Respiratory Research最新文献

{"title":"Diagnosis of early idiopathic pulmonary fibrosis: current status and future perspective.","authors":"Xinya Wang, Xinrui Xia, Yihan Hou, Huaizhe Zhang, Wenyang Han, Jianqi Sun, Feng Li","doi":"10.1186/s12931-025-03270-1","DOIUrl":"10.1186/s12931-025-03270-1","url":null,"abstract":"<p><p>The standard approach to diagnosing idiopathic pulmonary fibrosis (IPF) includes identifying the usual interstitial pneumonia (UIP) pattern via high resolution computed tomography (HRCT) or lung biopsy and excluding known causes of interstitial lung disease (ILD). However, limitations of manual interpretation of lung imaging, along with other reasons such as lack of relevant knowledge and non-specific symptoms have hindered the timely diagnosis of IPF. This review proposes the definition of early IPF, emphasizes the diagnostic urgency of early IPF, and highlights current diagnostic strategies and future prospects for early IPF. The integration of artificial intelligence (AI), specifically machine learning (ML) and deep learning (DL), is revolutionizing the diagnostic procedure of early IPF by standardizing and accelerating the interpretation of thoracic images. Innovative bronchoscopic techniques such as transbronchial lung cryobiopsy (TBLC), genomic classifier, and endobronchial optical coherence tomography (EB-OCT) provide less invasive diagnostic alternatives. In addition, chest auscultation, serum biomarkers, and susceptibility genes are pivotal for the indication of early diagnosis. Ongoing research is essential for refining diagnostic methods and treatment strategies for early IPF.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"192"},"PeriodicalIF":5.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102935","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":"Transcription factor ZNF266 suppresses cancer progression by modulating CA9-mediated intracellular pH alteration in lung adenocarcinoma.","authors":"Shencheng Ren, Junkan Zhu, Guangyao Shan, Jiaqi Liang, Yunyi Bian, Han Lin, Haochun Shi, Binyang Pan, Guangyin Zhao, Huiqin Yang, Xiaolong Huang, Cheng Zhan, Di Ge, Guoshu Bi","doi":"10.1186/s12931-025-03278-7","DOIUrl":"10.1186/s12931-025-03278-7","url":null,"abstract":"<p><strong>Background: </strong>Lung cancer remains the leading cause of cancer-related mortality globally, with lung adenocarcinoma (LUAD) being the most prevalent subtype. Despite extensive research efforts, the role of transcription factors in LUAD progression remains largely uncharacterized. In this study, we focused on ZNF266, a transcription factor whose impacts on LUAD have not been investigated.</p><p><strong>Methods: </strong>Using high-throughput sequencing data, we observed a significant downregulation of ZNF266 expression in LUAD tissues. To validate this finding, we conducted a retrospective analysis of nearly three thousand LUAD patients' data from public databases and our institution. Functional studies were performed using cell lines, organoids, and xenograft models to assess the role of ZNF266 in LUAD progression. RNA sequencing, chromatin immunoprecipitation, DNA pull-down assays, and dual-luciferase reporter assays were employed to elucidate the underlying mechanism. Additionally, adeno-associated virus (AAV)-mediated overexpression of ZNF266 was used to evaluate its therapeutic potential.</p><p><strong>Results: </strong>Patients with low ZNF266 expression had poorer prognosis compared to those with high expression. ZNF266 inhibits the malignant phenotypes of LUAD, including proliferation, migration, and invasion. Mechanistically, ZNF266 binds to the promoter region of CA9, suppressing its transcription. This leads to a reduction in intracellular pH and subsequent inhibition of the mTOR signaling pathway, which is crucial for cancer cell growth and survival. Furthermore, AAV-mediated overexpression of ZNF266 significantly inhibited tumor growth in patient-derived xenograft models.</p><p><strong>Conclusions: </strong>Our study demonstrated that ZNF266 inhibits LUAD progression in a pH-dependent manner via modulating CA9 expression, uncovering its therapeutic significance for LUAD treatment.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"191"},"PeriodicalIF":5.