Lung最新文献

{"title":"Serum Soluble Toll-Like Receptor 4 is a Predictive Biomarker for Acute Exacerbation and Prognosis of Idiopathic Pulmonary Fibrosis: A Retrospective Study.","authors":"Erika Kitadai, Kakuhiro Yamaguchi, Hiroshi Iwamoto, Kiyofumi Shimoji, Shinjiro Sakamoto, Yasushi Horimasu, Takeshi Masuda, Taku Nakashima, Shinichiro Ohshimo, Hironobu Hamada, Noboru Hattori","doi":"10.1007/s00408-025-00800-y","DOIUrl":"10.1007/s00408-025-00800-y","url":null,"abstract":"<p><strong>Purpose: </strong>Toll-like receptor 4 (TLR4) is a transmembrane receptor promoting pro-inflammatory signalling, that is associated with the pathogenesis of pulmonary fibrosis. TLR4 is abundantly expressed on monocytes and the acceleration of TLR4 signalling induces the secretion of soluble TLR4 isoforms (sTLR4) in circulation. The aim of study was to evaluate the association of serum levels of sTLR4 with acute exacerbation (AE) and prognosis of patients with idiopathic pulmonary fibrosis (IPF).</p><p><strong>Methods: </strong>This retrospective cohort study included 97 patients with IPF and 76 healthy participants. The association of serum sTLR4 levels with the onset of AE and the prognosis in 97 patients with IPF was analyzed.</p><p><strong>Results: </strong>No significant difference in sTLR4 serum level was observed between the patients with IPF and healthy participants. Kaplan-Meier curves showed that patients with sTLR4 ≥ 2.2 ng/mL had a significantly higher incidence of AE-IPF and a significantly lower 5-year survival rate. Univariate and multivariate Cox hazard analyses demonstrated that sTLR4 ≥ 2.2 ng/mL was significantly associated with higher incidence of AE and poorer survival. In an exploratory analysis, a weak correlation was observed between sTLR4 levels and monocyte counts, and the incidence of AE-IPF was the highest in the patients with sTLR4 ≥ 2.2 ng/mL and monocyte counts ≥ 381/μL.</p><p><strong>Conclusion: </strong>High sTLR4 level is associated with an increased incidence of AE-IPF and poor prognosis in patients with IPF. The combination of sTLR4 level and monocyte count might be used to stratify patients with IPF according to the risk for AE via reflecting monocyte activation.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"43"},"PeriodicalIF":4.6,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143615829","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":"Supratherapeutic Inhaled Corticosteroid Use in Patients Initiating on Biologic Therapies for Severe Asthma: A Nationwide Cohort Study.","authors":"Frederikke Hjortdahl, Marianne Baastrup Soendergaard, Susanne Hansen, Anne-Sofie Bjerrum, Anna von Bülow, Ole Hilberg, Barbara Bonnesen, Claus Rikard Johnsen, Sofie Lock Johansson, Linda Makowska Rasmussen, Johannes Martin Schmid, Charlotte Suppli Ulrik, Anne Byriel Walls, Celeste Porsbjerg, Kjell Erik Julius Håkansson","doi":"10.1007/s00408-025-00796-5","DOIUrl":"10.1007/s00408-025-00796-5","url":null,"abstract":"<p><strong>Background: </strong>In severe asthma, intensive (\"supratherapeutic\") doses of inhaled corticosteroids (ICS) are often used. The prevalence of supratherapeutic ICS use and its impact on corticosteroid-related comorbidities is poorly understood. We aimed to describe the prevalence of supratherapeutic ICS use in severe asthma, its relation to corticosteroid-related comorbidities, and changes in prescribed and redeemed ICS dose after 12 months of biologic therapy.</p><p><strong>Methods: </strong>Patients from the nationwide Danish Severe Asthma Register (DSAR) receiving biologic therapy > 12 months were included. Supratherapeutic doses were defined as > 1600 µg budesonide daily. Baseline characteristics, comorbidity burden, and change in ICS use after 12 months of biologic therapy was stratified according to ICS use at baseline.</p><p><strong>Results: </strong>We included 652 patients in our analyses and 156 (24%) were supratherapeutic ICS users prior to initiation of biologic therapy. Supratherapeutic ICS users had a higher baseline prevalence of cataracts at 14 vs 8.1%; p = 0.025. No differences in other corticosteroid-related comorbidities were observed. No change in prevalence of prescribed supratherapeutic ICS was seen after 12 months of biologic therapy. However, a reduction in ICS adherence among supratherapeutic users was observed with 72% of patients demonstrating > 80% adherence at 12 months, compared to 83% at baseline (p < 0.001).