{"title":"Start SPREADing the News: Biosensors Detect Ripples of Extracellular Signal-regulated Kinase Signaling in Airway Epithelial Cells.","authors":"Luis F Vilches, John D Dickinson","doi":"10.1165/rcmb.2024-0547ED","DOIUrl":"10.1165/rcmb.2024-0547ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"469-471"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715031","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}
Yue Yang, Weiyu Shen, Zheming Zhang, Youai Dai, Zixiao Zhang, Tingting Liu, Jinyan Yu, Shulun Huang, Yu Ding, Rong You, Ziteng Wang, Yan Wu, Tao Bian
{"title":"FSP1 Acts in Parallel with GPX4 to Inhibit Ferroptosis in Chronic Obstructive Pulmonary Disease.","authors":"Yue Yang, Weiyu Shen, Zheming Zhang, Youai Dai, Zixiao Zhang, Tingting Liu, Jinyan Yu, Shulun Huang, Yu Ding, Rong You, Ziteng Wang, Yan Wu, Tao Bian","doi":"10.1165/rcmb.2023-0467OC","DOIUrl":"10.1165/rcmb.2023-0467OC","url":null,"abstract":"<p><p>GPX4 (glutathione peroxidase 4) has recently been reported to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). FSP1 (ferroptosis suppressor protein-1) is a protein that defends against ferroptosis in parallel with GPX4, but its role in the pathogenesis of COPD remains unexplored, and further research is needed. Normal and COPD lung tissues were obtained from lobectomy and lung transplant specimens, respectively. FSP1-overexpressing mice were established by monthly transfection with adenoassociated virus 9-FSP1 through modified intranasal administration. The expression of FSP1, GPX4, and PTGS2 (prostaglandin-endoperoxide synthase 2) was measured by Western blotting, immunohistochemistry and other methods. The correlation between FSP1 and ferroptosis and the role of FSP1 in COPD were explored by screening the expression of ferroptosis-related genes in a COPD cell model after the inhibition and overexpression of FSP1. We then explored the underlying mechanism of low FSP1 expression in patients with COPD <i>in vitro</i> by methylated RNA immunoprecipitation quantitative qPCR. We found that cigarette smoke exposure can lead to an increase in lipid peroxide production and ultimately ferroptosis, which is negatively regulated by FSP1 activity. FSP1 overexpression can prevent ferroptosis and alleviate emphysema. Next, we found that decreased FSP1 expression was caused by increased N6-methyladenosine modification of FSP1 mRNA. Moreover, the level of FSP1 decreased in a YTHDF2-dependent manner. These results indicate that METTL3-induced FSP1 mRNA methylation leading to low FSP1 expression is a potential therapeutic target for COPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"551-562"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493008","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":"Circulating Mitochondrial <i>N</i>-Formyl Peptides Are Associated with Acute Respiratory Distress Syndrome after Cardiopulmonary Bypass and Regulate Endothelial Barrier through FPR2.","authors":"Peng Lu, Xiaopei Li, Jinqiang Wang, Xiangyu Li, Zihao Shen, Yuanpu Qi, Mingyu Chu, Xin Yao, Xiao Zhang, Yu Zheng, Faliang Zhan, Meijuan Song, Xiaowei Wang","doi":"10.1165/rcmb.2024-0076OC","DOIUrl":"10.1165/rcmb.2024-0076OC","url":null,"abstract":"<p><p>Cardiopulmonary bypass (CPB) increases the risk of acute respiratory distress syndrome (ARDS) because of endothelial cell (EC) barrier dysfunction. However, the specific role of mitochondrial <i>N</i>-formyl peptides (mtNFPs) in ARDS after CPB remains unexplored. Here, we investigated the differential expression of circulating mtNFPs in patients after CPB, focusing on the novel role of FPR2 (formyl-peptide receptor 2) in ECs. Concentrations of circulating mtNFPs were assessed using ELISA. Several mtNFPs (ND4 [nicotinamide adenine dinucleotide dehydrogenase subunit 4], ND5, ND6, and Cox1) were significantly upregulated in patients with ARDS at Day 1 after CPB compared with patients without ARDS. Higher concentrations of ND6 were correlated with worse ratios of arterial oxygen pressure to fraction of inspired oxygen (<i>r</i> = -0.2219; <i>P</i> < 0.0001) and cardiac troponin T (<i>r</i> = 2.107; <i>P</i> < 0.0001). Using patient-derived serum and a rat lung ischemia-reperfusion injury model, we observed a positive correlation between serum ND6 concentration and ARDS, which is also associated with EC barrier dysfunction. <i>In vitro</i> experiments, using transendothelial electric resistance measurements and fluorescence microscopy with FITC-labeled vascular endothelial cadherin, demonstrated that ND6 disrupts the EC barrier through FPR2. Furthermore, FPR2 controls the release of ND6 out of mitochondria and cytoplasm under hypoxia-reoxygenation. Activated FPR2 leads to the upregulation of NF-κB by inducing IκBα phosphorylation, promoting ICAM1 (intercellular cell adhesion molecule-1) and VCAM1 expression, thereby compromising EC barrier integrity. Circulating proinflammatory and barrier-disruptive mtNFPs, particularly ND6, are associated with ARDS in patients undergoing CPB. The novel ND6-FPR2 axis regulates inflammation and EC permeability through the NF-κB pathway.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"533-550"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602774","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":"Channeling Relaxation through Multiple Means: TMEM16A Antagonism for Asthma.","authors":"Arun K Jannu, Raymond B Penn","doi":"10.1165/rcmb.2024-0521ED","DOIUrl":"10.1165/rcmb.2024-0521ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"466-468"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715029","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}
