American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"ANT1 Deficiency Impairs Macrophage Metabolism and Migration, Protecting Against Emphysema in COPD.","authors":"Justin Sui, Aaron R Johnson, Theodore S Kapellos, Sruti Shiva, Corrine R Kliment","doi":"10.1165/rcmb.2024-0469OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0469OC","url":null,"abstract":"<p><p>Macrophage-mediated inflammation drives various lung diseases, including chronic obstructive pulmonary disease (COPD). COPD macrophages have dysfunctional mitochondrial metabolism and function which lead to a chronic inflammatory lung environment. However, the factors regulating this altered metabolism have not been elucidated. Adenine nucleotide translocase 1 (ANT1) is a mitochondrial ATP transporter critical to mitochondrial metabolism. We demonstrate that human alveolar macrophages from patients with moderate COPD (GOLD stage 2) have reduced ANT1 expression while macrophages from very severe COPD (GOLD stage 4) have elevated ANT1 compared to normal control subjects. <i>Ant1</i>-deficient mice were protected against cigarette smoke (CS)-induced emphysema with failure of recruited immune cells to migrate into alveoli. <i>Ant1</i>-null alveolar macrophages had reduced ATP production and mitochondrial respiration, upregulated fewer inflammatory pathways after CS and reduced migratory capacity. Conditional <i>Ant1</i> knockout in Cx3cr1-positive monocytes and adoptive transfer of <i>Ant1</i>-deficient bone marrow into CS-treated mice phenocopied the migratory defect in the lung. Our data indicate that ANT1 is a critical regulator of lung macrophage inflammatory signaling and CS-triggered cell migration in the lung, suggesting that metabolic modulation may be a promising therapeutic avenue for COPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172434","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":"Biased Orthosteric Agonism and Allosteric Modulation: Emerging Strategies for Developing New Class of β-Agonists for Obstructive Airway Diseases.","authors":"Sushrut D Shah, Deepak A Deshpande","doi":"10.1165/rcmb.2025-0144TR","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0144TR","url":null,"abstract":"<p><p>The obstructive lung diseases (OLDs) asthma and chronic obstructive pulmonary disease are characterized by bronchoconstriction and difficulty in breathing. Agonists of β2-adrenergic receptors (β-agonists) are the most commonly used bronchodilators. To enhance their clinical effectiveness, extensive attempts have been made to improve their receptor subtype selectivity and duration of action, resulting in the development of long- and ultra-long-acting β-agonists. While these drugs effectively alleviate OLD symptoms, concerns have arisen regarding their safety, reduced therapeutic benefits, and the potential for worsening asthma symptoms. These concerns have led to restrictions on β-agonist use. Recent advances in G protein-coupled receptor (GPCR) pharmacology and biochemistry have introduced new concepts in drug development, such as \"biased agonism\" and \"allosteric modulation.\" These advancements stem from a deeper understanding of the molecular interactions between β2-adrenergic receptors (β2AR) and various intracellular proteins (e.g., heterotrimeric G-proteins and β-arrestins), which induce a diverse array of functional changes in airway cells. Biased agonism and allosteric modulation offer new avenues for developing the next generation of β-agonists with improved pharmacological properties. This review explores the application of these concepts in developing new β2AR ligands, including orthosteric and allosteric ligands, that selectively enhance therapeutically beneficial Gs signaling while minimizing harmful β-arrestin-mediated effects in airway cells.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172435","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":"Pulmonary Microvascular Endothelial Cells Support Alveolar Epithelial Growth via Bone Morphogenetic Protein 6 Secretion.","authors":"Luke van der Koog, Xinhui Wu, Dyan F Nugraha, Abilash Ravi, Justina C Wolters, Fien M Verhamme, Peter L Horvatovich, Ken R Bracke, Anne M van der Does, Pieter S Hiemstra, Jill R Johnson, Martin C Harmsen, Anika Nagelkerke, Reinoud Gosens","doi":"10.1165/rcmb.2024-0409OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0409OC","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow limitation and emphysema development, associated with enhanced tissue destruction and defective repair. Supporting cells in the alveolar niche play a crucial role in guiding the activation of alveolar epithelial progenitor cells during repair. Despite their close anatomical proximity, understanding of the supportive role of the pulmonary microvascular endothelium in adult alveolar epithelial repair remains limited. We hypothesized that factors secreted by pulmonary endothelial cells support alveolar epithelial cell growth. Here, we report that human pulmonary microvasculature endothelial cells (HPMECs) support murine and human alveolar organoid formation through paracrine signaling via the secretion of extracellular vesicles and soluble factors. Transcriptomic and proteomic analysis pinpointed HPMEC-derived bone morphogenetic protein 6 (BMP6) as a critical factor for alveolar organoid formation. BMP6 promoted alveolar epithelial cell growth, whereas function-blocking antibodies targeting BMP6 inhibited the beneficial effect of endothelial cells on murine alveolar organoid formation. Transcriptomic analysis revealed that BMP6 specifically enhances distal epithelial cell markers and increases Wnt signaling in epithelial progenitors. In contrast, BMP6 deficiency in mouse lungs was associated with reduced Wnt signaling and augmented oxidative stress signaling in murine lung tissue. Taken together, our findings highlight BMP6 as a key regulator of adult epithelial repair and suggest its potential as a therapeutic target for defective epithelial repair, particularly in individuals with early stages of COPD.