</p><p><strong>Conclusion: </strong>Supratherapeutic doses of ICS were used by almost one-fourth of the patients prior to initiation of biologic therapy and were associated with a higher prevalence of cataracts. Physician-driven ICS reduction was rare, yet supratherapeutic ICS users were found to self-regulate ICS therapy when treated with biologic therapy.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"42"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11897081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605291","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":"SIRT2 Regulates Apoptosis Signaling in Hyperoxic Acute Lung Injury.","authors":"Yu Jin Lee, Mi Na Kim, Eun Gyul Kim, Chang Hyun Park, Joo Yeon Cho, Byung Chan Ko, Min Jung Kim, Yoon Hee Kim, Soon Min Lee, Kyung Won Kim, Tae Won Song, Myung Hyun Sohn","doi":"10.1007/s00408-025-00794-7","DOIUrl":"https://doi.org/10.1007/s00408-025-00794-7","url":null,"abstract":"<p><strong>Purpose: </strong>Oxygen therapy is helpful for patients with breathing difficulties; however, sustained supplementation with high-concentration oxygen can cause hyperoxic acute lung injury. Sirtuin 2 (SIRT2), a nicotinamide adenine dinucleotide (NAD⁺)-dependent deacetylase, has been shown to be involved in pulmonary fibrosis, apoptosis, and inflammation. Here, we elucidated the role of SIRT2 in hyperoxic acute lung injury.</p><p><strong>Methods: </strong>Wild-type (WT) mice and SIRT2-deficient (SIRT2^-/-) mice were exposed to room air or hyperoxia for 72 h. Thereafter, changes in hyperoxia-induced responses were evaluated in WT and SIRT2^-/- mice.</p><p><strong>Results: </strong>SIRT2 expression was elevated in WT mice after hyperoxic exposure. We also observed that the levels of SIRT2 were higher in tracheal aspirates from newborns with bronchopulmonary dysplasia (BPD) than in those without BPD. Hyperoxia-induced inflammation and apoptosis were more considerably attenuated in SIRT2^-/- mice than in WT mice. We also observed an interaction between SIRT2 and forkhead box O3 (FOXO3), and that SIRT2 deficiency was associated with altered acetylation levels of FOXO3 and changes in the expression of its downstream targets. Further investigation of the therapeutic effect of SIRT2 showed that hyperoxic acute lung injury was alleviated when AGK2, a SIRT2 inhibitor, was administered.</p><p><strong>Conclusion: </strong>Taken together, SIRT2 plays a critical role in the pathogenesis of hyperoxic acute lung injury by regulating apoptotic signaling. These findings indicated that SIRT2 is potentially a novel therapeutic strategy for hyperoxic acute lung injury.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"41"},"PeriodicalIF":4.6,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605316","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":"Predictors of Long-Term Survival in Patients with Idiopathic Pulmonary Fibrosis: Data from the IPF-PRO Registry.","authors":"Hyun J Kim, Jeremy M Weber, Megan L Neely, Amy Hajari Case, Aiham H Jbeli, Peide Li, Amy L Olson, Laurie D Snyder","doi":"10.1007/s00408-025-00797-4","DOIUrl":"10.1007/s00408-025-00797-4","url":null,"abstract":"<p><strong>Purpose: </strong>We used data from the IPF-PRO Registry of patients with idiopathic pulmonary fibrosis (IPF) to identify characteristics that predicted survival for a further > 5 years.</p><p><strong>Methods: </strong>Participants had IPF that was diagnosed or confirmed at the enrolling center in the previous 6 months. Patients were followed prospectively. A Classification And Regression Tree (CART) was used to identify predictors of survival > 5 versus ≤ 5 years following enrollment. The following variables, assessed at enrollment, were considered: age; body mass index (BMI); former smoker; current smoker; time from first imaging evidence, symptoms, or diagnosis of IPF to enrollment; forced vital capacity (FVC) % predicted; diffusing capacity of the lungs for carbon monoxide (DLco) % predicted; antifibrotic drug use; supplemental oxygen use; history of cardiac disease; pulmonary hypertension; COPD/emphysema; and rural location.