Sarah Commodore, Jonathan Hawkins, Cheyret Wood, Cuining Liu, Russell P Bowler, Laura Crotty Alexander, Peter Castaldi, Fernando Holguin, Katerina Kechris, Sunita Sharma
{"title":"A Pilot Study on the Impact of Vaping on Adolescent Lung Function and Nasal Epithelial Gene Expression.","authors":"Sarah Commodore, Jonathan Hawkins, Cheyret Wood, Cuining Liu, Russell P Bowler, Laura Crotty Alexander, Peter Castaldi, Fernando Holguin, Katerina Kechris, Sunita Sharma","doi":"10.1165/rcmb.2024-0332LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0332LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 5","pages":"594-597"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967571","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}
Aurélie Tréfier, Nihad Tousson-Abouelazm, Lama Yamani, Sajida Ibrahim, Kwang-Bo Joung, Adam Pietrobon, Julien Yockell-Lelievre, Terence E Hébert, Reese J Ladak, Tomoko Takano, Mark Nellist, Yoon Namkung, David Chatenet, William L Stanford, Stephane A Laporte, Arnold S Kristof
{"title":"Enhanced Gαq Signaling in <i>TSC2</i>-Deficient Cells Is Required for Their Neoplastic Behavior.","authors":"Aurélie Tréfier, Nihad Tousson-Abouelazm, Lama Yamani, Sajida Ibrahim, Kwang-Bo Joung, Adam Pietrobon, Julien Yockell-Lelievre, Terence E Hébert, Reese J Ladak, Tomoko Takano, Mark Nellist, Yoon Namkung, David Chatenet, William L Stanford, Stephane A Laporte, Arnold S Kristof","doi":"10.1165/rcmb.2024-0111OC","DOIUrl":"10.1165/rcmb.2024-0111OC","url":null,"abstract":"<p><p>Inherited or sporadic loss of the <i>TSC2</i> gene can lead to pulmonary lymphangioleiomyomatosis (LAM), a rare cystic lung disease caused by protease-secreting interstitial tumor nodules. The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage (LAM cells). Their aberrant growth is attributed to increased activity of mechanistic target of rapamycin complex 1 (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G protein-coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in <i>TSC2</i>-deficient cells remained unknown. Using a human pluripotent stem cell-derived <i>in vitro</i> model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and proneoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric Gαq/11 (Gαq). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking <i>TSC2</i> demonstrated selective and enhanced activation of Gαq and its RhoA-associated effectors compared with wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with Gαq and TSC2. The augmented Gαq signaling in <i>TSC2</i>-deleted cells was independent of mTOR activity and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of Gαq. These studies identify potential mTORC1-independent proneoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"578-590"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602776","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}
Amy Wu, Aisha Kuforiji, Yi Zhang, Dingbang Xu, Jose Perez-Zoghbi, Charles Emala, Jennifer Danielsson
{"title":"TMEM16A Antagonism: Therapeutic Potential with Desensitization of β-Agonist Responsiveness in Asthma.","authors":"Amy Wu, Aisha Kuforiji, Yi Zhang, Dingbang Xu, Jose Perez-Zoghbi, Charles Emala, Jennifer Danielsson","doi":"10.1165/rcmb.2024-0231OC","DOIUrl":"10.1165/rcmb.2024-0231OC","url":null,"abstract":"<p><p>The efficacy of β-agonists in asthma is severely limited by β-adrenoceptor desensitization, which results in poorly managed symptoms and refractory bronchoconstriction. Thus, there is a need to identify novel therapeutic pathways and to clarify the relationship between novel therapeutics and functional β-adrenoceptor responsiveness. We have previously demonstrated that acute antagonism of the calcium-activated chloride channel, transmembrane member 16A (TMEM16A), relaxes airway smooth muscle (ASM). We sought to determine the efficacy and role of TMEM16A antagonism in the context of desensitization β-adrenoceptor responsiveness. For these studies, we exposed murine tracheal rings on wire myography and precision-cut lung slices to contractile mediators in the presence or absence of TMEM16A antagonists and β-agonists with or without prior β-adrenoceptor desensitization. Contractile studies were also performed with human tracheal and bronchial ASM. Finally, the ability of TMEM16A antagonism to prevent desensitization of β<sub>2</sub>-adrenoceptor-induced cAMP synthesis was measured in human ASM cells. From these studies, we demonstrate that acute TMEM16A antagonism is effective in relaxing β-agonist-desensitized ASM in central and peripheral murine ASM and human ASM. Furthermore, we demonstrate that chronic pretreatment with TMEM16A antagonists prevents functional desensitization of β-agonist responsiveness in mouse and human upper airways and prevents desensitization of β-agonist-mediated cAMP production in human ASM cells. Taken together, the present study demonstrates a favorable therapeutic profile of TMEM16A antagonism for ASM relaxation despite functional desensitization of β-agonist responsiveness, which may be a novel therapeutic approach in the face of β-adrenoceptor tachyphylaxis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"510-519"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666795","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}
