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

{"title":"Fibrotic and Emphysematous Murine Lung Mechanics Under Negative-Pressure Ventilation.","authors":"K A M Quiros, T M Nelson, A Ulu, E C Dominguez, T M Nordgren, M Eskandari","doi":"10.1152/ajplung.00087.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00087.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and the progressive nature heightens the calamity of the disease. Despite countless existing COPD studies, lung mechanics are often reported under positive-pressure ventilation (PPV) and implications and extrapolations made from these studies pose serious restrictions as recent works have divulged disparate elastic and energetic results between PPV and more physiological negative-pressure counterparts (NPV). This non-equivalence of PPV and NPV needs to be investigated under diseased states to augment our understanding of disease mechanics. To assess the comparability of diseased pulmonary mechanics in PPV and NPV, we pose a novel study to parse out the currently entangled contributions of ventilation mode and diseased state by analyzing murine PV curves from elastase-induced emphysema and dust-induced fibrosis models under positive- and negative-pressure and exploring biomarker resolution. We find that, for emphysema, under NPV, volume, compliance (<i>C, C_start, C_def</i>), and hysteresis are increased in diseased states and that under PPV only compliance (<i>C, C_start</i>) is increased. For fibrosis, under NPV, volume, compliance (<i>C, C_inf, C_def,</i> K), and hysteresis are decreased whereas under PPV only volume and static compliance decreased. These significances were observed solely at higher pressures (40 cmH₂O). Our nuanced conclusions indicate the detection capabilities of multiple mechanics-based biomarkers are sensitive to the ventilation mode, where NPV exhibits more altered mechanics metrics in emphysema and fibrosis compared to PPV counterparts, suggesting the resolution of biomarkers when applied under NPV research considerations may offer greater versatility.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982362","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 mysterious case of missing lymphocytes: a cautionary tale of inter-institutional variability in outcomes of lung dissociation protocols.","authors":"Olivia S Harlow, Vijay Raaj Ravi, Fang Ke, Nathan L Sanders, Elise Armstrong, Joseph P Mizgerd, Anukul T Shenoy","doi":"10.1152/ajplung.00323.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00323.2024","url":null,"abstract":"<p><p>Rigor and reproducibility are vital to scientific advancement. It is unclear whether a protocol optimized for tissue dissociation in one institution performs well universally. Here, we share our brand-new lab's experience with inter-institutional variability that led to the discovery that a protocol optimized for murine lung dissociation at Boston University (BU) fails to reproduce similar CD4⁺ T cell, CD8⁺ T cell, and B cell outcomes at the University of Michigan at Ann Arbor (U-M). We report that the type 2 collagenase-based protocol from BU yields reduced numbers of lung lymphocytes at U-M, and this appeared to be a result of harsher collagenase activity despite using identical protocols, reagents, and vendors at both institutions. This variability could not be explained by higher Ca2⁺ levels in Ann Arbor water (which we posited may heighten the collagenase activity) but instead appeared to be due to technical details within the protocol that led to the protocols behaving in an institution-specific manner. Indeed, we find that mere switching between the protocol from BU and a newly optimized protocol at U-M was sufficient to improve (or worsen) lymphocyte yields from murine lungs when synchronously performed at both institutions. Taken together, although the reason(s) for the inter-institutional variability in lymphocyte outcomes remains unknown, this report serves as a cautionary tale against directly adopting lung dissociation protocols across institutions without re-optimization, and calls for careful inspection of cross-institutional reproducibility of previously described protocols.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941552","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":"Vitamin D as an add-on therapy to phosphodiesterase-5 inhibitor in experimental pulmonary arterial hypertension.","authors":"Rui Adão, Bianca Barreira, Elena Paternoster, Daniel Morales-Cano, Miguel A Olivencia, Begoña Quintana-Villamandos, Diego A Rodriguez-Chiaradía, Angel Cogolludo, Francisco Perez-Vizcaino","doi":"10.1152/ajplung.00319.