhibiting H⁺ transport/secretion through carbonic anhydrases, Na⁺/H⁺ exchanger 1, or vacuolar-type H⁺-ATPase did not prevent this pH shift following hypoxia. Although the putative monocarboxylate transporter 1 (MCT1) and -4 (MCT4) inhibitor syrosingopine prevented the pH shift, the specific MCT1 inhibitor AZD3965 and/or the MCT4 inhibitor VB124 were without effect, suggesting that syrosingopine targets the glycolytic pathway independent of H⁺ export. Furthermore, 2-DG and syrosingopine prevented enhanced ASIC1a-mediated store-operated Ca²⁺ entry in PASMCs from CH rats. These data suggest that multiple H⁺ transport mechanisms contribute to extracellular acidosis and that inhibiting glycolysis-rather than specific H⁺ transporters-more effectively prevents extracellular acidification and ASIC1a activation. Together, these data reveal a novel pathological relationship between glycolysis and ASIC1a activation in hypoxic PHTN.<b>NEW & NOTEWORTHY</b> In pulmonary hypertension, a metabolic shift to aerobic glycolysis drives a hyperproliferative, apoptosis-resistant phenotype in pulmonary arterial smooth muscle cells. We demonstrate that this enhanced glycolysis induces extracellular acidosis and activates the proton-gated ion channel, acid-sensing ion channel 1a (ASIC1a). Although multiple H⁺ transport/secretion mechanisms are upregulated in PHTN and likely contribute to extracellular acidosis, inhibiting glycolysis with 2-deoxy-d-glucose or syrosingopine effectively prevents extracellular acidification and ASIC1a activation, revealing a promising therapeutic avenue.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L439-L451"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892695","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":"LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension.","authors":"Jochen Steppan, Huilei Wang, Kavitha Nandakumar, Mahin Gadkari, Alan Poe, Lydia Pak, Travis Brady, Dan E Berkowitz, Larissa A Shimoda, Lakshmi Santhanam","doi":"10.1152/ajplung.00327.2023","DOIUrl":"10.1152/ajplung.00327.2023","url":null,"abstract":"<p><p>Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance have emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen cross-linking enzyme lysyl oxidase like 2 (LOXL2) in this study. Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from the pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe pulmonary hypertension (PH). Similarly, LOXL2 protein and mRNA levels were increased in the pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from the rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in vivo with PAT-1251. Importantly, PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Hypoxia-induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH and pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 could be a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH.<b>NEW & NOTEWORTHY</b> Pulmonary arterial stiffening contributes to the progression of PAH and the deterioration of right heart function. This study shows that LOXL2 is upregulated in rat models of PH. LOXL2 inhibition halts pulmonary vascular remodeling and improves PA contractility, endothelial function, and PA pressure, resulting in prolonged survival. Thus, LOXL2 is an important mediator of PA remodeling and stiffening in PH and a promising target to improve PA pressures and survival in PH.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L423-L438"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619057","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":"A lentiviral toolkit to monitor airway epithelial cell differentiation using bioluminescence.","authors":"Jessica C Orr, Asma Laali, Pascal F Durrenberger, Kyren A Lazarus, Marie-Belle El Mdawar, Sam M Janes, Robert E Hynds","doi":"10.1152/ajplung.00047.2024","DOIUrl":"10.1152/ajplung.00047.2024","url":null,"abstract":"<p><p>Basal cells are adult stem cells in the airway epithelium and regenerate differentiated cell populations, including the mucosecretory and ciliated cells that enact mucociliary clearance. Human basal cells can proliferate and produce differentiated epithelium in vitro. However, studies of airway epithelial differentiation mostly rely on immunohistochemical or immunofluorescence-based staining approaches, meaning that a dynamic approach is lacking, and quantitative data are limited. Here, we use a lentiviral reporter gene approach to transduce primary human basal cells with bioluminescence reporter constructs to monitor airway epithelial differentiation longitudinally. We generated three constructs driven by promoter sequences from the <i>TP63</i>, <i>MUC5AC</i>, and <i>FOXJ1</i> genes to quantitatively assess basal cell, mucosecretory cell, and ciliated cell abundance, respectively. We validated these constructs by tracking differentiation of basal cells in air-liquid interface and organoid (\"bronchosphere\") cultures. Transduced cells also responded appropriately to stimulation with interleukin 13 (IL-13; to increase mucosecretory differentiation and mucus production) and IL-6 (to increase ciliated cell differentiation). These constructs represent a new tool for monitoring airway epithelial cell differentiation in primary epithelial and/or induced pluripotent stem cell (iPSC)-derived cell cultures.<b>NEW & NOTEWORTHY</b> Orr et al. generated and validated new lentiviral vectors to monitor the differentiation of airway basal cells, goblet cells, or multiciliated cells using bioluminescence.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L587-L599"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974844","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}