Kathryn M Polkoff, Ross Lampe, Nithin K Gupta, Yanet Murphy, Jaewook Chung, Amber Carter, Jeremy M Simon, Katherine Gleason, Adele Moatti, Preetish K Murthy, Laura Edwards, Alon Greenbaum, Aleksandra Tata, Purushothama Rao Tata, Jorge A Piedrahita
{"title":"Novel Porcine Model Reveals Two Distinct LGR5 Cell Types during Lung Development and Homeostasis.","authors":"Kathryn M Polkoff, Ross Lampe, Nithin K Gupta, Yanet Murphy, Jaewook Chung, Amber Carter, Jeremy M Simon, Katherine Gleason, Adele Moatti, Preetish K Murthy, Laura Edwards, Alon Greenbaum, Aleksandra Tata, Purushothama Rao Tata, Jorge A Piedrahita","doi":"10.1165/rcmb.2024-0040OC","DOIUrl":"10.1165/rcmb.2024-0040OC","url":null,"abstract":"<p><p>Cells expressing leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) play a pivotal role in homeostasis, repair, and regeneration in multiple organs, including skin and gastrointestinal tract, but little is known about their role in the lung. Findings from mice, a widely used animal model, suggest that lung LGR5 expression differs from that of humans. In this work, using a new transgenic pig model, we identify two main populations of LGR5<sup>+</sup> cells in the lung that are conserved in human but not mouse lungs. Using RNA sequencing, three-dimensional imaging, and organoid models, we determine that in the fetal lung, epithelial LGR5 expression is transient in a subpopulation of SOX9<sup>+</sup>/ETV5<sup>+</sup>/SFTPC<sup>+</sup> progenitor lung tip cells. In contrast, epithelial LGR5 expression is absent from postnatal lung but is reactivated in bronchioalveolar organoids derived from basal airway cells. We also describe a separate population of mesenchymal LGR5<sup>+</sup> cells that surrounds developing and mature airways, lies adjacent to airway basal cells, and is closely associated with nerve fibers. Transcriptionally, mesenchymal LGR5<sup>+</sup> cells include a subset of peribronchial fibroblasts that express unique patterns of <i>SHH</i>, <i>FGF</i>, <i>WNT</i>, and <i>TGF-β</i> signaling pathway genes. These results support distinct roles for LGR5<sup>+</sup> cells in the lung and describe a physiologically relevant animal model for further studies on the function of these cells in repair and regeneration.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"496-509"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581619","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}
Mereena G Ushakumary, Song Feng, Gautam Bandyopadhyay, Heather Olson, Karl K Weitz, Heidi L Huyck, Cory Poole, Jeffrey M Purkerson, Soumyaroop Bhattacharya, M Cecilia Ljungberg, Thomas J Mariani, Gail H Deutsch, Ravi S Misra, James P Carson, Joshua N Adkins, Gloria S Pryhuber, Geremy Clair
{"title":"Cell Population-resolved Multiomics Atlas of the Developing Lung.","authors":"Mereena G Ushakumary, Song Feng, Gautam Bandyopadhyay, Heather Olson, Karl K Weitz, Heidi L Huyck, Cory Poole, Jeffrey M Purkerson, Soumyaroop Bhattacharya, M Cecilia Ljungberg, Thomas J Mariani, Gail H Deutsch, Ravi S Misra, James P Carson, Joshua N Adkins, Gloria S Pryhuber, Geremy Clair","doi":"10.1165/rcmb.2024-0105OC","DOIUrl":"10.1165/rcmb.2024-0105OC","url":null,"abstract":"<p><p>The lung is a vital organ that undergoes extensive morphological and functional changes during postnatal development. To disambiguate how different cell populations contribute to organ development, we performed proteomic and transcriptomic analyses of four sorted cell populations from the lung of human subjects 0-8 years of age with a focus on early life. The cell populations analyzed included epithelial, endothelial, mesenchymal, and immune cells. Our results revealed distinct molecular signatures for each of the sorted cell populations that enable the description of molecular shifts occurring in these populations during postnatal development. We confirmed that the proteome of the different cell populations was distinct regardless of age and identified functions specific to each population. We identified a series of cell population protein markers, including those located at the cell surface, that show differential expression and distribution on RNA <i>in situ</i> hybridization and immunofluorescence imaging. We validated the spatial distribution of alveolar type 1 and endothelial cell surface markers. Temporal analyses of the proteomes of the four populations revealed processes modulated during postnatal development and clarified the findings obtained from whole-tissue proteome studies. Finally, the proteome was compared with a transcriptomics survey performed on the same lung samples to evaluate processes under post-transcriptional control.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"484-495"},"PeriodicalIF":5.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12051933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493006","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}