Respiratory Research最新文献

{"title":"A novel dual fixation method for improving the reliable assessment of pulmonary vascular morphology in pulmonary hypertension rats.","authors":"Yan Xu, Pu Liao, Xinyu Song, Wenchuan Guo, Bingxun Liu, Tong Ye, Ting Zhang, Rui Xiao, Liping Zhu, Yujun Shen, Yanjiang Xing, Jing Wang, Qinghua Hu","doi":"10.1186/s12931-024-03091-8","DOIUrl":"10.1186/s12931-024-03091-8","url":null,"abstract":"<p><p>This study introduced a novel dual fixation method for the pulmonary vasculature and lung tissue in pulmonary hypertension (PH) rats, addressing the limitations of traditional fixation methods that failed to accurately preserve the in vivo status of pulmonary vascular morphology. The modified method involved a dual fixation process, combining individualized ventilation support and vascular perfusion to simulate the respiratory motion, pulmonary artery pressure and right ventricular output of the rat under in vivo conditions. Utilizing a monocrotaline-induced PH rat model, this study compared the dual fixation with the traditional immersion fixation, focusing on the quantitative assessment of alveolar expansion degree, capillary patency, endothelial cell quantity and wall thickness of pulmonary vein and artery. The results demonstrated that the dual fixation is superior in maintaining the authenticity and integrity of lung tissue and more sensitive in the evaluation of pulmonary artery hypertrophy, providing a more reliable representation of pulmonary vascular remodeling associated with PH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"26"},"PeriodicalIF":5.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11742800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014683","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":"Cortisol regulates neonatal lung development via Smoothened.","authors":"Shanshan Lu, Yifei Chen, Jiawen Song, Liangliang Ren, Jun Du, Donglai Shen, Jiayin Peng, Yao Yin, Xia Li, Yuqing Wang, Yan Gao, Siman Han, Yichang Jia, Yun Zhao, Yizheng Wang","doi":"10.1186/s12931-025-03104-0","DOIUrl":"10.1186/s12931-025-03104-0","url":null,"abstract":"<p><strong>Background: </strong>Neonatal respiratory distress syndrome (NRDS), one of the main causes of neonatal death, is clinically characterized by progressive dyspnea and cyanosis 1 to 2 h after birth. Corticosteroids are commonly used to prevent NRDS in clinical. However, the protective mechanism of the corticosteroids remains largely unclear.</p><p><strong>Methods: </strong>In this study, the simulation of the molecular docking by Autodock, in vitro binding experiments, and Sonic Hedgehog (SHH) pathway examination in cells were performed to study the directly binding of cortisol to Smoothened (SMO). To explore the effect of cortisol action on the SHH pathway on neonatal lung development, we generated a genetic mouse, in which leucine 116 (L112 in human) of SMO was mutated to alanine 116 (L116A, Smo^a/a) by the CRISPR-Cas9, based on sequence differences between human and mice. Then, we performed morphological analysis, single-cell RNA sequencing (scRNA-seq) on lung tissue and fluorescence in situ hybridization (FISH).</p><p><strong>Results: </strong>In this study, we reported that cortisol, the endogenous glucocorticoid, inhibited the sonic hedgehog (Shh)/SMO-mediated proliferation of lung fibroblasts to maintain the normal lung development. Specifically, cortisol competed with cholesterol for binding to the cysteine-rich domain (CRD) in SMO to inhibit the activation of Shh/SMO signaling, a critical signaling known for cell proliferation. Cortisol did not inhibit the activation of SMO when L112 in its CRD was mutated to A112. Moreover, Smo^a/a (L116A) mice exhibited the immature lungs in which over-proliferation of interstitial fibroblasts and reduction in the surfactant protein were evident.</p><p><strong>Conclusion: </strong>Together, these results suggested that cortisol regulated cholesterol stimulation of SMO by competitively binding to the CRD to regulate neonatal lung maturation in mice.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"27"},"PeriodicalIF":5.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014712","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":"Optimization of a micro-scale air-liquid-interface model of human proximal airway epithelium for moderate throughput drug screening for SARS-CoV-2.","authors":"Chandani Sen, Tammy M Rickabaugh, Arjit Vijey Jeyachandran, Constance Yuen, Maisam Ghannam, Abdo Durra, Adam Aziz, Kristen Castillo, Gustavo Garcia, Arunima Purkayastha, Brandon Han, Felix W Boulton, Eugene Chekler, Robert Garces, Karen C Wolff, Laura Riva, Melanie G Kirkpatrick, Amal Gebara-Lamb, Case W McNamara, Ulrich A K Betz, Vaithilingaraja Arumugaswami, Robert Damoiseaux, Brigitte N Gomperts","doi":"10.1186/s12931-025-03095-y","DOIUrl":"10.1186/s12931-025-03095-y","url":null,"abstract":"<p><strong>Background: </strong>Many respiratory viruses attack the airway epithelium and cause a wide spectrum of diseases for which we have limited therapies. To date, a few primary human stem cell-based models of the proximal airway have been reported for drug discovery but scaling them up to a higher throughput platform remains a significant challenge. As a result, most of the drug screening assays for respiratory viruses are performed on commercial cell line-based 2D cultures that provide limited translational ability.