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102939","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":"Decoding mechanisms and protein markers in lung-brain axis.","authors":"Shiqian Huang, Yuxi Zhou, Haipeng Ji, Tianhao Zhang, Shiya Liu, Lulin Ma, Daling Deng, Yuanyuan Ding, Linlin Han, Shaofang Shu, Yu Wang, Xiangdong Chen","doi":"10.1186/s12931-025-03272-z","DOIUrl":"10.1186/s12931-025-03272-z","url":null,"abstract":"<p><strong>Background: </strong>The lung-brain axis represents a complex bidirectional communication network that is pivotal in the crosstalk between respiratory and neurological functions. This review summarizes the current understanding of the mechanisms and protein markers that mediate the effects of lung diseases on brain health.</p><p><strong>Main findings: </strong>In this review, we explore the mechanisms linking lung injury to neurocognitive impairments, focusing on neural pathways, immune regulation and inflammatory responses, microorganism pathways, and hypoxemia. Specifically, we highlight the role of the vagus nerve in modulating the central nervous system response to pulmonary stimuli; Additionally, the regulatory function of the immune system is underscored, with evidence suggesting that lung-derived immune mediators can traverse the blood-brain barrier, induce neuroinflammation and cognitive decline; Furthermore, we discuss the potential of lung microbiota to influence brain diseases through microbial translocation and immune activation; Finally, the impact of hypoxemia is examined, with findings indicating that it can exacerbate cerebral injury via oxidative stress and impaired perfusion. Moreover, we analyze how pulmonary conditions, such as pneumonia, ALI/ARDS, and asthma, contribute to neurological dysfunction. Prolonged mechanical ventilation can also contribute to cognitive impairment. Conversely, brain diseases (e.g., stroke, traumatic brain injury) can lead to acute respiratory complications. In addition, protein markers such as TLR4, ACE2, A-SAA, HMGB1, and TREM2 are crucial to the lung-brain axis and correlate with disease severity. We also discuss emerging therapeutic strategies targeting this axis, including immunomodulation and microbiome engineering. Overall, understanding the lung-brain interplay is crucial for developing integrated treatment strategies and improving patient outcomes. Further research is needed to elucidate the molecular mechanisms and foster interdisciplinary collaboration.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"190"},"PeriodicalIF":5.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12090670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144102800","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":"Geranylgeranyl diphosphate synthase deficiency impairs efferocytosis and resolution of acute lung injury.","authors":"Jiajia Jin, Lihong Ma, Lulu Li, Xinyu Zhou, Suhua Zhu, Kaikai Shen, Qiuli Xu, Bei Jiang, Yanli Gu, Qianshan Ding, Hong Qian, Tangfeng Lv, Yong Song","doi":"10.1186/s12931-025-03241-6","DOIUrl":"10.1186/s12931-025-03241-6","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) are major causes of mortality of critically ill patients. Impaired macrophage-mediated clearance of apoptotic cells (efferocytosis) in ARDS contributes to prolonged inflammation, yet the underlying mechanisms remain unclear. In this study, we investigated the role of geranylgeranyl diphosphate synthase (GGPPS) in efferocytosis during lung injury resolution. We identified dynamic changes in GGPPS expression in lung macrophages and circulating monocytes throughout the progression and resolution phases of acute lung injury (ALI). Myeloid-specific GGPPS knockout mice exhibited prolonged lung inflammation, increased accumulation of apoptotic neutrophils, a higher number of recruited macrophages, and a reduced number of resident macrophages. Notably, recruited macrophages play a dominant role in efferocytosis compared to resident macrophages. GGPPS deficiency suppressed efferocytosis in both macrophage subsets in vivo and in vitro. Mechanistically, GGPPS knockout disrupted AXL signaling in recruited macrophages. Importantly, administration of geranylgeraniol (GGOH) rescued the delayed resolution of lung injury, restored efferocytosis, and increased the suppressed AXL expression in CKO mice. Collectively, this study identifies GGPPS as a key regulator of AXL-mediated efferocytosis in recruited macrophages, highlighting its potential as a therapeutic target to accelerate ARDS resolution.