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00319.2024","url":null,"abstract":"<p><p>Severe vitamin D (vitD) deficiency is a very common condition in patients with pulmonary arterial hypertension (PAH) and it is predictor of poor prognosis. There is emerging evidence suggesting a connection between the insufficient response to phosphodiesterase-5 inhibitors (PDE5i) and vitD deficiency in patients with PAH. In the present translational study, vitD deficiency was induced in Wistar rats by exposure to vitD free diet for 5 weeks and followed by Su5416 administration and hypoxia (10%) for 3 weeks, a standard experimental model of PAH. Then rats were randomized to either 1) the PDE5i tadalafil and continuing vitD free diet, or 2) tadalafil plus a single dose of vitD and standard diet for four weeks. VitD supplementation improved exercise capacity and right ventricular function and decreased systolic right ventricular pressure, right atrial hypertrophy, right ventricular hypertrophy, and pulmonary arterial remodeling. VitD improved the ex vivo endothelium-dependent response to acetylcholine, indicating an improvement NO bioavailability, which also resulted in an acute ex vivo response to sildenafil. Thus, the restoration of vitD, by rescuing endothelial function and PDE5i effectiveness, significantly improved the histological, hemodynamic, and functional features of rats with PAH. VitD may be especially beneficial for PDE5i treated PAH patients.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942641","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":"Carotid bodies mediate glial cell activation and neuroinflammation in the NTS following long-term intermittent hypoxia: role in cardiorespiratory dysfunction.","authors":"Katherin Pereyra, Esteban Diaz-Jara, Ignacio Bernal-Santander, Sinay Vicencio, Rodrigo Del Rio, Rodrigo Iturriaga","doi":"10.1152/ajplung.00280.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00280.2024","url":null,"abstract":"<p><p>Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, heightened chemosensory discharges of the carotid body (CB), which contributes to potentiate the ventilatory hypoxic response and elicits hypertension. We aimed to determine: 1) whether the persistence of cardiorespiratory alterations found in long-term CIH depend on the inputs from the CB and, 2) in what extension the activation of glial cells and neuroinflammation in the caudal region of the nucleus of the Solitary Tract (NTS) requires functional CB chemosensory activity. To evaluate these hypotheses, we exposed male mice to CIH for 60 days. At 50 days of CIH, CBs were denervated and animals were kept in CIH for 10 additional days. At the end of the experiments, we measured arterial blood pressure, breathing regularity, and hypoxic ventilatory response (HVR) and assessed astrocyte and microglia cell activation. Compared to Sham, CIH induces hypertension (MABP: 83.47±1.39 vs. 95.00±2.18 mmHg), disordered breathing (IS: 7.77±0.49 vs. 12.56±1.66), increased the HVR (1.69±0.17 vs. 4.31±0.87 ΔV_E/min), and produced an early transient activation of astrocytes followed by a late and persistent activation of microglia in the NTS. In addition, CIH increased IL-1β, IL-6, and TNF-α levels in the NTS. Bilateral CB denervation after 50 days of CIH results in the restoration of normal glial cell activation in the NTS, lower levels of IL-6 and TNF-α, reductions in arterial blood pressure (83.47±1.38 mmHg) and HVR (1.63±0.43 ΔV_E/min). Present results suggest that CB inputs to the NTS during long-term CIH contributes to maintain the cardiorespiratory alterations and the formation of a neuroinflammatory niche at the NTS by modifying glial cell activity.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942647","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":"Caspase Inhibition Restores Collagen I α1 and Fibronectin Release in Cigarette Smoke Extract-Exposed Human Lung Fibroblasts.","authors":"Agnese La Mensa, Marco Buscetta, Roy R Woldhuis, Maura Cimino, Maria Rita Giuffrè, Marta Cristaldi, Paola Dino, Luigi Fiore, Alberto Fucarino, Giovanna Lo Iacono, Alessandro Bertani, Corry-Anke Brandsma, Fabio Bucchieri, Chiara Cipollina","doi":"10.1152/ajplung.00214.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00214.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstructed airflow, airway remodeling, and inflammation, with cigarette smoke (CS) exposure being the main risk factor. While CS extract (CSE) has been shown to activate caspases in various cell types, the role of caspases in human lung fibroblasts (hLFs), in COPD remains poorly understood. Recent studies have linked caspases to extracellular matrix (ECM) remodeling in skin and kidney fibrosis. Caspase activation can be triggered by oxidative stress, with active caspase-3 executing the pore-forming protein gasdermin E (GSDME) in the cleaved N-terminal form GSDME-NT. We investigated whether CSE activates caspases and GSDME in hLFs, and their role in ECM remodeling. MRC-5 lung fibroblasts were treated with CSE with or without the antioxidant N-acetyl cysteine (NAC), and the caspase-8 inhibitor z-IETD-fmk. We measured the effects on caspase-1-8-3/7 activation, GSDME cleavage, ECM remodeling (procollagen Iα1, COLIα1, and fibronectin, FN), and mitochondrial superoxide (mSOX) generation. Key findings were validated in patient-derived hLFs (phLFs). Our results showed that CSE induced caspase-1-8-3/7 activation, mSOX generation, and decreased COLIα1 and FN levels in MRC-5. CSE caused caspase-8-dependent activation of caspase-3, leading to the GSDME cleavage. Treatment with NAC inhibited mSOX and caspase activation. Inhibition of caspase-8 and mSOX restored FN and COLIα1 levels. In phLFs, we confirmed caspase-1 and -8 activation, mSOX increase, COLIα1/FN decrease, and the effects of NAC. Our findings highlight the role of the axis caspase-8-3/7-GSDME and mSOX in regulating ECM protein, suggesting that these pathways may contribute to remodeling in COPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942649","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":"Role of voltage-gated Ca²⁺ channels and Ano1 Ca²⁺-activated Cl^- channels in M2 muscarinic receptor-dependent contractions of murine airway smooth muscle.","authors":"Srijit Ghosh, Tuleen Alkawadri, Lorcan P McGarvey, Mark A Hollywood, Keith D Thornbury, Gerard P Sergeant","doi":"10.1152/ajplung.00188.