Respiratory Research最新文献

{"title":"Two novel genetic variants in the WFDC2 gene from patients with bronchiectasis.","authors":"Jeong-Min Kim, Soojin Hwang, Hye-Won Cho, Youngjun Kim, Dong Mun Shin, Eun Lee, Myungshin Kim, Cheonghwa Lee, Jong-Won Kim, Hyun-Young Park, Beom Hee Lee, Mi-Hyun Park","doi":"10.1186/s12931-025-03183-z","DOIUrl":"https://doi.org/10.1186/s12931-025-03183-z","url":null,"abstract":"<p><strong>Background: </strong>Bronchiectasis is a chronic respiratory condition characterized by irreversible dilation and damage of the bronchial walls, leading to impaired mucociliary clearance and recurrent infections. Its etiology is diverse; however, genetic factors are critical in its congenital and severe forms. Therefore, we aimed to identify two novel variants of the WFDC2 gene, known as antiprotease, from patients with bronchiectasis and/or related phenotypes using trio-based whole-genome sequencing analysis.</p><p><strong>Methods: </strong>Patients with bronchiectasis were recruited as trio or quad, and their genomic DNA was isolated. The whole genome sequence was produced and analyzed to find causative genetic variants through an internal pipeline using GATK-DRAGEN-Hail. Variant interpretation and pathogenicity assessment using various in-silico tools were performed to identify causative variants. Clinical characteristics were collected from the patients with identified variants.</p><p><strong>Results: </strong>In this discovery study involving four patients from three families, two novel variants in the WFDC2 gene were identified and suggested as causative pathogenic variants for bronchiectasis. The first variant (c.291 C > G, p.(Cys97Trp)) is a homozygous variant that was not found in the population genome data. However, the second variant (c.278G > C, p.(Cys93Ser)) was identified in another patient as a heterozygous variant, forming a compound heterozygous state with the first variant. Notably, both variants, located at cysteine residues that are conserved across many species, are crucial in forming disulfide bonds essential for protein structure and function. In-silico analyses classified both variants as pathogenic; they were also identified as likely pathogenic according to the American College of Medical Genetics and Genomic guidelines. Furthermore, in an expansion study, the homozygous variant was also found in two unrelated patients.</p><p><strong>Conclusion: </strong>We identified two novel bi-allelic variants located at cysteine residues in the WFDC2 gene from patients with bronchiectasis who had previously not received a genetic diagnosis. Therefore, considering prior research on the pivotal role of the WFDC2 protein in the respiratory system, these two novel variants may serve as potential diagnostic markers and therapeutic targets for bronchiectasis.</p><p><strong>Clinical trial number: </strong>Not Applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"108"},"PeriodicalIF":5.8,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671689","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":"Deciphering the transcriptomic landscape of systemic lupus erythematosus-associated pulmonary arterial hypertension.","authors":"Yutong Li, Junyan Qian, Xiaoyue Deng, Leyao Ma, Qizhi Yuan, Qian Wang, Zhuang Tian, Xiaofeng Zeng, Xinzhuang Yang, Jiuliang Zhao, Mengtao Li","doi":"10.1186/s12931-025-03169-x","DOIUrl":"10.1186/s12931-025-03169-x","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multi-organ damage. Pulmonary arterial hypertension (PAH) is one of the life-threatening complications of SLE. The underlying cause of systemic lupus erythematosus-associated pulmonary arterial hypertension has not been fully comprehended. Besides the mechanisms implicated in the development of PAH, such as damage to the endothelial cells, the aberrant activation of the immune system also plays a substantial role in the pathogenesis of SLE-PAH.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this study, peripheral blood samples from 100 patients with SLE-PAH and 95 patients of SLE without PAH (SLE-nonPAH) were obtained for RNA sequencing and comprehensive transcriptomic analysis. Pathway enrichment analysis was performed based on differentially expressed genes (DEGs) between SLE-PAH and SLE-nonPAH to elucidate the mechanisms potentially driving the development of PAH in SLE patients. Utilizing consensus non-negative matrix factorization (cNMF), we also conducted a detailed analysis to identify distinct subgroups within the SLE-PAH population. Meanwhile, the protein-protein interaction (PPI) analysis was performed and hub genes among the SLE-PAH subgroups were detected. Common transcription factors (TFs) of detected hub genes were also discovered to serve as potential therapeutic targets.