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"189"},"PeriodicalIF":5.8,"publicationDate":"2025-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12084987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086841","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":"Inhibition of DLK1 regulates AT2 differentiation and alleviates established pulmonary fibrosis by upregulating TTF-1/CLDN6.","authors":"Yinzhen Li, Chen Zhou, Jiaxing Sun, Enhao Wang, Chunmei Wang, Xuan Liu, Xiaohui Zhou, Jianwen Bai","doi":"10.1186/s12931-025-03264-z","DOIUrl":"10.1186/s12931-025-03264-z","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is a devastating age-related disease with unknown causes and limited effective treatment. Dysregulation of Alveolar Type 2 (AT2) cells facilitates the initiation of IPF. While differentiation of AT2 into AT1 is necessary for restoring alveolar epithelium. Delta-like non-canonical Notch ligand 1 (DLK1) is a paternally imprinted gene that controls stem cell differentiation. However, the role of DLK1 on AT2 during lung fibrosis remains unclear.</p><p><strong>Methods: </strong>Lung specimens from 11 patients with IPF or contemporaneous non-IPF controls were collected to determine DLK1 expression. The murine model of bleomycin (BLM) -induced pulmonary fibrosis and cell models of transforming growth factor-beta (TGF-β)-treated A549, MRC5 or primary lung fibroblasts (PLFs) were established. Epithelial DLK1 knockdown mice were constructed by an alveolar epithelial -specific adeno-associated virus (AAV) 6 vector system. Besides, primary AT2 cells were isolated from SPC-EGFP mice and cultured in 2D and 3D organoids.</p><p><strong>Results: </strong>In the present study, we found that DLK1, predominantly expressed in AT2 cells, was upregulated in both IPF lungs and the murine fibrotic lung induced by BLM. AAV-mediated epithelial-specific knockdown of DLK1 promoted the proliferation and differentiation of AT2 into AT1 and alleviated the established lung fibrosis in murine BLM-induced models. In addition, recombinant DLK1 inhibited the renewal of AT2 and aggravated TGF-β-induced fibrosis in vitro, which can be rescued by si-DLK1 intervention. Mechanically, conditional knockdown of DLK1 upregulated TTF-1, a transcriptional factor that controls AT2 differentiation via CLDN6.</p><p><strong>Conclusion: </strong>DLK1 inhibition regulates AT2 differentiation and contributes to the mitigation of established fibrosis via TTF-1/CLDN6 pathway, which suggests that DLK1 may be a therapeutic target for IPF.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"188"},"PeriodicalIF":5.8,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12085069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144086930","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":"Angiotensin receptor blockers use and lung cancer risk in Chinese patients with chronic obstructive pulmonary disease: a population-based cohort study.","authors":"Wenhao Li, Qingqing Yang, Yahong Chen, Yexiang Sun, Peng Shen, Feng Sun, Jinzhu Jia","doi":"10.1186/s12931-025-03248-z","DOIUrl":"10.1186/s12931-025-03248-z","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is one of the most prevalent specific chronic respiratory diseases. It could worsen the development of cardiovascular diseases (CVD) and lung cancer. We aimed to elucidate the relationship between the use of angiotensin receptor blockers (ARBs) and the incidence of lung cancer among the COPD population in China.</p><p><strong>Methods: </strong>This retrospective cohort included COPD patients identified by the international classification of diseases 10th edition (ICD-10) codes in the Yinzhou Regional Health Care Database. The use of ARBs was defined according to the use and cumulative use. The lung cancer was defined by ICD-10 code (up to 2023). Time-varying Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of the use of ARBs on the risk of lung cancer.</p><p><strong>Results: </strong>This population-based COPD cohort comprised 25,436 patients with an average age of 68.2 years (standard deviation [SD]: 12.59 years), of which 60.6% were male. A total of 8,611 patients received at least one prescription for ARBs. After adjusting for multiple covariates, the results showed that cumulative annual exposure to ARBs was associated with a reduced risk of lung cancer (HR: 0.93, 95% CI: 0.90-0.97). The results of sensitivity analyses and negative control exposure analyses indicated that the associations were largely consistent and less likely to be influenced by unobserved confounding.</p><p><strong>Conclusions: </strong>The use of ARBs may reduce the risk of lung cancer among patients with COPD.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"186"},"PeriodicalIF":5.