Respiratory Research最新文献

{"title":"Mechanical stress facilitates calcium influx and growth of alveolar epithelial cells via activation of the BDKRB1/Ca²⁺/CaMKII/MEK1/ERK axis.","authors":"Ying Zhang, Qing-Dong Zhang, Quan Li, Zhi-Yue Shi, Cheng Pan, Rong-Shuang Yan, De-Rui Fei, Shi-Xin Xu, Yang Luo","doi":"10.1186/s12931-025-03240-7","DOIUrl":"https://doi.org/10.1186/s12931-025-03240-7","url":null,"abstract":"<p><strong>Background: </strong>Mechanical stress and calcium metabolism are associated with lung development and various pulmonary diseases. Our previous research demonstrated that BDKRB1/Ca²⁺ signal transduction may be involved in lung dysplasia resulting from scoliosis and thoracic insufficiency. Therefore, the present study aims to investigate the effects of mechanical stress on the growth and calcium influx in alveolar epithelial cells, as well as the role of BDKRB1/Ca²⁺ signaling in these processes.</p><p><strong>Methods: </strong>Flow cytometry, CCK-8, and EDU staining assay were employed to assess the cycle, calcium influx, activity, and proliferation in RLE-6TN cells subjected to mechanical stresses of varying amplitudes (5%, 10% and 15%). RT-qPCR and western blotting assay were performed to evaluate the effects of mechanical stress on BDKRB1/Ca²⁺/CaMKII/MEK1/ERK signaling in RLE-6TN cells.</p><p><strong>Results: </strong>Mechanical stress at 10% amplitudes effectively enhanced the viability, EDU positive ratio, S-phase percentage, and Ca²⁺ concentration of RLE-6TN cells, while reducing the G1-phase percentage. Conversely, 15% mechanical stress exerted an inhibitory effect on RLE-6TN cell proliferation. Additionally, 10% mechanical stress significantly upregulated the expression of BDKRB1, CaMKIIα/δ, p-MEK1 and p-ERK1/2 in RLE-6TN cells. Notably, BDKRB1 knockdown attenuated the 10% mechanical stress-induced increase in both growth and calcium influx in RLE-6TN cells. Moreover, BDKRB1 knockdown blocked the activation of the Ca²⁺/CaMKII/MEK1/ERK pathway induced by 10% mechanical stress.</p><p><strong>Conclusion: </strong>Appropriate levels of mechanical stress contribute to the growth and calcium influx of alveolar epithelial cells by modulating BDKRB1/Ca²⁺/CaMKII/MEK1/ERK signaling.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"168"},"PeriodicalIF":5.8,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12038983/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053154","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":"More accessible functional lung imaging: non-contrast CT-ventilation demonstrates strong association and agreement with PET-ventilation.","authors":"Hilary L Byrne, Nina Eikelis, Jonathan Dusting, Andreas Fouras, Paul J Keall, Piraveen Pirakalathanan","doi":"10.1186/s12931-025-03245-2","DOIUrl":"https://doi.org/10.1186/s12931-025-03245-2","url":null,"abstract":"<p><strong>Background: </strong>Computed Tomography (CT) ventilation imaging (CTVI) is an emerging ventilation imaging technique. CTVI implementations have been widely validated against alternative ventilation imaging techniques but have been limited to clinical research only. The first CTVI commercial product, CT LVAS (4DMedical, Melbourne, Australia), was recently released enabling its use in clinical practice. This study quantitatively compares ventilation images from CT LVAS and previously validated research CTVI algorithms to Galligas PET ventilation.</p><p><strong>Methods: </strong>16 patients with Galligas PET and paired inhale/exhale breath-hold CT images were taken from a publicly available dataset on The Cancer Imaging Archive. Ventilation images were produced using CT LVAS and two previously published algorithms: (1) utilising the Hounsfield Unit difference (CTVI_HU); and (2) utilising the Jacobian determinant (CTVI_Jac). CTVI images were compared to the reference standard Galligas PET using Bland-Altman analysis of lobar ventilation, voxel-wise Spearman correlation, and Dice similarity coefficient (DSC) of regions of interest representing the top 85% and 15% of ventilation function.</p><p><strong>Results: </strong>Bland-Altman analysis showed overall bias of < 0.01% for all CTVI methods (95% confidence interval: ±7.4% for CT LVAS, ± 9.1% for CTVI_HU, ± 7.9% for CTVI_Jac). The mean Spearman correlation between CTVI and Galligas PET was 0.61 ± 0.14 (p < 0.01) for CT LVAS, 0.68 ± 0.10 (p < 0.01) for CTVI_HU, and 0.57 ± 0.15 (p < 0.01) for CTVI_Jac. The mean DSC for the top 85% was 0.91 ± 0.03 for CT LVAS, 0.92 ± 0.02 for CTVI_HU, and 0.91 ± 0.03 for CTVI_Jac, with the DSC for CTVI_HU significantly higher than the other two CTVI methods. The DSC for the top 15% was 0.47 ± 0.17 for CT LVAS, 0.53 ± 0.16 for CTVI_HU, and 0.47 ± 0.18 for CTVI_Jac.