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172436","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":"<i>HERC6</i> and <i>KCNQ3</i> Expression Associated with Primary Ciliary Dyskinesia and Nasal Nitric Oxide Levels.","authors":"Minako Hijikata, Kozo Morimoto, Masashi Ito, Keiko Wakabayashi, Akiko Miyabayashi, Naoto Keicho","doi":"10.1165/rcmb.2025-0073LE","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0073LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961017","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":"HDLBP Promotes Glycolysis and CD8⁺ T Cell Exhaustion in Lung Adenocarcinoma by Stabilizing GJB2 RNA.","authors":"Li Xu, Bin Zhou, Kaiqi Jin, Tao Ge, Ming Deng, Hongdou Ding, Xinnan Xu","doi":"10.1165/rcmb.2024-0648OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0648OC","url":null,"abstract":"<p><p>Gap junction protein beta 2 (GJB2) has been associated with glycolysis and immunosuppression in human tumors. This research aims to explore the roles of GJB2 in these aspects in the context of lung adenocarcinoma (LUAD). GJB2 expression in LUAD was analyzed using bioinformatics tools and verified in human LUAD cells. RNA binding proteins (RBPs) that target GJB2 were predicted using bioinformatics and verified using RNA immunoprecipitation assays. Gain- or loss-of-function assays of GJB2 and high-density lipoprotein binding protein (HDLBP) were performed in LUAD cells, investigating their roles in glycolysis. These LUAD cells underwent co-culture with activated CD8⁺ T cells to examine the effect of gene interference on the exhaustion and activity of T cells. A mouse model of allograft tumor was established for <i>in vivo</i> validation. GJB2 exhibited aberrantly heightened expression in LUAD cells. Further overexpression of GJB2 in cancer cells increased glucose uptake, lactate production, and extracellular acidification rate, augmented aggressive phenotype of cancer cells, and increased exhaustion of the co-cultured CD8⁺ T cells. HDLBP, an RBP that binds to GJB2 RNA, was found to be highly expressed in LUAD as well, which enhanced GJB2 expression by stabilizing the GJB2 mRNA. Overexpression of HDLBP similarly rendered glycolysis and T cell inactivity, with these effects negated by GJB2 knockdown. Parallelly, GJB2 silencing in mouse 3LL cells suppressed tumorigenesis, glycolysis, and T cell exhaustion in mice promoted by HDLBP. This research suggests that HDLBP-mediated GJB2 RNA stabilization augments glycolysis and CD8⁺ T cell exhaustion in LUAD progression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956363","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":"Casein Kinase 1 Delta (CK1δ) Is Implicated in TGF-β1 Activation of Human Lung Myofibroblasts.","authors":"Meina Li, Stephanie S Zhang, Trudi Harris, Qianyu Chen, Alastair G Stewart","doi":"10.1165/rcmb.2024-0421LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0421LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952700","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":"Matrix Softness Induces an Afibrogenic Lipofibroblast Phenotype in Fibroblasts from IPF Patients.","authors":"Asres Berhan, Avanka Gunatilaka, Chiaohwei Lee, Stephanie Zhang, Daniel Tan, Trudi Harris, Jade Jaffar, Fernando Jativa, Ingrid Lönnstedt, Monther Alhamdoosh, Milica Ng, Shenna Langenbach, Swati Varshney, Nicholas A Williamson, Peter V S Lee, Nick Wilson, Bryan Gao, Glen Westall, Alastair G Stewart","doi":"10.1165/rcmb.2025-0030OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0030OC","url":null,"abstract":"<p><p>Contractile myofibroblasts immersed in stiffened remodelled extracellular matrix (ECM) characterise fibrotic lesions in idiopathic pulmonary fibrosis (IPF). Lipofibroblasts are lipid-droplet containing interstitial fibroblasts that support functional homeostasis of the developing and adult lung. We show that stiff substrates augment myofibroblast differentiation and ECM production <i>in vitro</i> under basal conditions and following transforming growth factor-β1 (TGF-β1) incubation when cultured on tissue culture plastic, whereas culture in soft microenvironments (as spheroids or on soft collagen-coated substrate) redirects myofibroblast to a lipofibroblast-like phenotype (identified by expression of adipose differentiation-related protein (ADRP) and intracellular lipid droplets), with reduced basal alpha-smooth muscle actin (α-SMA), collagen I, vimentin (VIM) and fibronectin (FN1) expression. The fibrogenic effects of TGF-β1 are prevented in fibroblasts cultured in soft settings. Global proteomics showed similar numbers of TGF-β1-induced differentially expressed proteins in stiff and soft settings (271 and 436, respectively). Of these, only 33 were similarly altered by TGF-β1; 200 were exclusively altered by TGF-β1 in stiff setting; 365 in soft setting, while 38 showed opposite responses. Reductions in YAP/TAZ, beta-catenin and SMAD expression and their limited nuclear levels in soft settings may explain the \"afibrogenic\" characteristic of these lipofibroblasts. Thus, in spheroids of lipofibroblasts TGF-β1 intracellular signalling is redirected and uncoupled from fibrogenesis, including YAP/TAZ, β-catenin and SMAD. Understanding the proximal causal mechano-transduction signalling networks that are differentially active in soft and stiff microenvironments may reveal novel drug targets for fibrosis treatment.