</p><p><strong>Methods: </strong>We optimized a primary human stem cell-based mucociliary airway epithelium model of SARS-CoV-2 infection, in 96-well air-liquid-interface (ALI) format, which is amenable to moderate throughput drug screening. We tested the model against SARS-CoV-2 parental strain (Wuhan) and variants Beta, Delta, and Omicron. We applied this model to screen 2100 compounds from targeted drug libraries using a high throughput-high content image-based quantification method.</p><p><strong>Results: </strong>The model recapitulated the heterogeneity of infection among patients with SARS-CoV-2 parental strain and variants. While there were heterogeneous responses across variants for host factor targeting compounds, the two direct-acting antivirals we tested, Remdesivir and Paxlovid, showed consistent efficacy in reducing infection across all variants and donors. Using the model, we characterized a new antiviral drug effective against both the parental strain and the Omicron variant.</p><p><strong>Conclusion: </strong>This study demonstrates that the 96-well ALI model of primary human mucociliary epithelium can recapitulate the heterogeneity of infection among different donors and SARS-CoV-2 variants and can be used for moderate throughput screening. Compounds that target host factors showed variability among patients in response to SARS-CoV-2, while direct-acting antivirals were effective against SARS-CoV-2 despite the heterogeneity of patients tested.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"18"},"PeriodicalIF":5.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014691","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":"Signatures of H3K4me3 modification predict cancer immunotherapy response and identify a new immune checkpoint-SLAMF9.","authors":"Tao Fan, Chu Xiao, Ziqin Deng, Shuofeng Li, He Tian, Yujia Zheng, Bo Zheng, Chunxiang Li, Jie He","doi":"10.1186/s12931-024-03093-6","DOIUrl":"10.1186/s12931-024-03093-6","url":null,"abstract":"<p><p>H3 lysine 4 trimethylation (H3K4me3) modification and related regulators extensively regulate various crucial transcriptional courses in health and disease. However, the regulatory relationship between H3K4me3 modification and anti-tumor immunity has not been fully elucidated. We identified 72 independent prognostic genes of lung adenocarcinoma (LUAD) whose transcriptional expression were closely correlated with known 27 H3K4me3 regulators. We constructed three H3K4me3 modification patterns utilizing the expression profiles of the 72 genes, and patients classified in each pattern exhibited unique tumor immune infiltration characteristics. Using the principal component analysis (PCA) of H3K4me3-related patterns, we constructed a H3K4me3 risk score (H3K4me3-RS) system. The deep learning analysis using 12,159 cancer samples from 26 cancer types and 725 cancer samples from 5 immunotherapy cohorts revealed that H3K4me3-RS was significantly correlated with cancer immune tolerance and sensitivity. Importantly, this risk-score system showed satisfactory predictive performance for the ICB therapy responses of patients suffering from several cancer types, and we identified that SLAMF9 was one of the immunosuppressive phenotype and immunotherapy resistance-determined genes of H3K4me3-RS. The mice melanoma model showed Slamf9 knockdown remarkably restrained cancer progression and enhanced the efficacy of anti-CTLA-4 and anti-PD-L1 therapies by elevating CD8 + T cell infiltration. This study provided a new H3K4me3-associated biomarker system to predict tumor immunotherapy response and suggested the preclinical rationale for investigating the roles of SLAMF9 in cancer immunity regulation and treatment.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"17"},"PeriodicalIF":5.8,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014772","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":"Comparative analysis of real-world data on the efficacy and safety of and adherence to ICS/LABA combinations in asthma management.","authors":"Hee Sun Park, Jungkuk Lee, Hasung Kim, Seong-Dae Woo","doi":"10.1186/s12931-024-03084-7","DOIUrl":"10.1186/s12931-024-03084-7","url":null,"abstract":"<p><strong>Background: </strong>Choosing effective devices (inhaled corticosteroid [ICS]-long-acting β2 agonist [LABA] combination inhalers) as maintenance treatment is critical for managing patients with asthma. We aimed to compare ICS/LABA combination efficacy, safety, and adherence across inhaler types and components in patients newly diagnosed with asthma.