American Journal of Respiratory Cell and Molecular Biology最新文献_第6页

A-Kinase-Anchoring-Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle. A-Kinase-Anchoring 蛋白亚型对人气道平滑肌中 GPCR 信号和功能的不同调控。

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-14 DOI: 10.1165/rcmb.2023-0358OC

Elham Javed, Ajay P Nayak, Arun K Jannu, Aaron H Cohen, Isabella Dewes, Ruping Wang, Dale D Tang, Deepak A Deshpande, Raymond B Penn

{"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":"A-kinase-anchoring proteins (AKAPs) act as scaffold proteins that anchor the regulatory subunits of the cAMP-dependent protein kinase A (PKA) to coordinate and compartmentalize signaling elements and signals downstream of Gs-coupled G protein-coupled receptors (GPCRs). The beta-2-adrenoceptor (β2AR), as well as the Gs-coupled EP2 and EP4 receptor subtypes of the E-prostanoid (EP) receptor subfamily, are effective regulators of multiple airway smooth muscle (ASM) cell functions whose dysregulation contributes of asthma pathobiology. Here, we identify specific roles of the AKAPs Ezrin and Gravin, in differentially regulating PKA substrates downstream of the β2AR, EP2 receptor (EP2R) and EP4 receptor (EP4R). Knockdown of Ezrin, Gravin, or both in primary human ASM cells caused differential phosphorylation of the PKA substrates vasodilator-stimulated phosphoprotein (VASP) and heat shock protein 20 (HSP20). Ezrin knockdown, as well as combined Ezrin + 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.","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-14","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}

引用次数: 0

Deciphering the Complexities of Pulmonary Hypertension: The Emergent Role of Single-Cell Omics. 解读肺动脉高压的复杂性：单细胞分子生物学的新作用。

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-14 DOI: 10.1165/rcmb.2024-0145PS

Ruslan Rafikov, Vinicio de Jesus Perez, Aleksandr Dekan, Tatiana V Kudryashova, Olga Rafikova

{"title":"Deciphering the Complexities of Pulmonary Hypertension: The Emergent Role of Single-Cell Omics.","authors":"Ruslan Rafikov, Vinicio de Jesus Perez, Aleksandr Dekan, Tatiana V Kudryashova, Olga Rafikova","doi":"10.1165/rcmb.2024-0145PS","DOIUrl":"10.1165/rcmb.2024-0145PS","url":null,"abstract":"Expanding upon the critical advancements brought forth by single-cell omics in pulmonary hypertension (PH) research, this review delves deep into how these technologies have been piloted in a new era of understanding this complex disease. By leveraging the power of single cell transcriptomics (scRNA-seq), researchers can now dissect the complicated cellular ecosystem of the lungs, examining the key players such as endothelial cells, smooth muscle cells, pericytes, and immune cells, and their unique roles in the pathogenesis of PH. This more granular view is beyond the limitations of traditional bulk analysis, allowing for the identification of novel therapeutic targets previously obscured in the aggregated data. Connectome analysis based on single-cell omics of the cells involved in pathological changes can reveal a clearer picture of the cellular interactions and transitions in the cellular subtypes. Furthermore, the review acknowledges the challenges that lie ahead, including the need for enhancing the resolution of scRNA-seq to capture even finer details of cellular changes, overcoming logistical barriers in processing human tissue samples, and the necessity of integrating diverse omics approaches to fully comprehend the molecular underpinnings of PH. The promise of these single-cell technologies is immense, offering the potential for targeted drug development and the discovery of biomarkers for early diagnosis and disease monitoring. Through these advancements, the field moves closer to realizing the goal of precision medicine for patients with PH.","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981496","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}

引用次数: 0

The Hidden Link Between Chronic Kidney Disease and Lung Injury. 慢性肾病与肺损伤之间的隐秘联系

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-13 DOI: 10.1165/rcmb.2024-0326ED

Elizabeth F Redente

引用次数: 0

"It's A Trap!": Eosinophils Caught Between Pro- and Anti-inflammatory Responses. "这是一个陷阱！"：嗜酸性粒细胞夹在促炎和抗炎反应之间。

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-13 DOI: 10.1165/rcmb.2024-0325ED

Akshat Sharma, Amali E Samarasinghe

引用次数: 0

Mapping Host-Microbe Omics Interactions in Severe Community-acquired Pneumonia. 绘制严重社区获得性肺炎中宿主-微生物 Omics 相互作用的图谱

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-13 DOI: 10.1165/rcmb.2024-0346ED

Hong-Long James Ji, Gang Liu

引用次数: 0

One More Negative Regulator of AC6: S-Nitrosylation. AC6 的另一个负调控因子：S-亚硝基化

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-13 DOI: 10.1165/rcmb.2024-0350ED

Isabella Cattani-Cavalieri, Rennolds S Ostrom

引用次数: 0

Sex Matters: A Deep Dive into Sex Differences in COPD. 性别问题：深入研究慢性阻塞性肺病的性别差异。

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-13 DOI: 10.1165/rcmb.2024-0344ED

Yun Michael Shim, Jamie L MacLeod

引用次数: 0

Epigenomic Dysregulation in Youth Vapers: Implications for Disease Risk Assessment. 青少年吸食者表观基因组失调：对疾病风险评估的影响。