</p><p><strong>Results: </strong>The analysis cohort comprised 819 patients, of whom 278 (33.9%) survived > 5 years. DLco % predicted, supplemental oxygen use and FVC % predicted were the most important variables for predicting survival > 5 versus ≤ 5 years after enrollment. The importance of these variables (scaled such that the most important had an importance of 100%) was 100%, 78.2% and 74.2%, respectively. The optimism-corrected area under the curve (AUC) of the CART was 0.72, with an accuracy of 0.72.</p><p><strong>Conclusion: </strong>Among patients enrolled in the IPF-PRO Registry, a decision tree that included DLco % predicted, oxygen use and FVC % predicted facilitated the prediction of survival > 5 years. Understanding predictors of longer-term survival may facilitate conversations with patients about their prognosis and treatment.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"40"},"PeriodicalIF":4.6,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11891094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586204","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":"FLRT3 Overexpression Attenuates Ischemia-Reperfusion Induced Vascular Hyperpermeability and Lung Injury Through RND3.","authors":"Yongmei Cao, Shiyang Sheng, Yong Zhong, Jiawei Shang, Cui Jin, Qin Tan, Feng Ping, Weifeng Huang, Yongchao Liu, Yingchuan Li","doi":"10.1007/s00408-025-00791-w","DOIUrl":"10.1007/s00408-025-00791-w","url":null,"abstract":"<p><strong>Purpose: </strong>Pulmonary ischemia/reperfusion injury (IRI) causes endothelial barrier dysfunction and increased vascular permeability. Fibronectin leucine-rich transmembrane protein-3 (FLRT3) is known to regulate endothelial cell function, but its role in pulmonary IRI remains unexplored.</p><p><strong>Methods: </strong>We established both a mouse lung I/R model and a hypoxia/reoxygenation (H/R) cell culture model using human pulmonary microvascular endothelial cells (HPMECs). The effects of FLRT3 manipulation were assessed through lentiviral-mediated overexpression and knockdown approaches. Lung injury was evaluated by histological analysis, immunohistochemistry, and lung injury scoring. Endothelial barrier function was assessed using transmission electron microscopy, Evans blue extravasation, and endothelial permeability assays.</p><p><strong>Results: </strong>FLRT3 expression was predominantly localized in pulmonary endothelial cells and was downregulated following I/R injury. Lentiviral vectors overexpressing FLRT3 (LV-FLRT3, 1 × 10⁹ TU/ml) via tail vein injection before I/R surgery. FLRT3 overexpression effectively protected against lung injury by maintaining vascular integrity and reducing edema formation in I/R-challenged mice. In H/R-treated HPMECs, we identified that FLRT3 protein underwent autophagic-lysosomal degradation. Mechanistically, FLRT3 preserved endothelial barrier function through interaction with Rho family GTPase 3 (RND3), which prevented RhoA pathway-mediated cytoskeletal disruption. FLRT3 overexpression in HPMECs promoted cell migration, maintained cytoskeletal structure, and reduced endothelial hyperpermeability under H/R conditions. Importantly, RND3 knockdown in vivo significantly attenuated FLRT3's protective effects against I/R injury, as evidenced by increased lung injury scores, vascular permeability, and RhoA pathway activation.</p><p><strong>Conclusions: </strong>Our findings reveal FLRT3, a critical regulator of endothelial barrier function during IRI through the RND3-RhoA pathway, is a potential therapeutic target for pulmonary IRI.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"39"},"PeriodicalIF":4.6,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11885377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567250","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":"Toll-Like Receptor 4 and 8 are Overexpressed in Lung Biopsies of Human Non-small Cell Lung Carcinoma.","authors":"Silvia Ceccarelli, Viola Pasqua Marzolesi, Jacopo Vannucci, Guido Bellezza, Claudia Floridi, Giuseppe Nocentini, Luigi Cari, Giovanna Traina, Davide Petri, Francesco Puma, Carmela Conte","doi":"10.1007/s00408-025-00793-8","DOIUrl":"10.1007/s00408-025-00793-8","url":null,"abstract":"<p><strong>Purpose: </strong>Lung cancer is the leading cause of cancer death worldwide which includes two main types of carcinoma distinguished in non-small cell lung cancer (NSCLC) involving epithelial cells, and small cell lung cancer (SCLC) affecting neuronal cells and hormone secreting cells. Studies have shown a causal link between inflammation/innate immunity and onset of NSCLC. The present study aimed to evaluate the expression of Toll-like receptors (TLRs) 4 and TLR8 in peripheral blood mononuclear cells (PBMC) and in lung tissues of patients with NSCLC, useful for future prognostic tools for NSCLC.