American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Circular RNA: an emerging layer of regulation of allergic rhinitis and type I hypersensitivity reactions.","authors":"Yang Jin, David Center","doi":"10.1093/ajrcmb/aanag028","DOIUrl":"10.1093/ajrcmb/aanag028","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"981-983"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832056","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":"Altered cholesterol immunometabolism activates the macrophage NLRP3-inflammasome in lung fibrosis.","authors":"Mariza Vaso, Matija Dukic, Peter Pennitz, Artür Manukyan, Scott Collum, Wanchang Lin, Catherine L Winder, Warwick B Dunn, Jonas C Schupp, Peter Braubach, Malgorzata Wygrecka, Dewei Ren, Erik E Suarez, Howard J Huang, Rahat Hussain, Bela Patel, Harry Karmouty-Quintana, Altuna Akalin, Markus Landthaler, Geraldine Nouailles, Matthias Ochs, Elena Lopez-Rodriguez, Sonia Giambelluca","doi":"10.1093/ajrcmb/aanag029","DOIUrl":"10.1093/ajrcmb/aanag029","url":null,"abstract":"<p><p>Previous research has highlighted dysregulation in lipid metabolism during lung fibrosis. However, the impact of cholesterol immunometabolism during lung fibrosis progression remains unclear but has been related to the NLRP3-inflammasome activation in cardiovascular diseases. The main objective of this work was to investigate the link between altered cholesterol metabolism and NLRP3 inflammasome activation in fibrotic lungs. Different pulmonary fibrosis patient cohorts (from 2 centers and a publicly available dataset) and a murine model of lung fibrosis (aged SP-C-/-) were included. Expression of cholesterol metabolism proteins and cholesterol content were determined in lungs from patients and bronchoalveolar lavage fluid (BALF) cells of aging SP-C-/- mice. Metabolomic and lipidomic analyses were conducted in BALF and BALF cells of SP-C-/- versus wild-type (WT) mice. NLRP3 inflammasome components were assessed by immunoblotting, ELISA, and immunofluorescence. Lung samples from fibrosis patients showed higher cholesterol content, altered cholesterol metabolism, and higher IL-18 levels compared to controls. Moreover, key genes related to inflammasome activation and cholesterol metabolism were differentially expressed in alveolar macrophages from IPF patients with idiopathic pulmonary fibrosis. Accordingly, BALF cells of SP-C-/- mice showed alteration of their cholesterol metabolism and inflammasome activation with age and fibrosis development. Lipidomic analysis pointed at cholesterol esters as potential activating agent. The molecular mechanism linking cholesterol esters to NLRP3 inflammasome and fibrosis markers was confirmed in vitro in a human macrophage model. In conclusion, altered cholesterol esterification activates the NLRP3 inflammasome in alveolar macrophages during pulmonary fibrosis in a murine model and patients with fibrosis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"1114-1124"},"PeriodicalIF":5.4,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13424602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147281769","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":"AP-1 mediated chromatin changes govern alveolar type 2 cell transition in lung injury-repair.","authors":"Anne M Lynch, Tala Noun, Sujuan Yang, Tieling Zhou, Minyue Chen, Scott E Evans, Humam Kadara, Jichao Chen","doi":"10.1093/ajrcmb/aanag157","DOIUrl":"10.1093/ajrcmb/aanag157","url":null,"abstract":"<p><p>Facultative stem cells including lung alveolar type 2 (AT2) cells must toggle between unipotent specialization at baseline and multipotent plasticity during injury-repair. The underlying molecular switches and epigenetic changes remain unclear yet dictate regenerative versus pathological outcomes. Using multiomics and mouse genetics, we show that AP-1 members FOS, FOSB, and JUNB promote an injury-induced transitional AT2 cell state and associated chromatin landscape. Joint transcriptomic-epigenomic profiling and immunostaining distinguish CLDN4+ AT2 cells as a KRT8high subset with open chromatin highly enriched for AP-1 motifs. JUNB and FOSB accumulate in these cells upon viral injury and, along with constitutive FOS, are required for CLDN4 induction, AT2 cell dispersion, senescence signaling, and fibroblast activation, while impacting region-specific alveolar type 1 (AT1) differentiation. AP-1 activation also occurs in mouse AT2 cells expressing oncogenic Kras and transitional cells in human lung tissues with premalignant or adenocarcinoma lesions. Our work refines AT2 transitional states and reveals a gene regulatory logic shared by tissue repair and