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Inflammatory signaling pathways, notably those involving interferon and TNFα, were found to play an important role in the SLE-PAH. Utilizing cNMF method, three unique subgroups of SLE-PAH patients were delineated, each characterized by a distinct level of inflammatory activity. Specifically, the high inflammation subgroup, marked by the activity of Interleukin-6 (IL-6), exhibited a milder form of PAH. In contrast, the subgroup with moderate inflammation displayed the most pronounced PAH symptoms. Further disease enrichment analysis revealed that, beyond the dysregulated inflammatory pathways, patients with the most severe PAH exhibited distinct pathogenic transcriptomic profiles that disrupted vascular smooth muscle homeostasis, a critical component of vascular health. In the most severely affected subgroup, 13 hub genes were identified. Additionally, two transcription factors commonly associated with these genes, KLF1 and GATA1, were discovered, which may serve as potential therapeutic targets.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our investigation establishes inflammation as a key driver in the development of SLE-PAH. Patients who presented with concurrent dysregulations in inflammatory responses along with PAH-specific pathogenic markers exhibited a marked increase in the severity of their PAH. The insights gleaned from our transcriptomic analysis reveal the intricate interplay between inflammatory mechanisms and the molecular substrates of PAH. This nuanced understanding paves the way for more targeted and effective therapeutic approaches","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"106"},"PeriodicalIF":5.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921494/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658975","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":"Perspective and update: intrapleural fibrinolytic therapy for pleural infections and other forms of pleural organization.","authors":"Torry A Tucker, Andrey A Komissarov, Steven Idell","doi":"10.1186/s12931-025-03184-y","DOIUrl":"https://doi.org/10.1186/s12931-025-03184-y","url":null,"abstract":"<p><p>Intrapleural fibrinolytic therapy (IPFT), also known as intrapleural enzymatic therapy (IET), has been utilized for decades to treat pleural infections by expediting drainage in patients with pleural organization. The successful MIST2 trial demonstrated that IPFT improves pleural opacification, reduces hospital stays, and decreases short-term surgical referrals. Despite significant progress, gaps remain in identification of the optimal fibrinolytic agents, dosing, and safety improvements. IPFT is generally recommended for patients with loculation and failed pleural drainage, with a consensus panel advocating for combined tissue plasminogen activator (tPA) and DNase therapy. How each agent may affect the activity or function of the other in the combination remains unclear. While IPFT can reduce the need for surgical intervention, there are relatively few comparative clinical trials to guide initial therapy. Emerging low-dose IPFT treatment approaches may benefit patients who are poor surgical candidates. Personalized IPFT candidate approaches, such as the Fibrinolytic Potential Assay (FPA), could refine dosing and improve outcomes. Additionally, biomarkers like pleural fluid PAI-1 and suPAR concentrations may predict clinical outcomes and guide treatment. New therapeutic agents, including PAI-1 inhibiting peptides and mesothelial profibrogenic targets, are under investigation to enhance IPFT efficacy. These advances hold promise for improving the management of pleural infections and other forms of pleural organization.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"105"},"PeriodicalIF":5.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659030","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":"Extracellular vesicle-bound S100A8/A9 is differentially expressed in septic shock and prompts acute lung injury.","authors":"Jiangmei Wang, Weiliang Wu, Tingting Wen, Guoping Zheng, Guanguan Qiu, Huifeng Qian, Ruoyang Zhang, Jie Xia, Yaoqin Hu, Ruoqiong Huang, Ruoxi Zang, Zhenkai Le, Qiang Shu, Jianguo Xu","doi":"10.1186/s12931-025-03181-1","DOIUrl":"10.1186/s12931-025-03181-1","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a common indirect insult leading to acute respiratory distress syndrome (ARDS). Circulating extracellular vesicles (EVs) have been reported to participate in the pathogenesis of sepsis. However, the alteration of EV-bound S100A8/A9 during septic shock, along with the role of S100A8/A9 in driving acute lung injury, remains unexplored.</p><p><strong>Methods: </strong>EVs were isolated from the plasma of patients upon admission with sepsis or septic shock, as well as from healthy controls. Levels of EV S100A8/A9 were assayed via ELISA. To examine the effects and underlying mechanisms of septic shock EVs in acute lung injury, these EVs were administered intratracheally into wild-type C57BL/6 mice or mice with a deficiency of advanced glycation end-products (RAGE). In addition, a mouse model of polymicrobial sepsis was introduced using cecal ligation and puncture (CLP).