American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Inhibition of Myocardin-related Transcription Factor A Ameliorates Pathological Remodeling of the Pressure-loaded Right Ventricle.","authors":"Mark F Rzepka, Sonja Raschzok, Xavier A Lee, Kana Yazaki, John Dauz, Mei Sun, Theo Meister, Linda Nghiem, Golam Kabir, Jean-Francois Desjardins, Wolfgang M Kuebler, Andras Kapus, Kim A Connelly, Mark K Friedberg","doi":"10.1165/rcmb.2023-0465OC","DOIUrl":"10.1165/rcmb.2023-0465OC","url":null,"abstract":"<p><p>Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions in which RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor-β1 signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. In this study, we investigated whether MRTF-A inhibition improves RV profibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure loading. Rats were assigned into either sham or PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75 mg/kg in a subset of PAB animals. Echocardiography and pressure-volume hemodynamics were obtained at a terminal experiment 6 weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and profibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, whereas diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of Yes-associated protein (YAP) and its paralog transcriptional coactivator with PDZ-binding motif (TAZ). We also confirmed, using a second-generation MRTF-A inhibitor CCG-203971, that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to transforming growth factor-β1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of profibrotic signaling in RV pressure loading and as potential targets to improve RV profibrotic remodeling.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"158-168"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008133","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":"Airway Epithelium-derived CXCL14 Promotes Eosinophil Accumulation in Allergic Airway Inflammation.","authors":"Takunori Ogawa, Yohei Maki, Shusaku Takahashi, Takeshi Ono, Kimiya Sato, Akihiko Kawana, Yoshifumi Kimizuka","doi":"10.1165/rcmb.2024-0142OC","DOIUrl":"10.1165/rcmb.2024-0142OC","url":null,"abstract":"<p><p>CXCL14 (C-X-C motif chemokine ligand 14) is expressed in the airway epithelial cells of patients with asthma. However, the mechanisms of CXCL14 secretion and its effects on asthma pathogenesis remain unclear. Here, we investigated the role of CXCL14 in allergic airway inflammation and its effects on eosinophil infiltration. Our findings showed that <i>Alternaria alternata</i>, a major environmental allergen, stimulated CXCL14 secretion from airway epithelial cells via reactive oxygen species generated in mitochondrial oxidative phosphorylation complexes, especially in oxidative phosphorylation complex II. <i>In vivo</i>, in a mouse model of allergic airway inflammation, intranasal administration of anti-CXCL14 antibody suppressed eosinophil and dendritic cell infiltration into the airways and goblet cell hyperplasia. <i>In vitro</i>, in human eosinophil-like cells, CXCL14 promoted cell migration through CXCR4 binding. Eosinophil CXCR4 expression was upregulated by <i>Alternaria</i> stimulation via reactive oxygen species production. These findings suggest that the cross-talk between <i>Alternaria</i>-stimulated airway epithelial CXCL14 secretion and eosinophil CXCR4 upregulation plays an important role in eosinophil infiltration into the lungs during allergic airway inflammation. In summary, this study demonstrates that CXCL14 could be a therapeutic target for allergic airway inflammation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"145-157"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981494","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":"February Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.72i2RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.72i2RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"72 2","pages":"iii-iv"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063245","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":"A-Kinase-Anchoring Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle.","authors":"Elham Javed, Ajay P Nayak, Arun K Jannu, Aaron H Cohen, Isabella Dewes, Ruping Wang, Dale D Tang, Deepak A Deshpande, Raymond B Penn","doi":"10.1165/rcmb.2023-0358OC","DOIUrl":"10.1165/rcmb.2023-0358OC","url":null,"abstract":"<p><p>AKAPs (A-kinase-anchoring proteins) act as scaffold proteins that anchor the regulatory subunits of the cAMP-dependent PKA (protein kinase A) to coordinate and compartmentalize