</p><p><strong>Conclusions: </strong>In a comparison to Galligas PET ventilation imaging, CT LVAS performs similarly to previous CTVI methods. Bland-Altman analysis for quantification of lobar ventilation demonstrates negligible bias. Mean voxel-wise Spearman correlations are moderate to good. DSC of functionally thresholded lung regions are similar for all CTVI methods. These results warrant further investigation of CT LVAS as a readily available ventilation imaging tool in disease characterisation, lung health assessment, and surgical and targeted treatment planning.</p><p><strong>Trial registration: </strong>Australian New Zealand Clinical Trials Registry (ANZCTR) registration number ACTRN12612000775819, registered on 23/07/2012.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"163"},"PeriodicalIF":5.8,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12034206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993163","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":"Medical thoracoscopy combined with argon plasma coagulation as an alternative treatment for intractable pneumothorax: a retrospective study.","authors":"Rui Xu, Kaige Wang, Jingyu Shi, Panwen Tian, Dan Liu","doi":"10.1186/s12931-025-03255-0","DOIUrl":"https://doi.org/10.1186/s12931-025-03255-0","url":null,"abstract":"<p><strong>Background: </strong>A significant proportion of patients with pneumothorax who do not tolerate surgery develop intractable pneumothorax after prolonged failure of conservative treatment. This significantly lengthens the duration of hospitalization and patients' quality of life. As the application of medical thoracoscopy (MT) in the management of pleural diseases is explored, MT combined with argon plasma coagulation (APC) may be an alternative option for the treatment of intractable pneumothorax.</p><p><strong>Methods: </strong>A retrospective analysis was conducted on thirteen patients with intractable pneumothorax whose duration of the air leak exceeded seven days and subsequently treated with MT combined with APC at West China Hospital of Sichuan University. Under MT, we first dissected the pleural adhesions with an electrocautery knife, probed for the rupture located in the pulmonary bullae or pleural and cauterised it with APC. Subsequently, all pulmonary bullae were cauterised and human fibrin sealant was sprayed locally on the cauterised surface. Preoperative, intraoperative, and more than one year of postoperative follow-up information was collected from these patients. We divided the patients into two groups with and without detected ruptures treated under MT to compare the overall efficacy and safety of this treatment.</p><p><strong>Results: </strong>All patients had pulmonary comorbidities and the median duration of the current pneumothorax episode before MT treatment was 30 days. Nine patients had a history of recurrent pneumothorax episodes, two of whom had been treated with video-assisted thoracoscopic surgery (VATS). Regarding efficacy, the overall median time of time to air leak cessation was 2.5 days, with 2 days in the group with detected ruptures treated and 5 days in the group without detected ruptures treated, and the overall median time of time to chest tube removal was 6 days, with 4 days in the group with detected ruptures treated and 7 days in the group without detected ruptures treated. Regarding safety, only 2 patients experienced postoperative adverse events of fever and chest pain.</p><p><strong>Conclusions: </strong>For intractable pneumothorax patients with pleural adhesions that may limit lung re-expansion, who are not candidates for surgery, MT combined with APC can be an alternative treatment option.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"162"},"PeriodicalIF":5.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032783/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144023942","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":"High-flow nasal oxygen vs. conventional oxygen therapy in patients with COVID-19 related acute hypoxemic respiratory failure and a do not intubate order: a multicentre cohort study.","authors":"Daphne J T Sjauw, Lisa M Hessels, Marieke L Duiverman, Judith Elshof, Matthijs L Janssen, Yasemin Türk, Leo Heunks, Sara J Baart, Evert-Jan Wils","doi":"10.1186/s12931-025-03231-8","DOIUrl":"https://doi.org/10.1186/s12931-025-03231-8","url":null,"abstract":"<p><strong>Background: </strong>High-flow nasal oxygen (HFNO) is frequently used to treat patients with acute hypoxemic respiratory failure (AHRF) due to viral pneumonia, including COVID-19. However, its clinical effect compared to conventional oxygen therapy (COT) remains largely unexplored in patients with a do not intubate (DNI) order. We aimed to assess whether HFNO compared to COT is associated with improved clinical outcomes in hospitalized patients with AHRF due to COVID-19 and a DNI order.