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

{"title":"Global knockout of melanoma differentiation-associated protein 5 protects mice from chronic hypoxia/SU5416-induced pulmonary hypertension.","authors":"Dania Abu-Saleh, Ganesh R Koshre, Bryce Piper, Cankun Wang, Cameron Peirce, Benjamin S Johnson, Daniela Farkas, Richard S Nho, Jeffrey C Horowitz, Qin Ma, Rama K Mallampalli, Elena A Goncharova, Laszlo Farkas","doi":"10.1152/ajplung.00299.2025","DOIUrl":"10.1152/ajplung.00299.2025","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a severe disease affecting the pulmonary arteries, causing increased blood pressure due to narrowing of the pulmonary artery lumen. Aberrant proliferation of endothelial cells (ECs) and smooth muscle cells (SMCs), along with a dysregulation of the immune response, contributes to arterial remodeling. We hypothesized that the cytosolic RNA receptor melanoma differentiation-associated protein 5 (MDA5) contributes to PAH by dysregulating pulmonary vascular cell function and immune cell response. In lung tissue from control patients and patients with PAH, MDA5 immunoreactivity was widely distributed throughout the pulmonary artery wall. After exposing whole body <i>MDA5</i>^-/- mice to the chronic hypoxia/SU5416 (Hx/Su) protocol, we detected reduced right ventricular systolic pressure and pulmonary artery media wall thickness compared with wild-type mice. Proinflammatory mediators, interferon-regulated genes, and perivascular accumulation of CD11b⁺ myeloid cells were decreased in the lung tissue of Hx/Su-exposed <i>MDA5</i>^-/- mice. In cultured human pulmonary artery ECs, MDA5 gene silencing disrupted DNA synthesis and angiogenic network formation. Bulk RNA sequencing analysis revealed the differential expression of 2,533 genes, affecting gene ontologies such as immune response, cell cycle, and cholesterol metabolism. Analysis of a publicly available single-cell RNA-sequence dataset indicates increased expression of MDA5 in monocytes/macrophages in pulmonary arteries from patients with PAH, which is associated with an interferon gene signature. Knockdown of MDA5 in macrophage-like cells reduced the type I interferon gene signature. Our data suggest a protective effect of whole body MDA5 knockout in mice, which may be due to reduced immune dysregulation.<b>NEW & NOTEWORTHY</b> This study identifies the role of melanoma differentiation-associated protein 5 (MDA5) in the development of pulmonary hypertension and pulmonary artery muscularization. The results indicate that MDA5 is important for pulmonary artery mural cell function, and that MDA5 knockout reduces immune dysregulation by decreasing a type I interferon gene signature in immune cells, particularly monocytes and macrophages.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L713-L723"},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13218392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The importance of sex as a biological variable in pulmonary vascular research.","authors":"Mikala C Mueller, Sue Gu, Krithika Lingappan, R Blair Dodson, Chelsea M Magin","doi":"10.1152/ajplung.00036.2026","DOIUrl":"10.1152/ajplung.00036.2026","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L708-L712"},"PeriodicalIF":3.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809634","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":"Engineering function in lung biology: integrating imaging, regenerative constructs, and functional biodesign.","authors":"René A Girard, Jamie Tran, Yuqing Cai, Mary C Farach-Carson, Hadi T Nia, Allison M Greaney, Laura E Niklason, Hurley Killian, Elvin Blanco, Sinem Koc-Günel, Harry Karmouty-Quintana","doi":"10.1152/ajplung.00066.2026","DOIUrl":"10.1152/ajplung.00066.2026","url":null,"abstract":"<p><p>The lung is a uniquely demanding target for regeneration because its function depends on the coordinated integration of cellular diversity, three-dimensional architecture, cyclic mechanical forces, vascular perfusion, immune surveillance, and extracellular matrix remodeling. Although single-cell and spatial profiling, lineage tracing, and induced pluripotent stem cell (iPSC)-derived models have transformed our understanding of lung cell states and developmental potential, these descriptive approaches have also highlighted a central bottleneck: the field still lacks broadly adopted platforms to test whether engineered tissues and regenerative interventions restore \"function\" under physiological load. In this review, we focus on emerging technologies that enable functional biodesign in the lung biology by coupling engineered constructs to measurement systems that approximate native mechanics, flow, and immune dynamics. We highlight lung-scale experimental systems including engineered whole lung scaffolds, and we examine