</p><p><strong>Methods: </strong>Utilizing South Korea's National Health Insurance Service data, we conducted a population-based cohort study involving patients aged 18-80 years, newly diagnosed with asthma who received ICS/LABA combination therapy between January 2016 and December 2020. Outcomes assessed included treatment adherence, asthma exacerbations, hospitalizations, emergency-department visits, mortality, and safety outcomes within 3-month and 1-year post-index periods.</p><p><strong>Results: </strong>Overall, 13,850 eligible patients were included, with subgroups categorized and compared according to inhaler type and component (metered dose inhalers [MDIs] vs. dry powder inhalers [DPIs], budesonide vs. fluticasone, and formoterol vs. salmeterol). Efficacy and safety profiles did not significantly differ across device types or ICS/LABA combination components during the 3-month and 1-year follow-up periods. However, the DPI group exhibited a significantly higher mean proportion of days covered (0.67 ± 0.23 vs. 0.62 ± 0.23; P < 0.001) and a lower risk of discontinuation (adjusted hazard ratio, 0.867; 95% confidence interval, 0.804-0.927; P < 0.001) than did the MDI group, with no significant differences observed between the other subgroups.</p><p><strong>Conclusions: </strong>The choice of inhaler device (MDI vs. DPI) and specific ICS/LABA combination components does not significantly impact efficacy and safety profiles in patients newly diagnosed with asthma. However, DPI use may be associated with improved adherence. These results provide valuable insights for clinicians in selecting appropriate and individually tailored inhaler therapies in real-world settings.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"12"},"PeriodicalIF":5.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980512","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":"YTHDF1-mediated m6A modification of GBP4 promotes M1 macrophage polarization in acute lung injury.","authors":"Fengan Cao, Shilei Wang, Qiuyue Tan, Junna Hou, Yunlu Li, Wentao Ma, Shilong Zhao, Jing Gao","doi":"10.1186/s12931-024-03061-0","DOIUrl":"10.1186/s12931-024-03061-0","url":null,"abstract":"<p><strong>Background: </strong>Acute lung injury (ALI) is a severe condition with multifaceted causes, including inflammation and oxidative stress. This research investigates the influence of m6A (N6-methyladenosine) modification on GBP4, a protein pivotal for macrophage polarization, a critical immune response in ALI.</p><p><strong>Methods: </strong>Utilizing a mouse model to induce ALI, the study analyzed GBP4 expression in alveolar macrophages. By overexpressing or knocking down GBP4, the study assessed its impact on M1 macrophage polarization. The role of YTHDF1 was also explored through knockdown experiments to determine its effect on GBP4 expression and macrophage polarization.</p><p><strong>Results: </strong>Increased GBP4 expression was noted in ALI model mice, promoting M1 macrophage polarization. YTHDF1 was found to enhance GBP4 expression by recognizing m6A sites on its mRNA, which was linked to reduced inflammation in MLE-12 cells upon YTHDF1 knockdown.</p><p><strong>Conclusion: </strong>The study emphasizes the crucial roles of GBP4 and YTHDF1 in ALI development and immune response regulation. It suggests m6A modification as a potential therapeutic target, contributing to the understanding of ALI's molecular mechanisms and guiding future treatment strategies.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"11"},"PeriodicalIF":5.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980517","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":"A novel technique of cryodenervation for murine vagus nerve: implications for acute lung inflammation.","authors":"Di Wu, Ximing Liao, Jing Gao, Kun Wang, Wujian Xu, Feilong Wang, Zhixian Jin, Dandan Wu, Qiang Li, Wei Gao","doi":"10.1186/s12931-025-03108-w","DOIUrl":"10.1186/s12931-025-03108-w","url":null,"abstract":"<p><strong>Background: </strong>Neuroimmune interaction is an underestimated mechanism for lung diseases, and cryoablation is a competitive advantageous technique than other non-pharmacologic interventions for peripheral nerve innervating the lung. However, a lack of cryodenervation model in laboratory rodents leads to the obscure mechanisms for techniques used in clinic.