</p><p><strong>Methods: </strong>Patients surgically treated for NSCLC with anatomical resections and patients with benign disease were enrolled. The expression levels of TLR4 and TLR8 were determined by real time PCR and by immunohistochemical analysis in PBMC and in lung tissues, respectively. A preliminary in silico analysis including 1194 arrays from healthy and cancer tissues were extracted by Genevestigator database. The association between TLRs gene expression and survival outcome was also investigated.</p><p><strong>Results: </strong>Bioinformatics analysis revealed that downregulation of TLR4 and TLR8 positively impacts the survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). However, no significant differences in TLR4 and TLR8 gene expression between case and control groups were observed in PBMC. A positive correlation was found in their expression levels. Interestingly, immunohistochemical analysis showed that the levels of TLR4 and TLR8 were higher in the lung tissues of patients with NSCLC than in the control group in terms of staining intensity and positive cells.</p><p><strong>Conclusion: </strong>Albeit the precise role of TLRs is not fully defined, this study identified the potential involvement of TLR4 and TLR8 in the pathogenesis of NSCLC. Our data led us to hypothesize their potential role in overall survival which deserves to be explored further to establish whether TLR4 and TLR8 can represent positive prognostic indicators of disease in NSCLC.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"38"},"PeriodicalIF":4.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11872755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536652","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":"Differences in Blood Eosinophil Level During Stable Disease and During Exacerbation of COPD and Exacerbation Risks.","authors":"Wang Chun Kwok, Terence Chi Chun Tam, Chi Hung Chau, Fai Man Lam, James Chung Man Ho","doi":"10.1007/s00408-025-00792-9","DOIUrl":"10.1007/s00408-025-00792-9","url":null,"abstract":"<p><strong>Background: </strong>Although blood eosinophil count (BEC) has been extensively studied as a biomarker in chronic obstructive pulmonary disease (COPD), there remain challenges and controversy in using a single reading. It has not been determined whether the difference in BEC between baseline and that during an acute exacerbation of COPD (AECOPD) has any role in predicting subsequent AECOPD.</p><p><strong>Methods: </strong>A prospective study was conducted to investigate the possible role of differences in BEC from baseline to that during AECOPD to predict future AECOPD risk. The BEC difference was expressed as absolute eosinophil difference: BEC at index moderate-to-severe exacerbation (E_i) - baseline BEC (E₀).</p><p><strong>Results: </strong>Among 348 Chinese patients with COPD, 158 who experienced an index moderate-to-severe AECOPD were analyzed. Using the cut-off of 105 cells/µL for absolute eosinophil difference as determined by receiver operating characteristic (ROC) analysis, patients with absolute eosinophil difference ≥ 105 cells/µL had a shorter time to subsequent AECOPD with adjusted hazard ratio (aHR) of 1.68 (95% CI = 1.02-2.74; p = 0.040). They also had a higher annual number of subsequent AECOPD (2.49 ± 2.84/year vs 1.58 ± 2.44/year, p = 0.023). Similar findings were shown in the subgroup with stable-state baseline BEC < 300 cells/µL.</p><p><strong>Conclusion: </strong>Greater difference in BEC between baseline and upon moderate-to-severe AECOPD might be associated with shorter time to next AECOPD, as well as more episodes of subsequent AECOPD.