tumorigenesis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618075","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":"Lost in Translation: tRNAs emerge as active regulators in lung disease.","authors":"Moemen Eltobgy, Michael A Segreto, Rama K Mallampalli, Joseph S Bednash","doi":"10.1093/ajrcmb/aanag151","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag151","url":null,"abstract":"<p><p>The lung is a highly dynamic organ that depends on adaptable protein translation to maintain homeostasis during mechanical, metabolic, and infectious stress. Transcriptomic studies have mapped disease‑associated changes in mRNA expression across diverse lung disorders, but standard RNA‑sequencing approaches largely overlook transfer RNAs (tRNAs), obscuring an important layer of translational control. Recent advances in tRNA‑focused sequencing and functional studies have reframed tRNAs from passive adaptors to active regulators of lung biology. In this mini‑review, we highlight three major regulatory axes of tRNA biology-aminoacyl‑tRNA charging, tRNA methylation, and tRNA‑derived fragments-and their emerging roles in lung injury, infection, and cancer. We discuss how altered tRNA charging in anti-synthetase syndrome and stress response pathways, dysregulated tRNA methylation in lung cancer, and stress‑induced tRNA fragments that signal through pattern‑recognition receptors or Argonaute complexes converge on pathways controlling inflammation, remodeling, and cell survival. Finally, we outline current technical barriers to capturing tRNA species in lung omics and propose opportunities to integrate tRNA biology in future mechanistic and translational research.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148597634","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":"Low-dose ensifentrine exerts anti-inflammatory effects comparable to roflumilast in COPD airways.","authors":"Luigino Calzetta, Tara Rheault, Paola Rogliani","doi":"10.1093/ajrcmb/aanag154","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag154","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590237","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":"Emergence of Disease-relevant Aberrant Epithelial Cell States in Human Alveolar Organoids.","authors":"Holly E David, Abigail J Dietrich, Carla L Calvi, Lorraine B Ware, Jason J Gokey, Jonathan A Kropski, A Scott McCall","doi":"10.1093/ajrcmb/aanag150","DOIUrl":"10.1093/ajrcmb/aanag150","url":null,"abstract":"<p><p>Dysregulated alveolar epithelial repair is a central aspect of Idiopathic Pulmonary Fibrosis but it has proven challenging to reliably model alveolar epithelial cell biology in-vitro. We previously reported persistent activation of Hypoxia-inducible Factor 2 (HIF2) is a hallmark of aberrant epithelial cell phenotypes in IPF. We hypothesized that HIF2 activation primes AECs for aberrant differentiation. In these studies, we investigated how primary human alveolar epithelial organoids respond to a commonly-used commercial alveolar differentiation media intended to facilitate AT2->AT1 differentiation (ADM; which includes human serum and withdrawal of multiple growth factors/inhibitors) in isolation and following biased HIF activation. Alveolar organoids from donor lungs were expanded and transitioned to ADM with pharmacologic modulators to establish HIF-biased signaling. Multimodal analysis integrating scRNA-seq, quantitative label-free proteomics, and Cell Painting revealed that ADM induces expression of several AT1 markers, yet these conditions are insufficient to generate mature AT1-like cells but drives the emergence of KRT17+/KRT5- \"aberrant basaloid\" -like cells which demonstrate high transcriptional similarity to populations in end-stage IPF lungs (p = 3x10-286). HIF2-biased activation significantly exacerbated these aberrant transitions. Gene module co-expression analysis (hdWGCNA) linked ADM to cytoskeletal modulation and HIF2-biased signaling to metabolic shifts and cytoskeletal rearrangement. Proteomics reinforced protein-level induction of aberrant markers (e.g., GDF15) and revealed novel signatures, including increased complement production. Orthogonal transmission electron microscopy confirmed ultrastructural remodeling, including lysosomal inclusions and mitochondrial modulation. Collectively, these data establish that ADM models disease-emergent transitional states rather than homeostatic AT1 differentiation. These data further position HIF2 as a critical potentiator of aberrant alveolar epithelial cell states in PF.