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00188.2024","url":null,"abstract":"<p><p>Cholinergic tone is elevated in obstructive lung conditions such as COPD and asthma, but the cellular mechanisms underlying cholinergic contractions of airway smooth muscle (ASM) are still unclear. Some studies report an important role for L-type Ca²⁺ channels (LTCC) and Ano1 Ca²⁺-activated Cl™ channels (CACC) in these responses, but others dispute their importance. Cholinergic contractions of ASM involve activation of M3Rs, however stimulation of M2Rs exerts a profound hypersensitisation of these responses. Here we show that M2R-dependent potentiation of cholinergic nerve-evoked contractions of ASM was reversed by the LTCC blocker nifedipine and the Ano1 CACC inhibitors Ani9 and CaCC_inh-A01. Carbachol induced sustained contractions of ASM which were converted into oscillatory contractions when M3Rs were blocked with 4-DAMP. The 4-DAMP resistant contractions were absent in preparations taken from M2R knock out mice. The remaining M2R-dependent responses, observed in wild-type mice, were abolished by nifedipine and Ani9. Inhibition of sarcoplasmic endoplasmic reticulum Ca²⁺ ATPases (SERCA) with thapsigargin increased the amplitude of contractions induced by EFS and these effects were also reversed by nifedipine and Ani9. Thapsigargin also potentiated contractions of ASM induced by the LTCC activator FPL64176. Therefore, contractions of ASM that involved Ca²⁺ influx via LTCC were enhanced by inhibition of SERCA. Immunocytochemistry experiments revealed prominent SERCA staining around the periphery of ASM cells. These data indicate that M2R-dependent contractions of ASM involves Ano1 CACC and LTCC by a mechanism involving inhibition of buffering of Ca²⁺ influx by SERCA.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942589","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":"CFTR as a therapeutic target for severe lung infection.","authors":"Jaime L Hook, Wolfgang M Kuebler","doi":"10.1152/ajplung.00289.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00289.2024","url":null,"abstract":"<p><p>Lung infection is one of the leading causes of morbidity and mortality worldwide. Even with appropriate antibiotic and antiviral treatment, mortality in hospitalized patients often exceeds 10%, highlighting the need for the development of new therapeutic strategies. Of late, cystic fibrosis transmembrane conductance regulator (CFTR) is - in addition to its well-established roles in the lung airway and extrapulmonary organs - increasingly recognized as a key regulator of alveolar homeostasis and defense. In the alveolar epithelium, CFTR mediates alveolar fluid secretion and liquid homeostasis; in the microvascular endothelium, CFTR maintains vascular barrier function. CFTR also contributes to alveolar immunity. Yet, in lung infection, diverse molecular mechanisms reduce CFTR abundance and otherwise impair its function, promoting alveolar inflammation, edema, and cell death. Preservation or restoration of CFTR function by CFTR modulator drugs thus presents a promising avenue to combat lung infection in a pathogen-independent manner.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942652","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":"Lung Endothelial Cell Heterogeneity in Health and Pulmonary Vascular Disease.","authors":"K Mora Massad, Z Dai, I Petrache, C E Ventetuolo, T Lahm","doi":"10.1152/ajplung.00296.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00296.2024","url":null,"abstract":"<p><p>Lung endothelial cells (ECs) are essential for maintaining organ function and homeostasis. Despite sharing some common features with ECs from organ systems, lung ECs exhibit significant heterogeneity in morphology, function, and gene expression. This heterogeneity is increasingly recognized as a key contributor to the development of pulmonary diseases like pulmonary hypertension (PH). In this mini-review, we explore the evolving understanding of lung EC heterogeneity, particularly through the lens of single-cell RNA sequencing (scRNA-seq) technologies. These advances have provided unprecedented insights into the diverse EC subpopulations, their specific roles, and the disturbances in their homeostatic functions that contribute to PH pathogenesis. In particular, these studies identified novel and functionally distinct cell types such as aerocytes and general capillary ECs that are critical for maintaining lung