</p><p><strong>Methods: </strong>This analysis included patients with a DNI order and SARS-CoV-2 infection, selected from three observational studies, who were treated with COT only or HFNO. The primary endpoint was in-hospital mortality, the secondary endpoint was hospital length of stay (LOS). The effect of HFNO vs. COT was assessed using multivariable regression, accounting for pre-selected confounders.</p><p><strong>Results: </strong>Between March 2020 and September 2021, 116 patients received HFNO and 110 patients received COT. Median age was 78 [72-83], and 78% of the patients had a Clinical Frailty Scale score of 4 to 9. In-hospital mortality was 64% for HFNO and 71% for COT (p = 0.29), with an adjusted odds ratio of 0.72 (95% confidence interval [0.34-1.54], p = 0.40). Hospital LOS was 11 [6-18] days for HFNO, and 7 [4-12] days for COT (p < 0.001), with a remaining difference after adjusting for confounders (p < 0.01).</p><p><strong>Conclusion: </strong>The lack of survival benefit and increased hospital LOS should be taken into account when considering HFNO for patients with a DNI order, suffering from AHRF due to viral pneumonia, like COVID-19.</p><p><strong>Clinical trial registration: </strong>HFNO-COVID-19 study: DTR, NL9067 (Dutch Trial Registry), registration date: 27-11-2020.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"161"},"PeriodicalIF":5.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053144","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":"Characteristics of upper and lower respiratory tract microbiota after lung transplantation.","authors":"Yuhang Cai, Yuchen Fan, Ao Chen, Xiaohua Wang, Lulin Wang, Jiaqi Chen, Zhang Wang, Jia Li, Xinzhu Yi, Chunrong Ju","doi":"10.1186/s12931-025-03235-4","DOIUrl":"https://doi.org/10.1186/s12931-025-03235-4","url":null,"abstract":"<p><strong>Background: </strong>The composition and characteristics of airway microbiota offer critical insights for clinical decision-making. Current research on chronic lung diseases shows differences in the composition and characteristics of upper and lower respiratory tract microbiota compared with healthy individuals. However, the temporal changes of these microbial communities in lung transplant recipients remain poorly characterized.</p><p><strong>Methods: </strong>This is a longitudinal prospective study. Respiratory specimens were collected regularly from lung transplant recipients for testing and analysis. A total of 150 bronchoalveolar lavage fluid (BALF) samples, 150 throat swab samples, 51 sputum samples, and 36 lung tissue samples were collected from the recipients, at 7 days, 14 days, 1 month, 2 months, 3 months, and 6 months post-transplant for 16S rRNA gene sequencing and analysis.</p><p><strong>Results: </strong>Our study showed that there were significant differences in α-diversity and β-diversity among lung tissue, throat swab, and sputum samples, although α-diversity did not show a significant difference between lung tissue and BALF. Most amplicon sequence variants (ASVs) belonged to the families Enterobacteriaceae, Pseudomonadaceae, and Stenotrophomonas in BALF, while most ASVs belonged to the genera Streptococcus, Pseudomonadaceae, and Stenotrophomonas in sputum samples. Regarding dynamic changes, Corynebacterium and Staphylococcus were more prevalent in the early post-operative period but gradually decreased by 7 days post-operatively, while the common microbiota found in healthy populations based on literature became the most abundant ASVs at 6 months post-operatively in our study participants. Pseudomonadaceae and Stenotrophomonas contributed to the similarity in the composition of upper and lower respiratory microbiota.</p><p><strong>Conclusions: </strong>This study demonstrates that lung transplant recipients exhibit unique characteristics in their upper and lower respiratory tract microbiota, which are distinct ecological profiles, and both undergo significant changes within 6 months post-operatively. The similarity between upper and lower respiratory tract microbiota is associated with microbial diversity and taxonomic dominance.</p><p><strong>Clinical trial: </strong>The clinical trial was registered at Chinese Clinical Trial Registry (ChiCTR2200056908) in February 2022.