dynamic imaging platforms, exemplified by crystal ribcage approaches, that allow us to quantify alveolar mechanics, capillary perfusion, immune-cell behavior, and matrix remodeling in real time. We then discuss regenerative constructs as design problems defined by region-specific constraints and disease-associated transitional states, and we survey cell-based, molecular, and subcellular interventions that shift repair strategies from replacement toward targeted functional augmentation. Finally, we draw lessons from medical device translation, durability, infection resistance, and mechanical integrity, as nonnegotiable benchmarks for regenerative success. Together, these platforms establish an evidence framework, in which lung regeneration is evaluated by physiological performance rather than inferred from molecular or structural endpoints, accelerating progress from descriptive biology to reproducible, clinically actionable repair.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L653-L660"},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13198914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759937","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":"Intravascular hemolysis aggravates ventilator-induced lung injury in mice.","authors":"Maximilian Buttenberg, Victoria Bünger, Mahdi Taher, Nadja Höfer, Helen Rinderknecht, Borna Relja, Robert Klopfleisch, Roland C E Francis, Wolfgang M Kuebler, Jan A Graw","doi":"10.1152/ajplung.00355.2025","DOIUrl":"10.1152/ajplung.00355.2025","url":null,"abstract":"<p><p>Mechanical ventilation (MV), a common life-saving intervention in critical care medicine, can itself cause pulmonary damage. Intravascular hemolysis is common in sepsis and acute respiratory distress syndrome (ARDS). Although inflammation, infection, or atelectasis can enhance ventilator-induced lung injury (VILI), data are scarce on the interaction between hemolysis and VILI. Therefore, mice were ventilated with either lung-protective MV (LPV) or injurious MV (HPV), and selected mice received an intravascular infusion of hemolyzed murine red blood cells containing cell-free hemoglobin (CFH). Lung edema quantified by wet-to-dry weight ratio did not differ between mice receiving LPV or LPV + CFH but was significantly higher in mice receiving HPV + CFH compared with HPV alone. Pulmonary expression of proinflammatory cytokines such as interleukin-6 (IL-6) and tumor-necrosis factor alpha (TNF-α) did not differ between mice with LPV + CFH or LPV but increased significantly in mice receiving HPV. Norepinephrine (NE), used to simulate CFH-associated hypertension but not CFH itself, further increased IL-6 gene expression and concentration in bronchoalveolar lavage fluid in mice with HPV. However, mice with HPV + CFH showed significantly impaired lung mechanics compared with mice with HPV or HPV + NE. Analyzing 437 critically ill patients with severe ARDS and therapy with venovenous extracorporeal membrane oxygenation (ECMO) confirmed that increased plasma concentrations of CFH were associated with a reduced pulmonary compliance. The findings suggest that mice subjected to HPV + CFH show increased impairment of lung mechanics that is associated with lung edema but cannot be fully explained by the proinflammatory and proedematous effects of CFH-induced hypertension. Associated with reduced pulmonary compliance also in humans, increased CFH plasma concentrations might be a future therapeutical target.<b>NEW & NOTEWORTHY</b> Mechanical ventilation is frequently used in critically ill patients and can itself cause pulmonary damage. Furthermore, hemolysis is common in sepsis and ARDS. Mice receiving mechanical ventilation and an infusion of cell-free hemoglobin (CFH) demonstrated increased impairment of lung mechanics associated with lung edema not fully explainable by the proinflammatory and proedematous effects of CFH. Furthermore, increased plasma concentrations of CFH correlated with reduced pulmonary compliance in patients with severe ARDS and therapy with ECMO.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L696-L707"},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809677","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":"Beyond the epithelium: multicellular niches in lung regeneration and disease.","authors":"Sinem Koc-Gunel, Amy L Ryan, Robert E Hynds, Jaymin J Kathiriya","doi":"10.1152/ajplung.00419.2025","DOIUrl":"10.1152/ajplung.00419.2025","url":null,"abstract":"<p><p>Pulmonary homeostasis and regeneration require coordination between epithelial cells, immune populations, vascular networks, extracellular matrix, and stromal cells. This mini review examines recent advances in lung niche biology that were a focus of the 2025 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference. Here, we emphasize the impact