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081520","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":"Correction: The burden of cough in idiopathic pulmonary fibrosis and other interstitial lung diseases: a systematic evidence synthesis.","authors":"Rhiannon Green, Michael Baldwin, Nick Pooley, Kate Misso, Maureen Pmh Rutten-van Mölken, Nina Patel, Marlies S Wijsenbeek","doi":"10.1186/s12931-025-03227-4","DOIUrl":"10.1186/s12931-025-03227-4","url":null,"abstract":"","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"185"},"PeriodicalIF":5.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081528","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":"Cryopreservation of human lung tissue for 3D ex vivo analysis.","authors":"Nickolas G Diodati, Ganlin Qu, Borna Mehrad, Matthew A Schaller","doi":"10.1186/s12931-025-03265-y","DOIUrl":"10.1186/s12931-025-03265-y","url":null,"abstract":"<p><p>Ex vivo culture techniques have assisted researchers in narrowing the translational gap between the lab and the clinic by allowing the study of biology in human tissues. In pulmonary biology, however, the availability of such tissues is a limiting factor in experimental design and constrains the reproducibility and replicability of these models as scientifically rigorous complements to in vitro or in vivo methods. Cryopreservation of human lung tissue is a strategy to address these limitations by generating cryopreserved biobanks of donors in the ex vivo study of pulmonary biology. Modern cryopreservation solutions, incorporating blends of cryoprotective extracellular macromolecules and cell-permeant non-toxic small molecules, have enabled the long-term storage of human lung tissue, allowing repeated experiments in the same donors and the simultaneous study of the same hypothesis across multiple donors, therefore granting the qualities of reproducibility and replicability to ex vivo systems. Specific considerations are required to properly maintain fundamental aspects of tissue structure, properties, and function throughout the cryopreservation process. The examples of existing cryopreservation systems successfully employed to amass cryobanks, and ex vivo culture techniques compatible with cryopreservation, are discussed herein, with the goal of indicating the potential of cryopreservation in ex vivo human lung tissue culture and highlighting opportunities for cryopreservation to expand the utility of ex vivo human lung culture systems in the pursuit of clinically relevant discoveries.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"187"},"PeriodicalIF":5.8,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12082924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081566","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":"Impact of coal mine dust exposure and cigarette smoking on lung disease in Appalachian coalminers.","authors":"Rahul G Sangani, Andrew J Ghio, Vishal Deepak, Javeria Anwar, Vinita Vaidya, Zalak Patel, Amirahwaty Abdullah","doi":"10.1186/s12931-025-03260-3","DOIUrl":"https://doi.org/10.1186/s12931-025-03260-3","url":null,"abstract":"<p><strong>Introduction: </strong>Interactions have been demonstrated between cigarette smoking (CS) and occupational exposures to several particles. This study tested the postulate that CS interacts with coal mine dust exposure to impact and change radiological and histological endpoints of coal mine dust lung disease.</p><p><strong>Methods: </strong>A retrospective evaluation of coalminers with a high-resolution computed tomography (HRCT) of the chest was conducted at West Virginia University Hospital (2015- 2022). There was a consensus review of both radiology and histology findings and their comparative analysis with a non-miner surgical resection cohort collected from thoracic oncology clinic.</p><p><strong>Results: </strong>The study cohort (n=556) was divided into groups: coal-/smoking- (8.3%), coal-/smoking+ (26.6%), coal+/smoking- (22.3%), and coal+/smoking+ (42.8%). Miners were older males with a median duration of coal mine work (CMW) of 30-years. Ever-smokers (66% of miner cohort and 76% of non-miner cohort) smoked 35 and 28 composite pack years (CPY) respectively, where miners had greater intensity of smoking (22 vs 18 cigarettes/day) compared to non-miners. On HRCT, 1/3^rd and 1/5^th of miners had simple and complicated coal workers' pneumoconiosis (sCWP and cCWP), respectively. 