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"160"},"PeriodicalIF":5.8,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018380","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":"ETS2 aggravate allergic airway inflammation by regulating ANT2-mediated cytosolic mitochondrial DsRNA levels.","authors":"Hui Jiang, Yaona Jiang, Ran Dong, Chang-Yong Fu","doi":"10.1186/s12931-025-03233-6","DOIUrl":"https://doi.org/10.1186/s12931-025-03233-6","url":null,"abstract":"<p><strong>Background: </strong>ETS2 has been identified as a pivotal regulator in the development of human inflammatory diseases. Nevertheless, the functional aspects of ETS2 in asthma remain inadequately characterized. The release of mitochondrial dsRNA is recognized as an initiator of innate immune responses and implicated in intensifying inflammation triggered by alternative immunogens. The interplay between these mechanisms remains poorly understood, and only a limited number of direct targets that underpin the pro-inflammatory role of ETS2 have been identified.</p><p><strong>Methods: </strong>The expression of ETS2 in epithelial cells under immune responses was analyzed, and its effects on asthma progression were examined through clinical specimens, human bronchial epithelial cells, and an allergic asthma mouse model. Additionally, the potential involvement of adenine nucleotide translocase-2 in mediating the immune responses regulated by ETS2 was explored.</p><p><strong>Results: </strong>Increased expression of ETS2 in lung epithelial cells was observed in both asthma patients and ovalbumin (OVA)-induced asthma mice. The deficiency of ETS2 resulted in a substantial decline in inflammatory cell infiltration and markedly diminished IL-6, IL-5, and IL-13 levels in epithelial cells. Mechanistically, ETS2 overexpression was associated with elevated cytosolic mitochondrial RNA levels, whereas knockdown resulted in their suppression. Furthermore, adenine nucleotide translocase-2 (ANT2) expression was robustly upregulated by ETS2 through direct promoter binding. The advantageous effects of ETS2 on asthma development were abrogated in ANT2-deficient mice.</p><p><strong>Conclusions: </strong>The findings collectively underscore the role of ETS2 as an exacerbating factor in allergic airway inflammation during asthma progression, primarily by inducing ANT2 expression. Therapeutic targeting of epithelial ETS2 could represent a novel approach to asthma management.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"159"},"PeriodicalIF":5.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12023494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144044932","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":"Serum C-C motif chemokine ligand 17 as a predictive biomarker for the progression of non-idiopathic pulmonary fibrosis interstitial lung disease.","authors":"Takatoshi Enomoto, Yoshito Takeda, Yuya Shirai, Takehiro Hasegawa, Feng Zhao, Hanna Lunding, Moritz Pohl, Ryuya Edahiro, Shigeyuki Shichino, Takahiro Kawasaki, Hanako Yoshimura, Reina Hara, Saori Amiya, Makoto Yamamoto, Daisuke Nakatsubo, Satoshi Tanizaki, Mana Nakayama, Yoshimi Noda, Takayuki Niitsu, Yuichi Adachi, Mari Tone, Yuko Abe, Maiko Naito, Kentaro Masuhiro, Yujiro Naito, Takayuki Shiroyama, Kotaro Miyake, Shohei Koyama, Kiyoharu Fukushima, Kota Iwahori, Haruhiko Hirata, Izumi Nagatomo, Satoshi Nojima, Masahiro Yanagawa, Yoshikazu Inoue, Atsushi Kumanogoh","doi":"10.1186/s12931-025-03237-2","DOIUrl":"https://doi.org/10.1186/s12931-025-03237-2","url":null,"abstract":"<p><strong>Background: </strong>Interstitial lung disease (ILD), represented by idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), shows poor prognosis due to progressive fibrosis. Early therapeutic intervention is required to enhance the efficacy of antifibrotic drugs, highlighting the importance of early detection of ILD progression. Although candidate biomarkers for predicting ILD progression have been recently reported through omics analyses, clinically measurable biomarkers remain unestablished. This study aimed to identify clinically measurable biomarkers that could predict the degree of ILD progression.</p><p><strong>Methods: </strong>The serum levels of 13 candidate biomarkers were prospectively measured by chemiluminescent enzyme immunoassay and the utilities for predicting ILD progression were compared in the discovery cohort (total 252 patients). Moreover, we evaluated the utility of the identified biomarker in another independent cohort (154 patients with non-IPF-ILD) and examined the dynamics of the biomarker by immunoblotting and single-cell RNA sequencing (scRNA-seq) using samples of patients and a mouse model.