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560712","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":"PPARγ as an Integrator of Developmental Lung Reprogramming by Early-Life Per- and Polyfluoroalkyl Substances (PFAS) Exposure.","authors":"Virender K Rehan, Irfan Rahman","doi":"10.1093/ajrcmb/aanag148","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag148","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants increasingly detected in maternal serum, breast milk, drinking water, and indoor environments, raising concern for fetal and early postnatal exposure during critical periods of lung development. Although epidemiologic and experimental studies link early-life PFAS exposure with altered immune function, impaired lung maturation, and later respiratory vulnerability, the molecular pathways underlying these effects remain incompletely defined. In this mini-review, we propose peroxisome proliferator-activated receptor gamma (PPARγ) as a central integrator of developmental lung reprogramming by PFAS. PPARγ regulates key processes required for normal alveolar maturation, including epithelial-mesenchymal interactions, lipofibroblast differentiation, epithelial barrier integrity, macrophage polarization, and inflammatory homeostasis. Recent evidence, including our own, indicates that in the developing lung PFAS exposure is associated with suppression of pulmonary PPARγ expression and signaling while relatively sparing PPARα, and that pharmacologic modulation of PPARγ significantly alters PFAS-induced epithelial inflammatory responses. We discuss how PFAS-mediated disruption of PPARγ signaling, potentially through direct pulmonary effects as well as indirect placental and endocrine mechanisms, may link structural and immune reprogramming by altering lipofibroblast identity, impairing alveolar maturation, altering epithelial permeability, and promoting macrophage programs that amplify later allergic susceptibility. We further highlight developmental timing, exposure mixture, and sex-divergent outcomes as emerging modifiers of this pathway. Defining how PFAS perturbs PPARγ-dependent developmental programs may provide a practical mechanistic framework for understanding environmentally programmed respiratory disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534861","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":"Neonatal hyperoxia promotes macrophage senescence and lung injury via a p38MAPK-dependent secretome.","authors":"Sorel V Y Ouonkap, Bethany McGonnigal, Joselynn Wallace, Olivia Spielman, Ivy Lin, Ella Ma, Fanjie Lin, Xiaoyun Li, Joseph Suh, Alper Uzun, Hongwei Yao, Phyllis A Dennery","doi":"10.1093/ajrcmb/aanag141","DOIUrl":"10.1093/ajrcmb/aanag141","url":null,"abstract":"<p><strong>Rationale: </strong>Bronchopulmonary dysplasia (BPD), a chronic lung disease in premature infants exposed to ventilatory support and hyperoxia, involves alveolar and vascular simplification and is linked to cellular senescence. We previously found senescence predominantly in alveolar macrophages (AMs) after neonatal hyperoxic exposure, but the specific mechanisms driving this and its role in neonatal lung injury remain poorly understood.</p><p><strong>Objectives: </strong>This study investigated the mechanisms driving hyperoxia-induced AM senescence, the effects of senescence/hyperoxia on AM function and how the resulting secretome contributes to lung injury.</p><p><strong>Methods: </strong>scRNA-seq datasets from hyperoxia-exposed neonatal mice were used to score AM senescence and characterize senescent/hyperoxia-induced AM clusters. Hyperoxia-induced metabolic shifts were analyzed alongside AM motility and phagocytosis. Proteomics characterized the senescent AM secretome. Finally, the effects of senescent and hyperoxic secretomes on lung injury were assessed with and without p38MAPK inhibition.</p><p><strong>Results: </strong>scRNA-seq analysis confirmed that hyperoxia significantly increases senescence markers in AMs. This induction occurs via increased glycolysis and leads to reduced AM motility and phagocytosis. Proteomics identified p38MAPK-regulated proteins in the AM secretome including upregulated pro-fibrotic factors and downregulated structural regulators. Intranasal administration of senescent and/or hyperoxia-conditioned media caused alveolar and vascular simplification in neonatal mice, which was attenuated by p38MAPK inhibition.</p><p><strong>Conclusions: </strong>Hyperoxia causes glycolytic reprogramming in AMs, increasing senescence markers and impairing function. This also leads to a secretome that drives lung injury. Inhibiting macrophage glycolysis and p38MAPK pathways represent novel, promising therapeutic approaches to prevent lung injury.