</p><p><strong>Results: </strong>Levels of EV S100A8/A9 were significantly elevated in patients with sepsis or septic shock compared to healthy controls. Receiver operating characteristic (ROC) analysis demonstrated that EV S100A8/A9 effectively distinguished between septic shock and sepsis and had predictive potential for the development of ARDS. Notably, the levels of S100A8/A9 in EVs and alveolar macrophages from CLP mice were significantly higher than those in sham mice. Intratracheal administration of septic shock EVs directly induced acute lung injury and M1 macrophage polarization in a lipopolysaccharide-independent manner. Septic shock EVs were efficiently taken up by alveolar macrophages in vivo, leading to a significant increase in S100A8/A9 levels, which was inhibited by preincubating the EVs with an S100A8/A9 neutralizing antibody. Additionally, mice with deficiency in RAGE, a receptor for S100A8/A9, were partially protected from acute lung injury induced by septic shock EVs. In vitro, septic shock EVs prompted a proinflammatory response in bone marrow-derived macrophages. This response was blocked by preincubating the EVs with the S100A8/A9 neutralizing antibody.</p><p><strong>Conclusions: </strong>Our results suggested that EV S100A8/A9 has potential value in distinguishing septic shock from sepsis and predicting the development of ARDS. Septic shock EVs-induced lung injury is at least partially mediated through S100A8/A9-RAGE pathway, involving the activation of alveolar macrophages.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"107"},"PeriodicalIF":5.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11921512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658943","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":"Immunological landscape of children with Mycoplasma pneumoniae pneumonia in the post-COVID-19 era reveals distinctive severity indicators.","authors":"Ran Jia, Haiyan Guo, Aizhen Lu, Caiyan Zhang, Yuanyuan Qi, Dingmei Wang, Wen He, Qing Wang, Zimei Cheng, Yajing Gao, Guoping Lu, Libo Wang, Xiaowen Zhai, Jin Xu, Xiaobo Zhang, Yi Wang, Yufeng Zhou","doi":"10.1186/s12931-025-03189-7","DOIUrl":"10.1186/s12931-025-03189-7","url":null,"abstract":"<p><strong>Background: </strong>There is a recent global surge in Mycoplasma pneumoniae pneumonia (MPP). However, the key immune factors that contribute to the advancement of the disease remain unknown. Hence, we conducted this study to uncover the immunological profile in children affected by MPP.</p><p><strong>Methods: </strong>This study enrolled children visiting Children's Hospital of Fudan University from December 2023 to April 2024, including 34 healthy controls, 51 severe MPP (S-MPP), 27 non-severe MPP (NS-MPP), and 34 non-MPP pneumonia (NMP) cases. Their blood samples were analyzed using flow cytometry, multi-cytokine assays, and antibody detection methods.</p><p><strong>Results: </strong>Compared with NMP cases, MPP cases displayed higher frequencies of natural killer T cells, classical monocytes, and monocytic myeloid-derived suppressor cells. Notably, both T helper type 1 and activated regulatory T cells were more abundant in MPP cases, particularly in S-MPP, whereas CD8 + T cells displayed an exhaustion phenotype. The proportion of naïve B cells was reduced, while functional B cells, including memory B cells and plasmablasts, increased in S-MPP. 12 out of 95 clinical laboratory indicators and 3 out of 48 cytokines significantly differed between S-MPP and NS-MPP. Finally, we performed logistic and LASSO regression analyses and developed a predictive model for S-MPP that incorporates naïve B cell percentage from flow cytometry, cholinesterase from clinical laboratory tests, and interleukin 18 from the cytokine assay.</p><p><strong>Conclusions: </strong>These results clarify the immunological features in pediatric MPP cases, and identify novel markers for severe cases, providing insights for early diagnosis and immunological management in affected children.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"103"},"PeriodicalIF":5.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651573","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":"TLR5 activation in respiratory epithelial cells orchestrate mucosal Th17 response through both indirect and direct pathways.","authors":"Sijian Huang, Xu Li, Yuan Cao, Man Mou, Jianlun Li, Kexing Zhuo, Lijuan Wang, Zihang Zeng, Xianghong Wei, Chunlian Tang, Maohua Zhong","doi":"10.1186/s12931-025-03186-w","DOIUrl":"10.1186/s12931-025-03186-w","url":null,"abstract":"<p><strong>Background: </strong>Flagellin, a potent mucosal adjuvant administered via the intranasal route, has been widely recognized for its capacity to enhance immune responses against diverse pathogens. However, the effects and the underlying mechanisms by which flagellin modulates CD4⁺ T cell differentiation remain incompletely understood.