</p><p><strong>Results: </strong>In the discovery cohort, C-C motif chemokine ligand (CCL)17 could reliably predict ILD progression, particularly in patients with ILD other than IPF, and showed significant associations with mortality (hazard ratio [HR] 3.70; 95% confidence interval [CI] 1.19-11.49; P = 0.015; cut-off value = 418 pg/mL). Consistently, in the validation cohort, the CCL17 high group showed significantly higher mortality (HR: 2.15; 95% CI 0.99-4.69; P = 0.049), and CCL17 was identified as an independent prognostic factor from corticosteroid or immunosuppressive agents use and ILD-gender-age-physiology index. Similar to the results of serum studies, CCL17 levels in the lungs of patients with PPF and model mice were higher than those in controls. They were positively correlated with CCL17 levels in the serum, suggesting that the increased serum CCL17 levels could reflect an increase in CCL17 levels in lung tissues. The scRNA-seq analysis of lung tissues from model mice suggested that the levels of CCL17 derived primarily from conventional dendritic cells and macrophages increased, especially during the profibrotic phase.</p><p><strong>Conclusions: </strong>We identified serum CCL17 as a clinically measurable biomarker for predicting non-IPF-ILD progression. Serum CCL17 could enable the stratification of patients at risk of non-IPF-ILD progression, leading to appropriate early therapeutic intervention.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"157"},"PeriodicalIF":5.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144034512","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 longitudinal impact of low-dose morphine on diurnal cortisol profiles in people with chronic breathlessness and chronic obstructive pulmonary disease (COPD): an exploratory study.","authors":"Diana H Ferreira, Richella Ryan, Nina Smyth, Angela Clow, David C Currow","doi":"10.1186/s12931-025-03230-9","DOIUrl":"https://doi.org/10.1186/s12931-025-03230-9","url":null,"abstract":"<p><strong>Introduction: </strong>Stress activates the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is an end product. 'Allostatic load' is where systems including the HPA axis are exposed to high, cumulative, physiologic burdens (such as chronic breathlessness) leading to flatter diurnal cortisol slopes and poorer health outcomes. The aim of this hypothesis-generating study explored longitudinal changes in cortisol secretion and any associated changes in breathlessness after introducing regular, low dose morphine or placebo.</p><p><strong>Methods: </strong>This was an optional, hypothesis-generating sub-study embedded in a multi-site, randomised, double-blind, placebo-controlled trial (RCT) of regular, low-dose morphine for chronic breathlessness and chronic obstructive pulmonary disease. In a blinded dose-increment algorithm by week three, doses were 0 mg-32 mg. Participants in the RCT could elect to continue in a six-month blinded extension. This sub-study excluded people who used non-inhaled corticosteroids in the previous month or were on subcutaneous insulin. Participants collected saliva for cortisol assays for two days at baseline, and ends of weeks 1, 3 and 12 at 3,6 and 12 h after waking, generating sufficient data to calculate diurnal cortisol slopes and areas under the curve (AUC). Samples were analysed using ELISA. Correlations between diurnal cortisol profiles (slope and AUC) and a range of measures were explored.</p><p><strong>Results: </strong>Twenty mostly female former smokers were in this sub-study. At baseline and the end of week 1, one-way ANOVA between-group analyses showed no significant differences in the log-transformed cortisol slope or ln-AUC. There was a strong correlation between the age-adjusted Charlson Comorbidity Index (CCI) and ln-AUC (r=-0.70, p < 0.001) and moderate correlation with age (r=-0.43, p = 0.06). In the blinded extension study, there was a self-selecting blinded group (n = 7) all on active medication. Global impression of change (GIC) was highly correlated with the diurnal cortisol slope (rs = 0.98, p = 0.01), and with decrease in average breathlessness (r = 0.89, p = 0.04).</p><p><strong>Discussion: </strong>This hypothesis-generating study did not show a relationship between the diurnal cortisol profile and morphine in people with chronic breathlessness and COPD. For the sub-group still on study at 12weeks, the cortisol curves became steeper as average breathlessness decreased and as global impression of change (GIC) improved, suggesting that reducing breathlessness may potentially positively impact the HPA axis in a sub-group of people.</p><p><strong>Trial registration: </strong>Registration Number NCT02720822 date registered 28/03/2016.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"156"},"PeriodicalIF":5.