of nonepithelial compartments essential for tissue function and repair. Reflecting the conference's emphasis on comprehensive niche biology, we highlight how nonepithelial compartments, including stromal, vascular, and immune cells, serve as essential regulators of tissue function and repair, a perspective that unified many of the presentations and discussions. In diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease, disruption of these niche interactions, rather than isolated cellular defects, drives regenerative failure. Spatial transcriptomic approaches reveal how pathological cell states colocalize within aberrant microniches. These insights suggest that effective therapeutics must target entire multicellular ecosystems, with advanced organoid platforms offering promising tools for developing niche-modulating interventions.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L770-L779"},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147759921","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":"Correction for Wang et al., volume 301, 2011, p. L197-L206.","authors":"","doi":"10.1152/ajplung.00048.2011_COR","DOIUrl":"https://doi.org/10.1152/ajplung.00048.2011_COR","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"330 6","pages":"L767-L769"},"PeriodicalIF":3.5,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175107","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":"Biological sex influences immune response to influenza infection in juvenile outbred mice.","authors":"Ramakrishna Suresh, Brydie R Huckestein, Michelle L Manni, Danielle Antos, Jason E Shoemaker, John F Alcorn","doi":"10.1152/ajplung.00309.2025","DOIUrl":"10.1152/ajplung.00309.2025","url":null,"abstract":"<p><p>Children are highly susceptible to influenza virus infection and lung inflammation. The majority of studies of influenza pneumonia in mice are in adult, inbred, same-sex mice with limited variation in disease outcomes, unlike what is observed in children. In this study, juvenile outbred mice were challenged with influenza A/California/07/2009 H1N1 virus to examine the temporal effect of infection on lung inflammation in genetically dissimilar male and female mice. In this model, influenza infection induced variable disease severity characterized by viral load, airspace leak and inflammation, and lung function. This response was not only clustered by sex at 3 and 4 days postinfection but also was associated with disease severity by <i>day 8</i>. Influenza virus infection induced altered production of cytokines and chemokines by sex and timing. Males displayed an early cytokine and chemokine response driven by severity, whereas females showed a late response only in severe mice. This was independent of viral RNA load. Flow cytometry was then conducted to analyze lymphocytes. In male mice, neutrophil recruitment was elevated by disease severity. In contrast, female mice showed increased T cell numbers late in infection regardless of severity. Finally, unsupervised clustering of mice by immune parameters at <i>day 8</i> showed similarity by sex and severity, with more variability in male mice. These data demonstrate that the immune response to influenza virus infection is impacted by sex and disease severity in pediatric equivalent outbred mice. This complexity of immune activation is important to consider when evaluating drivers of disease pathogenesis or planning therapeutic interventions targeting immune mediators.<b>NEW & NOTEWORTHY</b> This study defines the temporal immune response to influenza A virus infection in the juvenile lung. Lung inflammation differs by biological sex and disease severity in juveniles, which is reflected in cytokine and chemokine mediators and innate and adaptive immune cells recruited to the tissue. These data inform future generations of computational models of severe disease drivers and impact the potential use of immunomodulatory therapy in children with influenza A pneumonia.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L724-L736"},"PeriodicalIF":3.8,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13664156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832312","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":"Publisher's note.","authors":"","doi":"10.1152/ajplung.00121.2026_NOT","DOIUrl":"https://doi.org/10.1152/ajplung.00121.2026_NOT","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"330 5","pages":"L624"},"PeriodicalIF":3.5,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832260","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":"Standardized pipeline for establishing, expanding, and differentiating airway and alveolar organoids from human BAL fluid.","authors":"Taryn B Gellner, Belinda Chen, Shreyas R Raini, Mackenzie S Jackson, Amy K Kraak, Sophie C Petta, Margherita