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961955","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":"VEGF-D Protects the Lung in Neonatal Hyperoxia-induced Lung Injury.","authors":"Lakshanie C Wickramasinghe, Elan L'Estrange-Stranieri, Bailey Cardwell, Caitlin A O'Brien, Ali Shad, Amy T Hsu, Peter van Wijngaarden, Gary P Anderson, Steven A Stacker, Marc G Achen, Evelyn Tsantikos, Margaret L Hibbs","doi":"10.1165/rcmb.2024-0544OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0544OC","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) is a serious lung disease that affects premature infants born with developmentally immature lungs. Supplemental oxygen, while a lifesaving treatment, provokes inflammation and oxidative stress causing microvasculature injury, pulmonary edema and abnormal lung development. Impaired pulmonary vascular development is implicated in BPD; however, the role of the lymphatics is poorly understood. Studies utilized an established animal model, where mice were exposed on day of birth for 14 days to 75% oxygen to induce hallmark features of BPD including pulmonary edema. Single cell RNA sequencing data was analysed to examine vascular endothelial growth factor-D (VEGF-D) expression in the neonatal lung and to define how fibroblasts and lymphatics were altered in response to hyperoxia. VEGF-D biology was interrogated by utilising mice with a null mutation in <i>Vegfd</i>, and qPCR was used to define mechanisms underlying phenotypes. Hyperoxia elicited expression of VEGF-D, a powerful lymphangiogenic growth factor that is expressed exclusively in lung fibroblasts. In response to hyperoxia, alveolar fibroblasts exhibited significant alterations to their transcriptional profile and changed signaling dynamics within the BPD microenvironment. Probing VEGF-D biology by genetic deletion revealed that VEGF-D deficiency worsened alveolar simplification in response to hyperoxia, exacerbated alveolar fluid accumulation, worsened inflammation, and deranged lymphatic architecture. These data identify an important interplay between alveolar fibroblasts, VEGF-D and lymphatics in regulating functional lymphangiogenesis and lymphatic vessel patterning in BPD that inform therapeutic and regenerative medicine strategies for this incurable disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962658","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":"The Acrolein - Lipopolysaccharide Mouse Model for Frequent Exacerbations in COPD.","authors":"Bernhard Fe Reiter, Natalie Bordag, Diana Schnoegl, Martina Delbeck, Tobias Madl, Hansjörg Habisch, Grazyna Kwapiszewska, Jörg Meding, Leigh M Marsh","doi":"10.1165/rcmb.2024-0507MA","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0507MA","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a severe progressive lung disease, often caused by prolonged exposure to cigarette smoke and environmental factors. Pre-clinical COPD research predominately relies on chronic smoke or elastase animal models, each with their own advantages and limitations, such as limited pathophysiological insights or long treatment times. Here we describe a novel and time efficient mouse model of COPD based on bacterial lipopolysaccharide (LPS) and the reactive aldehyde acrolein (Acro). Mice were treated once per week for four weeks with a combination of both LPS and Acro. Histological, inflammatory, and metabolomic alterations were analysed by histological quantification, multicolour flow cytometry, and nuclear magnetic resonance (NMR). Acro/LPS treatment induced moderate airspace enlargement and bronchial remodelling. These structural changes were associated with a distinct inflammatory profile marked by an increase in macrophages, and T-helper cells, as well as increased cytokines, including CXCL11, IL-17a, and TNF-α. Strong inflammation, consisting of T-helper and B-cells was detected in the perivascular and peribronchial space, and increased macrophages in the alveolar regions. Additionally, intervention with the steroid dexamethasone induced a strong reduction in T-cells and macrophages and partially ameliorated histological alterations. Furthermore, we could detect alterations in the metabolome of serum and tissue, including an increase in COPD associated metabolites like trimethylamine N-oxide, as well as a misbalance in energy related metabolites and several amino acids. In summary, we can describe a practical, representative, and time efficient mouse model of COPD, with the potential to study the immunological and pathophysiological development of the disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955903","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":"Reversing Alcohol-Dependent Effects on HIV Replication: Are There Roles for Pioglitazone and N-Acetylcysteine?","authors":"Anne M Manicone, Jourdan E Brune","doi":"10.1165/rcmb.2025-0236ED","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0236ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957577","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}