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"37"},"PeriodicalIF":4.6,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11868221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523925","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":"Oxidative Stress and Epithelial-Mesenchymal Transition: The Impact of Ubiquitin C-terminal Hydrolase L1 in Cigarette Smoke-Induced COPD.","authors":"Jing Jing Yang, Hong Jun Liu, Yu Xiu Wang, Li Ping Wang, Jian Jun Gu, Jun Yin Gao, Kai Qi Ren, Ling Feng Min","doi":"10.1007/s00408-025-00790-x","DOIUrl":"https://doi.org/10.1007/s00408-025-00790-x","url":null,"abstract":"<p><strong>Purpose: </strong>Cigarette smoke (CS) has been demonstrated to mediate oxidative stress (OS) and epithelial-mesenchymal transition (EMT) in bronchial epithelial cells, thereby contributing to airway remodeling in chronic obstructive pulmonary disease (COPD). Studies have shown upregulation of Ubiquitin C-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, in the airway epithelium of smokers. Many studies indicate that UCHL1's regulation of EMT and OS has a complex role in various cell types, including respiratory epithelium. Thus, we aimed to investigate UCHL1's regulation of EMT, OS, and related mechanisms in cigarette smoke-exposed airway epithelium.</p><p><strong>Methods: </strong>Exposure to cigarette smoke (CS) or cigarette smoke extract (CSE) was employed to establish both animal and cellular models. Protein expression was analyzed using immunohistochemistry, immunofluorescence, and Western blotting. Lentiviral UCHL1 or GPX1-siRNA was used to modulate UCHL1 or GPX1 expression, respectively. Transwell assays were employed to evaluate cell migration and EMT-related alterations. Oxidative stress levels were assessed using specific assay kits.</p><p><strong>Results: </strong>This study validated that exposure to CS induces UCHL1 expression in bronchial epithelial cells both in vitro and in vivo, a phenomenon positively correlated with increased OS and EMT in the airway. Notably, UCHL1 overexpression counteracted CSE's impact on EMT markers, cell migration, and oxidative stress in BEAS-2B cells, while UCHL1 knockdown exacerbated these effects. Furthermore, in BEAS-2B cells treated with CSE, upregulation of UCHL1 was found to enhance the expression of glutathione peroxidase 1 (GPX1), an antioxidant enzyme. The effect of UCHL1 overexpression on EMT-related protein markers and cell migration was reversed upon GPX1 silencing via siRNA.</p><p><strong>Conclusions: </strong>These findings suggest that UCHL1-mediated regulation of GPX1 expression alleviates cigarette smoke-induced EMT-related protein markers change and cell migration in BEAS-2B cell.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"36"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502002","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":"Prevalence and Predictors of Response to Antifibrotics in Long-Term Survivors with Idiopathic Pulmonary Fibrosis.","authors":"Elisabetta Cocconcelli, Nicol Bernardinello, Paolo Cameli, Rosangela Di Liberti, Esam H Alhamad, Dario Gregori, Tommaso Pianigiani, Cristina Dartora, Riccardo Messina, Irene Di Leo, Gioele Castelli, Tiziana La Blasca, Nicola Scichilone, Elena Bargagli, Paolo Spagnolo, Elisabetta Balestro","doi":"10.1007/s00408-025-00789-4","DOIUrl":"https://doi.org/10.1007/s00408-025-00789-4","url":null,"abstract":"<p><strong>Purpose: </strong>The natural history of IPF remains unpredictable despite antifibrotic treatment. In addition, some patients discontinue treatment due to the occurrence of adverse events. To date, no data exist on either the effect of long-term treatment or predictors of treatment response. In the present study, we aim to evaluate the functional trajectory of IPF patients treated with antifibrotics for at least three years and to establish predictors of treatment response.</p><p><strong>Methods: </strong>This multicenter study enrolled long-term survivors IPF patients provided they had stopped treatment for no longer than one month during at least three-year study period. Based on the absolute decline of FVC%predicted (pred.) observed during the 3-year treatment and normalized per year, patients were defined as progressors (≥ 5%) or non-progressors (< 5%).