35% of ever-smoking miners had radiologic patterns for probable usual interstitial pneumonitis, nonspecific interstitial pneumonitis, desquamative interstitial pneumonitis, and combined pulmonary fibrosis and emphysema. Radiologically, both coal-/smoking+ and coal+/smoking+ showed excessive emphysema (70-80%). Histologically, miners had more fibrosis (47% and 50% in coal+/smoking- and coal+/smoking+ vs. 11% and 28% in coal-/smoking- and coal-/smoking+). Never-smoking miners demonstrated more histological evidence of CWP than ever-smokers (60% and 27%); in addition, they had radiologic and histologic emphysema (30%), radiologic interstitial lung disease (ILD) (14.5%) and histologic evidence of fibrosis (47%). Ever-smokers demonstrated histologic emphysema more frequently (33% and 67% in coal+/smoking- and coal+/smoking+ vs. 24% and 72% in coal-/smoking- and coal-/smoking+). Logistic regression modeling showed the following associations: radiologic and histologic emphysema with CPY; histologic fibrosis, any ILD (not including RB-ILD), CPFE and anthracosis with both CPY and CMW; radiologic RB-ILD inclusive of small-opacities, cCWP with both CMW and silica; and sCWP and pulmonary artery dilation with CMW. Interestingly, CPY≥30 negatively correlated with radiologic cCWP and histologic CWP. Mortality was increased in smokers (14% and 29% in coal+/smoking- and coal+/smoking+ vs. 4% and 20% in coal-/smoking- and coal-/smoking+) with predictors being radiologic ILD, histologic CWP, and related co-morbid diseases including COPD, chronic kidney disease, and gastroesophageal reflux.</p><p><strong>Conclusion: </strong>CS demonstrated a major impact on","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"184"},"PeriodicalIF":5.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144081580","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":"Ovarian Cancer G protein-coupled receptor-1 signaling bias dictates anti-contractile effect of benzodiazepines on airway smooth muscle.","authors":"Dominic R Villalba, Arun K Jannu, Elham Javed, Isha Dandekar, Ruping Wang, Deepak A Deshpande, Steven S An, Reynold A Panettieri, Dale D Tang, Raymond B Penn, Ajay P Nayak","doi":"10.1186/s12931-025-03268-9","DOIUrl":"10.1186/s12931-025-03268-9","url":null,"abstract":"<p><strong>Background: </strong>We recently reported that the ovarian cancer G protein-coupled receptor-1 (OGR1) can be pharmacologically biased with specific benzodiazepines to couple with distinct heterotrimeric G proteins in human airway smooth muscle (ASM) cells. Lorazepam stimulated both G_s and G_q signaling via OGR1, whereas sulazepam only stimulated G_s signaling in ASM cells. The present study sought to determine the effects of sulazepam and lorazepam on contraction of human precision cut lung slices (hPCLS), and detail the biochemical mechanisms mediating these effects.</p><p><strong>Methods: </strong>Models of histamine (His) -stimulated contraction included imaging of ex vivo human precision cut lung slices (hPCLS) and Magnetic Twisting Cytometry (MTC) analysis of human ASM cell stiffness. To explore mechanisms of regulation, we examined effects on myosin light chain (pMLC) phosphorylation and PKA activity in primary human ASM cultures, as well as actin cytoskeleton integrity as defined by changes in the ratio of F to G actin assessed by immunofluorescence.</p><p><strong>Results: </strong>In a dose-dependent manner, sulazepam relaxed His-contracted hPCLS and reduced baseline cell stiffness. Lorazepam did not relax His-contracted hPCLS, and only at a maximal dose (100 μM) did lorazepam relax baseline cell stiffness. The G_s-biased ligand sulazepam stimulated PKA activity as evidenced by significant induction of VASP and HSP20 phosphorylation, which was associated with significant inhibition of His-induced pMLC phosphorylation. Conversely, the balanced ligand lorazepam did not significantly increase HSP20 phosphorylation or VASP phosphorylation and did not significantly inhibit His-induced MLC phosphorylation. Sulazepam was also able to inhibit histamine induced F-actin formation.</p><p><strong>Conclusions: </strong>The G_s-biased OGR1 ligand sulazepam relaxed contracted ASM in both tissue- and cell- based models, via inhibition of MLC phosphorylation in a PKA-dependent manner and through inhibition of actin stress fiber formation. The relative inability of the balanced ligand lorazepam to influence ASM contractile state was likely due to competitive actions of concomitant G_q and G_s signaling.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"26 1","pages":"183"},"PeriodicalIF":5.8,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12076885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043046","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}