</p><p><strong>Method: </strong>Herein, we developed a novel practical method for mouse peripheral nerve cryoablation, named visualized and simple cryodenervation (VSCD). We first estimated the feasibility, safety and effectiveness of the technique via haematoxylin-eosin staining, histochemistry or immunofluorescence staining and immunoblotting assay. We then constructed the acute lung injury (ALI) model triggered by lipopolysaccharide (LPS) to verify the effect of VSCD in the resolution of pulmonary inflammation. Besides, the IL-10 knockout mice were also applied to explain the underlying mechanism of the protective activity of VSCD in ALI mice.</p><p><strong>Result: </strong>We demonstrated that VSCD was able to induce a reliable and stable blockade of innervation, but reversible structural damage of mouse vagus nerve without detectable toxicity to lung tissues. Cholinergic parasympathetic nerve in the mouse lung coming from vagus nerve was activated at the initial stage (1 week) after VSCD, and blocked 3 weeks later. By use of the ALI mouse model, we found that VSCD effectively decreased pulmonary inflammation and tissue damage in the ALI mice. Moreover, the activated cholinergic anti-inflammatory pathway (CAP) and elevated IL-10 expression might explain the protective action of VSCD following LPS challenge.</p><p><strong>Conclusion: </strong>This study fills the gap in the cryoablation for mouse vagus nerve, thereby guiding the application of cryodenervation in clinical management of pulmonary diseases. It also offers evidence of anti-inflammatory potential of VSCD in ALI mouse model and opens therapeutic avenues for the intervention of acute lung inflammation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"15"},"PeriodicalIF":5.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980510","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":"STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines.","authors":"Pan Jiang, Huai Huang, Zilong Liu, Guiling Xiang, Xiaodan Wu, Shengyu Hao, Shanqun Li","doi":"10.1186/s12931-024-03062-z","DOIUrl":"10.1186/s12931-024-03062-z","url":null,"abstract":"<p><strong>Background: </strong>Obstructive sleep apnea (OSA) is frequently associated with increased incidence and mortality of pulmonary hypertension (PH). The immune response contributes to pulmonary artery remodeling and OSA-related diseases. The immunologic factors linked to OSA-induced PH are not well understood. STAT6 is crucial in the signaling pathway that modulates immune response. However, the status of phosphorylated STAT6 (p-STAT6) in an OSA-induced PH mouse model remains largely unexplored.</p><p><strong>Methods: </strong>Chronic intermittent hypoxia (CIH) plays a crucial role in the progression of OSA. This study utilized a in vivo CIH model to examine the role of STAT6 in CIH-induced PH.</p><p><strong>Results: </strong>CIH mice exhibited pulmonary artery remodeling and pulmonary hypertension, indicated by increased right ventricular systolic pressure (RVSP), higher right ventricular to left ventricular plus septum (RV/LV + S) ratios, and significant morphological alterations compared to normoxic (Nor) mice. Increased p-STAT6 in the lungs and elevated p-STAT6 + IL-4 + producing T cells in CIH mice. STAT6 deficiency (STAT6-/-) improved PH and PA remodeling in CIH-induced PH mouse models.STAT6 deficiency impaired the T helper 2 (Th2) immune response, affecting IL-4 and IL-13 secretion. IL-4, rather than IL-13, activated STAT6 in human pulmonary artery smooth muscle cells (hPASMCs). STAT6 knockdown decreased the proliferation in IL-4 treated hPASMCs.</p><p><strong>Conclusion: </strong>These findings exhibit the critical role of STAT6 in the pathogenesis of CIH induced PH by regulating Th2 immune response.STAT6 could be a significant therapeutic target for OSA-related PH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"13"},"PeriodicalIF":5.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980516","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":"Integrin α8 is a useful cell surface marker of alveolar lipofibroblasts.","authors":"Atsuki Fukada, Yasunori Enomoto, Ryo Horiguchi, Yoichiro Aoshima, Shiori Meguro, Hideya Kawasaki, Isao Kosugi, Tomoyuki Fujisawa, Noriyuki Enomoto, Naoki Inui, Takafumi Suda, Toshihide Iwashita","doi":"10.1186/s12931-025-03103-1","DOIUrl":"10.1186/s12931-025-03103-1","url":null,"abstract":"<p><strong>Background: </strong>Recent advances in comprehensive gene analysis revealed the heterogeneity of mouse lung fibroblasts. However, direct comparisons between these subpopulations are limited due to challenges in isolating target subpopulations without gene-specific reporter mouse lines. In addition, the properties of lung lipofibroblasts remain unclear, particularly regarding the appropriate cell surface marker and the niche capacity for alveolar epithelial cell type 2 (AT2), an alveolar tissue stem cell.