function in health and disease. In addition, multiple novel pathways and mechanisms have been identified that contribute to aberrant pulmonary vascular remodeling in PH. Emerging techniques like single-nucleus RNA sequencing and spatial transcriptomics have further pushed the field forward by discovering novel disease mediators. As research continues to leverage these advanced techniques, the field is poised to uncover novel EC subtypes and disease mechanisms, paving the way for new therapeutic targets in PH and other lung diseases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942655","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":"Mice with lymphatic dysfunction develop pathogenic lung tertiary lymphoid organs that model an autoimmune emphysema phenotype of COPD.","authors":"Barbara Summers, Kihwan Kim, Anjali Trivedi, Tyler M Lu, Sean Houghton, Jade Palmer-Johnson, Joselyn Rojas-Quintero, Juan Cala-Garcia, Tania Pannellini, Francesca Polverino, Raphaël Lis, Hasina Outtz Reed","doi":"10.1152/ajplung.00209.2024","DOIUrl":"10.1152/ajplung.00209.2024","url":null,"abstract":"<p><p>We have previously shown that mice with a loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development of emphysema. TLOs in CLEC2-deficient mice were rich in plasma cells and were a source of a broad array of autoantibodies. Chronic cigarette smoke exposure increased the size and number of lung TLOs in CLEC2-deficient mice and was associated with increased markers of antigen presentation and maturation, leading to increased autoantibody deposition. Using lung tissue from patients with COPD, we found an increase in lymphatic markers in patients with an emphysema phenotype and autoreactive TLOs compared with patients with COPD without emphysema that lack prominent TLOs. Taken together, these results demonstrate that emphysema in mice with lymphatic dysfunction can be partially rescued by blocking TLO formation and that these TLOs are the source of autoantibodies that are exacerbated by cigarette smoke. Our work suggests that lymphatic dysfunction in mice may recapitulate some aspects of an autoimmune emphysema phenotype that is seen in a subset of patients with COPD.<b>NEW & NOTEWORTHY</b> The lymphatic vasculature has been implicated in the pathogenesis of lung disease but remains understudied. Here, the authors use a mouse model to show that lymphatic dysfunction leads to a phenotype of emphysema that is characterized by lung tertiary lymphoid organs that are autoreactive and pathogenic. Analysis of human tissue showed increased lymphatic markers in autoimmune emphysema with prominent TLOs, compared with other COPD phenotypes.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L1-L14"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492938","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":"Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension.","authors":"Rashmi J Rao, Jimin Yang, Siyi Jiang, Wadih El-Khoury, Neha Hafeez, Satoshi Okawa, Yi Yin Tai, Ying Tang, Yassmin Al Aaraj, John C Sembrat, Stephen Y Chan","doi":"10.1152/ajplung.00048.2024","DOIUrl":"10.1152/ajplung.00048.2024","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive disease driven by endothelial cell inflammation and dysfunction, resulting in the pathological remodeling of the pulmonary vasculature. Innate immune activation has been linked to PAH development; however, the regulation, propagation, and reversibility of the induction of inflammation in PAH are poorly understood. Here, we demonstrate the role of interferon-inducible protein 16 (IFI16), an innate immune sensor, as a modulator of endothelial inflammation in pulmonary hypertension, using human pulmonary artery endothelial cells (PAECs). Inflammatory stimulus of PAECs with IL-1β upregulates <i>IFI16</i> expression, inducing proinflammatory cytokine upregulation and cellular apoptosis. <i>IFI16</i> mRNA stability is regulated by post-transcriptional m6A modification, mediated by Wilms' tumor 1-associated protein (WTAP), a structural stabilizer of the methyltransferase complex, via regulation of m6A methylation of <i>IFI16</i>. In addition, m6A levels are increased in the peripheral blood mononuclear cells of patients with PAH compared with control, indicating that quantifying this epigenetic change in patients may hold potential as a biomarker for disease identification. In summary, our study demonstrates that IFI16 mediates inflammatory endothelial pathophenotypes seen in pulmonary arterial hypertension.<b>NEW & NOTEWORTHY</b> Our work establishes a paradigm of the regulatory role of the Wilms' tumor 1-associated protein (WTAP)-interferon inducible protein 16 (IFI16) axis that uses m6A RNA methylation to drive endothelial inflammatory activation in pulmonary hypertension. Consequently, because m6A epigenetic modifications are both reversible and dynamic, this axis is an attractive diagnostic and therapeutic target in pulmonary hypertension and more broadly in endothelial immune activation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L148-L158"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806071","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}