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-12 DOI: 10.1165/rcmb.2024-0207OC

Stella Tommasi, Luciano Brocchieri, Silvia Tornaletti, Ahmad Besaratinia

{"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":"https://doi.org/10.1165/rcmb.2024-0207OC","url":null,"abstract":"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 non-users. Whereas vapers and smokers differ in 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 \"Hypermethylated In Cancer 1\" (HIC1), 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.","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-12","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}

引用次数: 0

Mechanical Stretch Induces Senescence of Lung Epithelial Cells and Drives Fibroblast Activation by Paracrine Mechanisms. 机械拉伸诱导肺上皮细胞衰老并通过旁分泌机制驱动成纤维细胞活化

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-12 DOI: 10.1165/rcmb.2023-0449OC

Paula Martín-Vicente, Cecilia López-Martínez, Inés López-Alonso, Sara M Exojo-Ramírez, Israel David Duarte-Herrera, Laura Amado-Rodríguez, Irene Ordoñez, Elias Cuesta-Llavona, Juan Gómez, Natalia Campo, Cecilia M O'Kane, Daniel F McAuley, Covadonga Huidobro, Guillermo M Albaiceta

{"title":"Mechanical Stretch Induces Senescence of Lung Epithelial Cells and Drives Fibroblast Activation by Paracrine Mechanisms.","authors":"Paula Martín-Vicente, Cecilia López-Martínez, Inés López-Alonso, Sara M Exojo-Ramírez, Israel David Duarte-Herrera, Laura Amado-Rodríguez, Irene Ordoñez, Elias Cuesta-Llavona, Juan Gómez, Natalia Campo, Cecilia M O'Kane, Daniel F McAuley, Covadonga Huidobro, Guillermo M Albaiceta","doi":"10.1165/rcmb.2023-0449OC","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0449OC","url":null,"abstract":"Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift towards a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. Here, we explore the contribution of mechanical stretch as trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared to senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed notch signaling as a potential responsible for the epithelial-mesenchymal crosstalk, as blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair.","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970431","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}

引用次数: 0

Adenylyl Cyclase Isoform 6 in the Pulmonary Artery Is Inhibited by Hypoxia via Cysteine Nitrosylation. 肺动脉腺苷酸环化酶异构体 6 通过半胱氨酸亚硝基化受缺氧抑制

IF 5.9 2区医学

American Journal of Respiratory Cell and Molecular Biology Pub Date : 2024-08-07 DOI: 10.1165/rcmb.2023-0447OC

Saeid Maghsoudi, Vikram Bhatia, Martha Hinton, Nisha Singh, Mohd Wasif Khan, Prashen Chelikani, Shyamala Dakshinamurti

{"title":"Adenylyl Cyclase Isoform 6 in the Pulmonary Artery Is Inhibited by Hypoxia via Cysteine Nitrosylation.","authors":"Saeid Maghsoudi, Vikram Bhatia, Martha Hinton, Nisha Singh, Mohd Wasif Khan, Prashen Chelikani, Shyamala Dakshinamurti","doi":"10.1165/rcmb.2023-0447OC","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0447OC","url":null,"abstract":"Persistent pulmonary hypertension of the newborn (PPHN) is a hypoxic disorder of pulmonary vascular relaxation, mediated in part by adenylyl cyclase (AC). Neonatal pulmonary arteries (PA) express mainly AC6 isoform, followed by AC3, 7 and 9. AC6 expression is upregulated in hypoxia. We reported AC enzyme inhibition due to S-nitrosylation in PPHN PA, and in PA myocytes exposed to hypoxia. We hypothesize that hypoxia promotes cysteine thiol nitrosylation of AC6, impairing cAMP production. HEK293T cells stably expressing AC isoforms (AC3, 5, 6, 7, 9), or cysteine-to-alanine mutants AC6_C1004A, AC6_C1145A or AC6_C447A were cultured in normoxia (21% O2) or hypoxia (10% O2) for 72 hours, or challenged with nitroso donor S-nitrosocysteine (CysNO). AC activity was determined by real-time live-cell cAMP measurement (cADDis assay) or terbium-norfloxacin AC catalytic assay, with or without challenge by allosteric agonist forskolin; protein S-nitrosylation detected by biotin switch method and quantified by affinity precipitation. Only AC6 catalytic activity is inhibited in hypoxia or by S-nitrosylating agent, in presence or absence of forskolin; impaired cAMP production in hypoxia correlates with increased cysteine nitrosylation of AC6. Selective AC6 inhibition in pulmonary artery myocytes extinguishes AC sensitivity to inhibition by hypoxia. Alanine substitution of C1004, but not of other cysteines, decreases S-nitrosylation of AC6. AC activity is diminished in AC6_C1004A compared to AC6 wild type. Substitution of C1004 also extinguishes the inhibition of AC6 by hypoxia. We conclude AC6 is uniquely S-nitrosylated in hypoxia, inhibiting its activity and cAMP generation. We speculate that S-nitrosylation at C1004 may inhibit AC6 interaction with Gαs, playing a role in PPHN pathophysiology.","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896540","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}

引用次数: 0