</p><p><strong>Methods: </strong>Recombinant flagellin proteins, including full-length flagellin (SF) and a TLR5-binding deficient variant (SFΔ90-97), were produced and purified. An OT-II derived CD4⁺ T cell adoptive transfer model, a classical intranasal immunization model and dendritic cell (DC)-CD4⁺ T co-culturing system were used. The proliferation and differentiation of CD4⁺ T cells were analyzed using flow cytometry analysis. RNA sequencing and neutralizing antibody blocking experiments were performed to determine the essential cytokines involved in flagellin modulated Th17 differentiation.</p><p><strong>Results: </strong>Flagellin preferentially promotes Th17 cells differentiation. Respiratory epithelial cells (RECs), acting as sentinel cells, are the first to encounter exogenous stimuli during intranasal immunization. Flagellin stimulates the secretion of various soluble cytokines by binding to TLR5 on the surface of RECs, with GM-CSF facilitating the functional activation of airway DCs. GM-CSF-conditioned DCs exhibit upregulated IL-6 expression which in turn drives the polarization of naïve CD4⁺ T cells toward the Th17 phenotype. Furthermore, TLR5-regulated REC-derived IL-6 synergizes with TLR5-modulated DCs to amplify Th17 polarization signals, thereby enhancing the Th17 induction.</p><p><strong>Conclusion: </strong>Flagellin preferentially induced a Th17-enhanced immune response and RECs were highlighted its essential roles during this process through both indirect and direct pathways. For indirect pathway, RECs modulate DC function through GM-CSF. Moreover, RECs directly contribute to Th17 differentiation by secreting IL-6.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"104"},"PeriodicalIF":5.8,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11916947/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651574","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":"Omega-6 polyunsaturated fatty acids and their metabolites: a potential targeted therapy for pulmonary hypertension.","authors":"Jiayao Wang, Shunlian Hu, Yahan Xu, Tao Wang","doi":"10.1186/s12931-025-03172-2","DOIUrl":"10.1186/s12931-025-03172-2","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a progressive and life-threatening cardiopulmonary disease that is not uncommon. The modulation of the pulmonary artery (PA) involves various fatty acids, including omega-6 polyunsaturated fatty acids (ω-6 PUFAs) and ω-6 PUFAs-derived oxylipins. These lipid mediators are produced through cyclooxygenase (COX), lipoxygenase (LOX), cytochrome P450 (CYP450), and non-enzymatic pathways. They play a crucial role in the occurrence and development of PH by regulating the function and phenotype of pulmonary artery endothelial cells (PAECs), pulmonary artery smooth muscle cells (PASMCs), pulmonary fibroblasts, alveolar macrophages, and inflammatory cells. The alterations in ω-6 PUFAs and oxylipins are pivotal in causing vasoconstriction, pulmonary remodeling, and ultimately leading to right heart failure in PH. Despite the limited understanding of the PH pathophysiology, there is potential for novel interventions through dietary and pharmacological approaches targeting ω-6 PUFAs and oxylipins. The aim of this review is to summarize the significant advances in clinical and basic research on omega-6 PUFAs and oxylipins in pulmonary vascular disease, particularly PH, and to propose a potential targeted therapeutic modality against omega-6 PUFAs.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"102"},"PeriodicalIF":5.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634697","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":"Pharmacological inhibition of MutT homolog 1 (MTH1) in allergic airway inflammation as a novel treatment strategy.","authors":"Anna Adler, Jesper Bergwik, Médea Padra, Praveen Papareddy, Tobias Schmidt, Madelene Dahlgren, Robin Kahn, Ulrika Warpman Berglund, Arne Egesten","doi":"10.1186/s12931-025-03175-z","DOIUrl":"10.1186/s12931-025-03175-z","url":null,"abstract":"<p><strong>Background: </strong>Despite progress in the treatment of asthma, there is an unmet need for additional therapeutic strategies, not least to avoid side-effects of corticosteroids. The enzyme MutT homolog 1 (MTH1) hydrolyzes oxidized purines and prevents their insertion to DNA. Small molecule inhibition of MTH1 has shown promising therapeutic effects in both cancer and inflammatory conditions. In this study, a small molecule inhibitor of MTH1 (TH1579), was investigated in models of allergic inflammation.</p><p><strong>Methods: </strong>In vitro, effects on T cell proliferation and apoptosis were investigated. Furthermore, a murine model, using female BALB/c mice, of OVA-induced allergic airway inflammation was used to investigate effects from MTH1-inhibition in vivo.</p><p><strong>Results: </strong>Inhibition of MTH1 prevented T cell proliferation in vitro and induced apoptosis in isolated human CD4⁺ T cells. However, the viability of isolated human eosinophils was unaffected by MTH1 inhibition in vitro. Pharmacological inhibition of MTH1 in a murine model of allergic airway inflammation reduced mucus production, recruitment of inflammatory cells, such as T cells and eosinophils in the BAL fluid and lung tissue, reduced plasma levels of total IgE and OVA-specific IgE, IgG, and IgG1, as well as reduced IL-13 levels in BAL fluid, lung tissue and plasma.