</p><p><strong>Methods and results: </strong>Using cell surface markers applicable even into wild-type mouse lungs, we could classify PDGFRα⁺ total lung resident fibroblasts into at least two major distinct subpopulations: integrin α8 (ITGA8)⁺ and SCA-1⁺ fibroblasts. We analyzed their characteristics, including lipid content, transcriptome profiles, and alveolar stem cell niche capacity. ITGA8⁺ fibroblasts showed higher positivity of intracellular lipid droplets compared to SCA-1⁺ fibroblasts (91.0 ± 1.5% vs. 5.0 ± 0.5% in LipidTOX staining; 91.3 ± 1.4% vs. 7.1 ± 1.7% in Oil Red O staining). The fluorescence intensity of LipidTOX in the ITGA8⁺ fibroblasts was highest in newborn compared to adult or aged lungs. The transcriptome profile of ITGA8⁺ fibroblasts in adult mouse lungs, evaluated through two independent single-cell RNA-seq datasets, consistently showed higher expression of Tcf21 and Plin2, which are canonical markers of lipofibroblasts. ITGA8⁺ fibroblasts were primarily located in the alveolar area, particularly in the neighborhood of AT2. Compared to SCA-1⁺ fibroblasts, ITGA8⁺ fibroblasts showed higher mRNA expression of potential AT2-supportive factors, Fgf10, Fgf7, and Wnt2, but unexpectedly, exhibited lower efficiency in alveolar organoid formation.</p><p><strong>Conclusions: </strong>ITGA8⁺ lung fibroblasts correspond to alveolar lipofibroblasts, but the alveolar niche capacity may be lower than SCA-1⁺ lung fibroblasts. Further studies are necessary for the functional distinction between lung fibroblast subpopulations.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"14"},"PeriodicalIF":5.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11731379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980514","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":"Potential drug targets for asthma identified through mendelian randomization analysis.","authors":"Xingxuan Chen, Yu Shang, Danting Shen, Si Shi, Zhe Wen, Lijuan Li, Hong Chen","doi":"10.1186/s12931-024-03086-5","DOIUrl":"10.1186/s12931-024-03086-5","url":null,"abstract":"<p><strong>Background: </strong>The emergence of new molecular targeted drugs marks a breakthrough in asthma treatment, particularly for severe cases. Yet, options for moderate-to-severe asthma treatment remain limited, highlighting the urgent need for novel therapeutic drug targets. In this study, we aimed to identify new treatment targets for asthma using the Mendelian randomization method and large-scale genome-wide association data (GWAS).</p><p><strong>Methods: </strong>We utilized GWAS data from the UK Biobank (comprising 56,167 patients and 352,255 control subjects) and the FinnGen cohort (including 23,834 patients and 228,085 control subjects). Genetic instruments for 734 plasma proteins and 154 cerebrospinal fluid proteins were derived from recently published GWAS. Bidirectional Mendelian randomization analysis, Steiger filtering, colocalization, and phenotype scanning were employed for reverse causal inference detection, further substantiating the Mendelian randomization results. A protein-protein interaction network was also constructed to reveal potential associations between proteins and asthma medications.</p><p><strong>Results: </strong>Under Bonferroni significance conditions, Mendelian randomization analysis revealed causal relationships between seven proteins and asthma. In plasma, we observed that an increase of one standard deviation in IL1R1[1.30 (95% CI 1.20-1.42)], IL7R[1.07 (95% CI 1.04-1.11)], ECM1[1.03 (95% CI 1.02-1.05)], and CD200R1[1.18 (95% CI 1.09-1.27)] were associated with an increased risk of asthma, while an increase in ADAM19 [0.87 (95% CI 0.82-0.92)] was found to be protective. In the brain, each 10-fold increase in IL-6 sRa [1.29 (95% CI 1.15-1.45)] was associated with an increased risk of asthma, while an increase in Layilin [0.61 (95% CI 0.51-0.73)] was found to be protective. None of the seven proteins exhibited a reverse causal relationship. Colocalization analysis indicated that ECM1 (coloc.abf-PPH4 = 0.953), IL-6 sRa (coloc.abf-PPH4 = 0.966), and layilin (coloc.abf-PPH4 = 0.975) shared the same genetic variation as in asthma.</p><p><strong>Conclusion: </strong>A causal relationship exists between genetically determined protein levels of IL1R1, IL7R, ECM1, CD200R1, ADAM19, IL-6 sRa, and Layilin (LAYN) and asthma. Moreover, the identified proteins may serve as attractive drug targets for asthma, especially ECM1 and Layilin (LAYN). However, further research is required to comprehensively understand the roles of these proteins in the occurrence and progression of asthma.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"16"},"PeriodicalIF":5.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11730137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980515","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}