signaling elements and signals downstream of Gs-coupled GPCRs (G protein-coupled receptors). The β₂AR (β-2-adrenoceptor), as well as the Gs-coupled EP2 and EP4 (E-prostanoid) receptor subtypes of the EP receptor subfamily, are effective regulators of multiple airway smooth muscle (ASM) cell functions whose dysregulation contributes to asthma pathobiology. Here, we identify specific roles of the AKAPs Ezrin and Gravin in differentially regulating PKA substrates downstream of the β₂AR, EP2R (EP2 receptor) and EP4R. Knockdown of Ezrin, Gravin, or both in primary human ASM cells caused differential phosphorylation of the PKA substrates VASP (vasodilator-stimulated phosphoprotein) and HSP20 (heat shock protein 20). Ezrin knockdown, as well as combined Ezrin and Gravin knockdown, significantly reduced the induction of phospho-VASP and phospho-HSP20 by β₂AR, EP2R, and EP4R agonists. Gravin knockdown inhibited the induction of phospho-HSP20 by β₂AR, EP2R, and EP4R agonists. Knockdown of Ezrin, Gravin, or both also attenuated histamine-induced phosphorylation of MLC20. Moreover, knockdown of Ezrin, Gravin, or both suppressed the inhibitory effects of Gs-coupled receptor agonists on cell migration in ASM cells. These findings demonstrate the role of AKAPs in regulating Gs-coupled GPCR signaling and function in ASM and suggest the therapeutic utility of targeting specific AKAP family members in the management of asthma.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"133-144"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981495","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":"Smooth Muscle Cell-Specific LKB1 Protects Against Sugen 5416/Hypoxia-induced Pulmonary Hypertension through Inhibition of BMP4.","authors":"Yan Liu, Xiaoping Ma, Lingli Lei, Lin Wang, Qiming Deng, Hanlin Lu, Hongxuan Li, Shuhui Tian, Xiaoteng Qin, Wencheng Zhang, Yuanyuan Sun","doi":"10.1165/rcmb.2023-0430OC","DOIUrl":"10.1165/rcmb.2023-0430OC","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a life-threatening syndrome associated with hyperproliferation of pulmonary artery smooth muscle cells (PASMCs), which exhibit features similar to those of cancer cells. Currently, there is no curative treatment for PH. LKB1 is known as a tumor suppressor gene with an antiproliferative effect on cancer cells. However, its role and mechanism in the development of PH remain unclear. Gain- and loss-of-function strategies were used to elucidate the mechanisms of LKB1 in regulating the occurrence and progression of PH. Sugen 5416/hypoxia (SuHx) PH model was utilized for <i>in vivo</i> study. We observed a decreased expression of LKB1 not only in the lung vessels of the SuHx mouse model but also in human PASMCs (HPASMCs) exposed to hypoxia. Smooth muscle-specific LKB1 knockout significantly aggravated SuHx-induced PH in mice. RNA-sequencing analysis revealed a substantial increase in bone morphogenetic protein 4 (BMP4) in the aortas of LKB1^SMKO mice compared with controls, identifying BMP4 as a novel target of LKB1. LKB1 knockdown in HPASMCs cultured under hypoxic conditions increased BMP4 protein level and HPASMC proliferation and migration. The coimmunoprecipitation analysis revealed that LKB1 directly modulates BMP4 protein degradation through phosphorylation. Therapeutically, suppressing BMP4 expression in smooth muscle cells alleviates PH in LKB1^SMKO mice. Our findings demonstrate that LKB1 attenuates PH by enhancing the lysosomal degradation of BMP4, thus suppressing the proliferation and migration of HPASMCs. Modulating the LKB1-BMP4 axis in smooth muscle cells could be a promising therapeutic strategy of PH.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"169-180"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139033","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":"Epigenomic Dysregulation in Youth Vapers: Implications for Disease Risk Assessment.","authors":"Stella Tommasi, Luciano Brocchieri, Silvia Tornaletti, Ahmad Besaratinia","doi":"10.1165/rcmb.2024-0207OC","DOIUrl":"10.1165/rcmb.2024-0207OC","url":null,"abstract":"<p><p>Despite the ongoing epidemic of youth vaping, the long-term health consequences of electronic cigarette use are largely unknown. We report the effects of vaping versus smoking on the oral cell methylome of healthy young vapers and smokers relative to nonusers. Whereas vapers and smokers differ in the number of differentially methylated regions (DMRs) (831 vs. 2,863), they share striking similarities in the distribution and patterns of DNA methylation, chromatin states, transcription