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519835","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":"Exploring the Void: Advances in Parenchymal Destruction. Workshop summary of the 2025 Aspen Lung Conference.","authors":"Farrah Kheradmand, Eszter K Vladar, Irina Petrache","doi":"10.1093/ajrcmb/aanag096","DOIUrl":"10.1093/ajrcmb/aanag096","url":null,"abstract":"<p><p>Emphysema, a heterogeneous and destructive disorder of the lung parenchyma driven by genetic and environmental factors, has long been considered irreversible. The 67th Aspen Lung Conference challenged this paradigm, highlighting emerging cellular, molecular, and structural findings that advance our understanding of emphysema pathogenesis and provide new mechanistic insights into alveolar regeneration. Presentations addressed monogenic forms of lung disease, environmental and sex-related modifiers of disease susceptibility, and pathways linking emphysema progression to impaired regenerative capacity, cellular senescence, and immune dysregulation. The meeting addressed four central themes: shared mechanisms in emphysema across chronic obstructive pulmonary disease and rare lung diseases with similar phenotypes; dynamic cellular and extracellular matrix remodeling underlying distal airspace destruction; innovative approaches to early detection, phenotyping, and endotyping emphysema; and emerging molecular and cellular targets for therapeutic intervention. This report synthesizes key concepts from presentations and discussions among experts regarding the critical remaining gaps in developing disease-modifying therapies.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148468451","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":"Innate Immune Cell and Epithelial Subsets Coordinate Airway Responses to Allergen.","authors":"Ryan C Murphy, Cecilia López-Martínez, Tristan Kooistra, Ying Lai, Matthew Liu, Patricia C Dela Cruz, Weston T Powell, Basilin Benson, Melissa Krueger, Jehan Alladina, Josalyn L Cho, Adrian M Piliponsky, Jason S Debley, Roma Sehmi, Gail M Gauvreau, Benjamin D Medoff, Sina A Gharib, Teal S Hallstrand","doi":"10.1093/ajrcmb/aanag149","DOIUrl":"https://doi.org/10.1093/ajrcmb/aanag149","url":null,"abstract":"<p><strong>Rationale: </strong>The mechanisms responsible for promoting allergic asthma remain incompletely understood, particularly the role of the crosstalk between innate immune cells and airway epithelium in coordinating the response to inhaled allergen.</p><p><strong>Objective: </strong>Identify transcriptional responses to allergen exposure in human airway samples and ex vivo airway epithelial cell (AEC) model systems.</p><p><strong>Methods: </strong>RNA-sequencing (RNA-seq) analyses were performed on induced sputum samples from individuals with allergic asthma that underwent inhaled allergen challenge. We integrated these results with a single cell RNA-seq (scRNA-seq) data set of epithelial brushings obtained before and after segmental allergen challenge (SAC). Finally, we performed RNA-seq analyses of primary AECs following house dust mite exposure in the context of priming with IL-13 (simulating a type-2 (T2) environment) or IFN-γ (simulating a type-1 (T1) environment).</p><p><strong>Results: </strong>Distinct kinetic patterns were identified in the diverse inflammatory response to allergen in induced sputum samples, including activation of mast cell (MC) and AEC genes. Using the SAC scRNA-seq data set, we demonstrated that MCs modestly increase in the airways following SAC and are a key source of IL5 and IL18 expression. In contrast, basophils are near absent in the airways at baseline but are present in the airways following allergen challenge and are key sources of IL4 and IL13 expression. RNA-seq analyses of AECs in ex vivo culture demonstrate a core AEC allergen response enriched in genes associated with glycolysis and cadherin binding but is significantly altered in the presence of either IL-13 or IFN-γ exposure. Finally, we integrate these data sets to demonstrate that basophil chemotaxis to the airways in allergic asthma is partly mediated by epithelial-derived CCL26.</p><p><strong>Conclusion: </strong>Allergen challenge promotes diverse pro-inflammatory transcriptional responses in the airways, and MCs, basophils, and AECs play distinct but critical roles in coordinating this response. However, airway responses to allergen may vary considerably based on the baseline airway inflammatory endotype.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.4,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454345","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}