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143993367","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":"An integrated machine learning model of transcriptomic genes in multi-center chronic obstructive pulmonary disease reveals the causal role of TIMP4 in airway epithelial cell.","authors":"Erkang Yi, Haiqing Li, Yu Liu, Qingyang Li, Chengshu Xie, Ruining Sun, Fan Wu, Zhishan Deng, Kunning Zhou, Hairong Wang, Xinru Ran, Yumin Zhou, Pixin Ran","doi":"10.1186/s12931-025-03238-1","DOIUrl":"10.1186/s12931-025-03238-1","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, resulting in inconsistent findings across studies. Identifying a core set of genes consistently involved in COPD pathogenesis, independent of patient variability, is essential.</p><p><strong>Methods: </strong>We integrated lung tissue sequencing data from patients with COPD across two centers. We used weighted gene co-expression network analysis and machine learning to identify 13 potential pathogenic genes common to both centers. Additionally, a gene-based model was constructed to distinguish COPD at the molecular level and validated in independent cohorts. Gene expression in specific cell types was analyzed, and Mendelian randomization was used to confirm associations between candidate genes and lung function/COPD. Preliminary in vitro functional validation was performed on prioritized core candidate genes.</p><p><strong>Results: </strong>Tissue inhibitor of metalloproteinase 4 (TIMP4) was identified as a key pathogenic gene and validated in COPD cohorts. Further analysis using single-cell sequencing from mice and patients with COPD revealed that TIMP4 is involved in ciliated cells. In primary human airway epithelial cells cultured at the air-liquid interface, TIMP4 overexpression reduced ciliated cell numbers.</p><p><strong>Conclusions: </strong>We developed a 13-gene model for distinguishing COPD at the molecular level and identified TIMP4 as a potential hub pathogenic gene. This finding provides insights into shared disease mechanisms and positions TIMP4 as a promising therapeutic target for further investigation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"158"},"PeriodicalIF":5.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12020095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144027587","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":"Proteogenomic verifies targets underlying erythromycin alleviate neutrophil extracellular traps-induced inflammation.","authors":"Nan Ma, Xiao Na Liang, Quan Fang Chen, Mei Hua Li, Guang Sheng Pei, Xiao Fei Yi, Li Yan Guo, Fu Gang Chen, Zhi Yi He","doi":"10.1186/s12931-025-03226-5","DOIUrl":"https://doi.org/10.1186/s12931-025-03226-5","url":null,"abstract":"<p><strong>Background: </strong>Neutrophil Extracellular Traps (NETs) are closely related to the progression of inflammation in Chronic Obstructive Pulmonary Disease (COPD). Erythromycin (EM) has been shown to inhibit inflammation in COPD, but its molecular mechanisms is still unclear. The aim of our study is investigate the molecular mechanisms of EM's anti-inflammatory effects in NETs-induced inflammation.</p><p><strong>Methods: </strong>Transcriptomics and proteomics data were obtained from U937 cells treated with NETs and EM. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were identified using R software. Pathway enrichment analyses, were employed to identify inflammation-related pathways. Cytoscape were utilized to construct network of hub targets regulated by EM which related with oxidative stress and inflammation. Additionally, Cytoscape and STRING were used to construct protein-protein interaction (PPI) network of key targets regulated by EM. The expression levels of key targets were further confirmed through WB and PCR experiments.</p><p><strong>Results: </strong>Both transcriptomics and proteomics indicate that EM decrease NETs -induced AKT1 expression. Enrichment analysis of DEGs and DEPs reveal multiple common pathways involved in EM's regulation inflammation, including the PI3K/AKT pathway, response to oxidative stress, IKK/NF-κB signaling and PTEN signaling pathway. Nine key targets in PI3K/AKT-related inflammatory pathways regulated by EM and ten targets of EM-regulated oxidative stress were identified. WB and PCR results confirmed that EM reversing the NETs-induced inflammation by modulating the activity of these targets. Furthermore, clinical samples and vitro experiments confirm that EM alleviates NETs-induced glucocorticoid resistance via inhibiting PI3K/AKT, thereby repressing inflammation.</p><p><strong>Conclusions: </strong>Our study provides a comprehensive proteogenomic characterization of how EM alleviates NET-related inflammation, and identify PI3K/AKT play a critical role in the mechanism by which EM inhibits inflammation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"155"},"PeriodicalIF":5.8,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12009532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065051","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}