factor binding motifs, and pathways. There is substantial overlap in DMR-associated genes between vapers and smokers, with the shared subset of genes enriched for transcriptional regulation, signaling, tobacco use disorders, and cancer-related pathways. Of significance is the identification of a common hypermethylated DMR at the promoter of <i>HIC1</i> (hypermethylated in cancer 1), a tumor suppressor gene frequently silenced in smoking-related cancers. Our data support a potential link between epigenomic dysregulation in youth vapers and disease risk. These novel findings have significant implications for public health and tobacco product regulation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"206-218"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141915853","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":"Tracheal Aspirate Metagenomics Reveals Association of Antibiotic Resistance with Nonpulmonary Sepsis Mortality.","authors":"Héctor Rodríguez-Pérez, Laura Ciuffreda, Tamara Hernández-Beeftink, Beatriz Guillen-Guio, David Domínguez, Almudena Corrales, Elena Espinosa, Julia Alcoba-Florez, Jose M Lorenzo-Salazar, Rafaela González-Montelongo, Jesús Villar, Carlos Flores","doi":"10.1165/rcmb.2024-0192LE","DOIUrl":"10.1165/rcmb.2024-0192LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"219-222"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455967","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":"Targeting Fibrosis in Right Ventricular Pressure Overload: Balancing on a Tightrope?","authors":"Jessie van Wezenbeek, Frances S de Man","doi":"10.1165/rcmb.2024-0377ED","DOIUrl":"10.1165/rcmb.2024-0377ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"119-121"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071821","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":"Circular RNA-Cacna1d Plays a Critical Role in Sepsis-induced Lung Injury by Sponging microRNA-185-5p.","authors":"Jiajia Wang, Jinhui Gao, Ling Ding, Xuanzhe Yang, Dong Zheng, Yuanyuan Zeng, Jianjie Zhu, Wei Lei, Cheng Chen, Zeyi Liu, Jian-An Huang","doi":"10.1165/rcmb.2024-0067OC","DOIUrl":"10.1165/rcmb.2024-0067OC","url":null,"abstract":"<p><p>The role of circular RNAs (circRNAs) in sepsis-induced lung injury is not clear. This study investigated the role and molecular mechanism of a novel circRNA in sepsis-induced lung injury and explored its prognostic value in patients with sepsis. In this study, aberrant circRNA expression profiling in lung tissues from mice with sepsis-induced lung injury was analyzed using high-throughput sequencing. circRNA-Cacna1d was verified by qRT-PCR, and its biological function in sepsis-induced lung injury was validated <i>in vitro</i> and <i>in vivo</i>. The interactions among circRNA-Cacna1d, microRNAs (miRNAs), and their downstream genes were verified. Furthermore, the clinical value of circRNA-Cacna1d in peripheral blood from patients with sepsis was also evaluated. We found that circRNA-Cacna1d expression was significantly increased in lung tissues of mice with sepsis and in microvascular endothelial cells after LPS challenge. circRNA-Cacna1d knockdown alleviated inflammatory response and ameliorated the permeability of vascular endothelium, thereby mitigating sepsis-induced lung injury and significantly improving the survival rate of mice with sepsis. Mechanistically, circRNA-Cacna1d directly interacted with miRNA-185-5p and functioned as a miRNA sponge to regulate the RhoA/ROCK1 signaling pathway. The expression level of circRNA-Cacna1d in patients with early sepsis was significantly higher than that in the healthy control subjects. Higher levels of circRNA-Cacna1d in patients with sepsis were associated with increased disease severity and poorer outcomes. In conclusions, circRNA-Cacna1d may play a role in sepsis-induced lung injury by regulating the RhoA/ROCK1 axis by acting as a miRNA-185-5p sponge. circRNA-Cacna1d is a potential therapeutic target for sepsis-induced lung injury and a prognostic biomarker in sepsis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"181-194"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139021","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":"Airway Smooth Muscle Dysfunction in Asthma: Releasing the Anchor.","authors":"Anthony N Gerber","doi":"10.1165/rcmb.2024-0374ED","DOIUrl":"10.1165/rcmb.2024-0374ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"117-118"},"PeriodicalIF":5.9,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034938","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}