</p><p><strong>Results: </strong>We identify 172 IPF patients who completed three years of antifibrotic treatment with no interruption. The 27% of these IPF patients progressed despite complete adherence to treatment. Progressors were more likely to be non-smokers compared to non-progressors, with higher occurrence of diarrhea and with a more preserved lung function at diagnosis. FVC %pred. and liters at diagnosis, a greater FVC decline in the 1-st year of follow up, being non-smokers, and complaining of diarrhea over treatment are independent predictors of progression.</p><p><strong>Conclusion: </strong>Almost one third of IPF patients adherent to three years of antifibrotics experience progression. A functional decline at first year of treatment despite preserved lung function at diagnosis, non-smoking status, and occurrence of diarrhea over treatment are independent predictors of disease progression.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"35"},"PeriodicalIF":4.6,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492181","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":"Inhibition of Mettl3 by STM2457 and Loss of Macrophage Mettl3 Alleviate Pulmonary Hypertension and Right Heart Remodeling.","authors":"Chunfeng He, Yingqun Ji, Yan Zhang, Jinbo Ou, Di Wu, Huan Qin, Jing Hua, Qiang Li, Hao Zheng","doi":"10.1007/s00408-025-00788-5","DOIUrl":"https://doi.org/10.1007/s00408-025-00788-5","url":null,"abstract":"<p><strong>Background: </strong>m6A RNA methylation is a critical epigenetic modification involved in the pathogenesis of pulmonary arterial hypertension (PAH). While macrophage-mediated inflammation plays a central role in PAH, the specific contributions of m6A regulators within macrophages are not yet fully understood. This study explores the role of METTL3 in macrophages, with particular emphasis on its contribution to the progression of PAH.</p><p><strong>Methods: </strong>SU5416/Hypoxia (SuHx) PAH mouse models were treated daily with STM2457, a selective METTL3 antagonist, or vehicle for 10 days. Additionally, SuHx PAH was induced in Mettl3flox/floxlyz2cre + and Mettl3flox/flox mice using genetic approaches. Pulmonary acceleration time to pulmonary ejection time (PAAT/PAET) and right ventricular free wall (RVFWD) were measured by ultrasound. Hemodynamic parameters, including right ventricular systolic pressure (RVSP), were assessed. Pulmonary vascular and right heart remodeling were evaluated using HE staining, while vascular and right heart fibrosis were assessed by Masson's trichrome staining. The expression of fibrosis-associated genes was quantified by qPCR. Macrophage activation in tissues was determined via CD86 and CD206 immunofluorescence staining, and the expression of inflammatory cytokines and fibrosis-associated genes was quantified by qPCR.</p><p><strong>Results: </strong>METTL3 expression was significantly upregulated in the lungs and macrophages of PAH models. Treatment with STM2457 reversed the progression of SuHx PAH, as evidenced by a reduction in RVSP, attenuation of pulmonary vascular and right heart remodeling, and decreased fibrosis in both the heart and lungs. Furthermore, the expression of fibrosis-associated genes in the right heart, including Col1a1, Col1a3, and α-SMA, was downregulated following STM2457 treatment and METTL3 depletion in macrophages. Both STM2457 treatment and METTL3 depletion resulted in a significant reduction in the number of CD86⁺ and CD206⁺ macrophages, accompanied by a suppression of pro-inflammatory cytokines such as IL-1β and iNOS, alongside an upregulation of anti-inflammatory cytokines, including IL-10 and Arg1.</p><p><strong>Conclusion: </strong>STM2457 treatment and METTL3 depletion in macrophages effectively reversed SuHx PAH by modulating macrophage inflammatory responses and alleviating pulmonary vascular and right heart remodeling, as well as fibrosis. These findings underscore the role of METTL3 in PAH pathogenesis by regulating macrophage function and inflammation.</p>","PeriodicalId":18163,"journal":{"name":"Lung","volume":"203 1","pages":"34"},"PeriodicalIF":4.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449147","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}