</p><p><strong>Conclusion: </strong>MTH1 inhibition reduced proliferation and promoted apoptosis of T cells in vitro. In vivo, TH1579 dampened the type 2 associated immune response in a murine model. These findings suggest that MTH1 could serve as a novel target to treat allergic airway inflammation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"101"},"PeriodicalIF":5.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634749","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":"Initial self-reported data on sleep and burnout in pulmonary, critical care and sleep medicine: an initiative from the Assembly on Sleep and Respiratory Neurobiology of the American Thoracic Society.","authors":"Sushmita Pamidi, Reena Mehra, Indira Gurubhagavatula, Mihaela Teodorescu","doi":"10.1186/s12931-025-03112-0","DOIUrl":"10.1186/s12931-025-03112-0","url":null,"abstract":"<p><strong>Rationale: </strong>Health worker burnout has reached crisis proportions, threatening workforce sustainability. Limited data exist on the burden of burnout in pulmonary, critical care and sleep medicine (PCCSM), a high-demand and strained specialty.</p><p><strong>Objective: </strong>At the Assembly of Sleep and Respiratory Neurobiology of the American Thoracic Society, we aimed to gather exploratory data on burnout in this group.</p><p><strong>Methods: </strong>During a dedicated series of five virtual town halls (THs), we polled the audience regarding self-reported burnout. Topics included the scope of the problem, role of sleep, impact on clinical and academic operations, contributors in vulnerable groups, and mitigation strategies.</p><p><strong>Results: </strong>A high proportion experienced burnout (45%) and 58% considered premature retirement. Insufficient sleep (53%) was common, most often due to excessive workload (57%) curtailing sleep through early morning meetings and electronic medical record (EMR) documentation. 36% also reported having a sleep disorder. Sleepiness (69%) and fatigue (58%) impaired work performance and patient care, and 54% reported a fatigue-related, personal-safety incident. Contributors to burnout in vulnerable communities included bias/discrimination (81%), harassment (44%) and assault (12%). Respondents predominantly endorsed organizational mitigating strategies: promoting a culture of \"recovery time\" (96%) and healthy sleep (86%), and periodic evaluation and accountability of leadership (86%).</p><p><strong>Conclusions: </strong>In this convenience sample of participants in a TH series regarding burnout in PCCSM, self-reported burnout was common. Sleep disturbance is a prevalent, under-recognized, but potentially modifiable contributor. The high reported rates of discrimination and harassment suggest that vulnerable groups may be at particular risk. To reduce burnout, system-level interventions aimed at transforming organizational culture and promoting leadership accountability were strongly endorsed.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"100"},"PeriodicalIF":5.8,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11909963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634696","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":"YAP/TAZ-mediated nuclear membrane rupture in promoting senescence of skeletal muscle associated with COPD.","authors":"Ge Gong, Shuping Shen, Shaoran Shen, Ran Wang, Tianping Zheng, Wei Xu, Jianqing Wu","doi":"10.1186/s12931-025-03170-4","DOIUrl":"10.1186/s12931-025-03170-4","url":null,"abstract":"<p><p>Patients with chronic obstructive pulmonary disease (COPD) often develop complications associated with sarcopenia; however, the underlying mechanisms remain unclear. Through a combination of in vitro and in vivo experiments, as well as bioinformatics analysis, our study identified YAP/TAZ as a key regulator of the aging phenotype in the skeletal muscle of COPD patients. In skeletal muscle affected by cigarette smoke-induced COPD, we observed significant reductions in YAP/TAZ levels, alongside markers indicative of skeletal muscle aging and dysfunction. Notably, overexpression of YAP/TAZ significantly improved these conditions. Our results suggest a novel mechanism whereby the maintenance of YAP/TAZ activity interacts with ACTR2 to preserve nuclear membrane integrity and reduce cytoplasmic dsDNA levels, thereby attenuating STING activation and cellular senescence. Additionally, we found that YAP is involved in the transcriptional regulation of the ACTR2 promoter region. Overall, preserving YAP/TAZ activity may help prevent skeletal muscle aging associated with COPD, representing a new strategy for intervening in COPD-related sarcopenia.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"98"},"PeriodicalIF":5.8,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617689","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}