Paschini, Lynn M Schnapp, Carla F Kim, Monica Yun Liu","doi":"10.1152/ajplung.00356.2025","DOIUrl":"10.1152/ajplung.00356.2025","url":null,"abstract":"<p><p>Lung organoids are versatile experimental models, but their broader use in studying human disease is limited by the scarcity of starting material and the complexity of current methods. To align organoid technology with common clinical practice, we developed airway and alveolar organoids using cells obtained from patients' bronchoalveolar lavage (BAL) fluid. Building on existing techniques, we showed that BAL is a reliable, accessible source of primary human epithelial cells, yielding airway and alveolar organoids within 10 days. Organoids can then be expanded over many passages for downstream analysis. Our streamlined methods do not require cell sorting or other complex procedures; all cells are derived from a single patient, and media are based on serum-free, chemically defined formulations. Here, we present detailed protocols for organoid establishment, standardized passaging and phenotyping, and differentiation of both airway and alveolar models. We provide a time course of BAL-derived airway organoid differentiation at the air-liquid interface, and we demonstrate proof of principle for the differentiation of BAL-derived alveolar organoids in three-dimensional culture. These methods can be readily adapted to generate and characterize organoids from lung tissue, tracheobronchial specimens, or other primary cells from humans or mice, expanding the potential to use lung organoids for disease modeling.<b>NEW & NOTEWORTHY</b> We provide streamlined protocols to generate both airway and alveolar epithelial organoids from a single, clinical BAL specimen. From standardized specimen collection to organoid plating to passaging and differentiation, we show that rare, primary epithelial cells in BAL can give rise to all the major airway and alveolar cell types. Our serum-free, feeder-free, and sorting-free methods offer a simplified starting point for using patient-derived organoids to model lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L576-L592"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147571895","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":"Fibroblast cross talk promotes mucin synthesis by COPD-derived airway epithelial cells.","authors":"Hataitip Tasena, Brady Rae, Maarten van den Berge, Alen Faiz, Marjan Reinders-Luinge, Machteld N Hylkema, Wim Timens, Corry-Anke Brandsma, Irene H Heijink","doi":"10.1152/ajplung.00315.2025","DOIUrl":"10.1152/ajplung.00315.2025","url":null,"abstract":"<p><p>Chronic mucus hypersecretion (CMH) is a common feature of chronic obstructive pulmonary disease (COPD). One of the major factors contributing to CMH is excessive mucin release by the airway epithelium. We hypothesized that fibroblasts support mucociliary differentiation and promote epithelial mucin release. Primary bronchial epithelial cells (PBECs) from COPD patients with CMH were cultured at air-liquid interface with and without primary airway fibroblasts (PAFs). mRNA expression of mucociliary markers and proinflammatory cytokines was assessed by qPCR. MUC5AC and MUC5B release in apical wash, and proinflammatory IL-6, CXCL8, and CCL20 release in basolateral supernatant were measured by ELISA. Immunohistochemical staining was performed on paraffin-embedded transwell inserts using alcian blue and acetylated α-tubulin. To assess the involvement of the proinflammatory mediator IL-6, cocultures of Calu-3 epithelial cells and PAFs were treated with a neutralizing antibody against IL-6. Upon coculture with PAFs, PBECs expressed more <i>MUC5B</i> mRNA and secreted higher levels of MUC5AC and MUC5B protein. These effects were accompanied by more pronounced mucous cell differentiation. PAFs expressed higher IL-6 mRNA and secreted more IL-6 upon coculture with airway epithelial cells (AECs), whereas IL-6 neutralization attenuated the increase in <i>MUC5B</i> expression by Calu-3 epithelial cells upon coculture with PAFs. This study demonstrates that fibroblasts support mucous cell differentiation and epithelial mucin release in vitro, and that IL-6 signaling contributes to this fibroblast-driven <i>MUC5B</i> expression. These findings support the notion that stromal-epithelium cross talk within the local niche may contribute to CMH in COPD.<b>NEW & NOTEWORTHY</b> Communication with airway fibroblasts promotes mucus production by COPD-derived airway epithelial cells. This mechanism, partly mediated by fibroblast-derived proinflammatory IL-6, may contribute to chronic mucus hypersecretion in COPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L615-L623"},"PeriodicalIF":3.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147643593","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}