American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"No Pain, No Gain (and No Cough)?: Discrete Brainstem Nuclei Coordinate Reflexive Cough and Pain Responses.","authors":"Ubaldo De La Torre, Matthew G Drake","doi":"10.1165/rcmb.2024-0432ED","DOIUrl":"10.1165/rcmb.2024-0432ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493009","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":"Multiple Neural Networks Originating from the Lateral Parabrachial Nucleus Modulate Cough-like Behavior and Coordinate Cough with Pain.","authors":"Mingtong Lin, Mingzhe Liu, Chuqin Huang, Shuirong Shen, Zhe Chen, Kefang Lai","doi":"10.1165/rcmb.2024-0084OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0084OC","url":null,"abstract":"<p><p>It has been reported that experimental pain could diminish cough sensitivity, the lateral parabrachial nucleus (LPBN) coordinated pain with breathing, whether LPBN regulates cough-like behaviors and pain-induced changes in cough sensitivity remains elusive. We investigated the roles of LPBN γ-aminobutyric acidergic (GABAergic) and glutamatergic neurons in the regulation of cough sensitivity and its relationship with pain in mice via chemogenetic approaches. Adeno-associated virus (AAV) tracing combined with chemogenetics was used to map the projections of LPBN GABAergic and glutamatergic neurons to the periaqueductal gray (PAG). LPBN neurons were activated by cough challenge, and nonspecific inhibition of LPBN neurons suppressed cough-like behavior. Chemogenetic suppression of LPBN GABAergic neurons reduced cough sensitivity in mice, whereas suppression of LPBN glutamatergic neurons counteracted the pain-driven decrease in cough sensitivity, so did silencing LPBN glutamatergic neurons projecting to the PAG. Our data suggest that GABAergic and glutamatergic neurons in the LPBN critically are involved in cough sensitivity and coordinate pain with cough through inhibitory or activating mechanisms at the midbrain level.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455965","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":"The RNA Binding Protein Tristetraprolin Contributes to <i>CFTR</i> mRNA Stability in Cystic Fibrosis.","authors":"Alexandra Pommier, Solenne Bleuse, Karine Deletang, Jessica Varilh, Marion Nadaud, Prisca Boisguerin, Arnaud Bourdin, Magali Taulan-Cadars","doi":"10.1165/rcmb.2023-0209OC","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0209OC","url":null,"abstract":"<p><p>Cystic Fibrosis (CF) is the most common inherited disorder and is characterized by an inflammatory phenotype. Here, we found that in bronchial epithelium reconstituted form lung tissue biopsies from patients with CF, the RNA-binding protein tristetraprolin (TTP), a key regulator of inflammation, is dysregulated in cells that strongly express cytokines and interleukins. TTP activity is regulated by extensive post-translational modifications, particularly phosphorylation. We found that in addition to mRNA downregulation, phosphorylated TTP (which cannot bind to mRNA) accumulated in CF cultures, suggesting that the imbalance in TTP phosphorylation status could contribute to the inflammatory phenotype in CF. We confirmed TTP destabilizing role on <i>IL8</i> mRNA through its 3'UTR sequence in CF cells. We next demonstrated that TTP phosphorylation is mainly regulated by MK2 through activation of ERK, which also was hyperphosphorylated. TTP is considered a mRNA decay factor with some exception, and we present a new positive role of TTP in CF cultures. We determined that TTP binds to specific ARE motifs on the 3'UTR of mRNA sequences and also, for the first time, to the 3'UTR of Cystic Fibrosis Transmembrane Conductance Regulator (<i>CFTR</i>) where TTP binding stabilizes the mRNA level. This study identified new partners that can be targeted in CF and proposes a new way to control <i>CFTR</i> gene expression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455966","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":"Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.","authors":"Maritza J Romero, Qian Yue, Won Mo Ahn, Jürg Hamacher, Yusra Zaidi, Stephen Haigh, Supriya Sridhar, Joyce Gonzales, Martina Hudel, Yuqing Huo, Alexander D Verin, Betty S Pace, Brian K Stansfield, Mazharul Maishan, Enid R Neptune, Perenlei Enkhbaatar, Yunchao Su, Trinad Chakraborty, Graydon Gonsalvez, Edith Hummler, William B Davis, Vladimir Y Bogdanov, David J R Fulton, Gabor Csanyi, Michael A Matthay, Douglas C Eaton, Rudolf Lucas","doi":"10.1165/rcmb.2023-0440OC","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0440OC","url":null,"abstract":"<p><p>Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NADPH oxidase 2 (NOX2), involving the pneumococcal virulence factor pneumolysin (PLY). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of the epithelial sodium channel (ENaC) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function -measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans Blue Dye incorporation in mouse lungs- following infection with pneumococci. PLY-induced hyperpermeability in HL-MVEC monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47^phox subunit (Western blotting) <i>in vitro</i> and by co-localization of CD31 and gp91^phox in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-α, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-α KO (enENaC-α KO) mice develop increased capillary leak upon i.t. instillation with PLY or pneumococci, compared to wild type (wt) animals. TIP peptide diminishes capillary leak in <i>Sp</i>-infected wt mice, without significantly increasing lung bacterial load. Lung slices from <i>Sp</i>-infected enENaC-α KO mice have a significantly increased endothelial NOX2 expression, as compared to infected CRE mice. In conclusion, endothelial ENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in ARDS, without impairing host defense.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455963","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":"MrgprC11⁺ Jugular Neurons Control Airway Hyperresponsiveness in Allergic Airway Inflammation.","authors":"Yanyan Xing, Yeseul Nho, Katy Lawson, Yuyan Zhu, Alexandra E Ellison, Margaret Y Chang, William Hancock, Liang Han","doi":"10.1165/rcmb.2024-0153OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0153OC","url":null,"abstract":"<p><p>The lung is densely innervated by sensory nerves, the majority of which are derived from the vagal sensory neurons. Vagal ganglia consist of two different ganglia, termed nodose and jugular ganglia, with distinct embryonic origins, innervation patterns, and physiological functions in the periphery. Since nodose neurons constitute the majority of the vagal ganglia, our understanding of the function of jugular nerves in the lung is very limited. This study aims to investigate the role of MrgprC11⁺ jugular sensory neurons in a mouse allergic asthma model. Our previous study has shown that MrgprC11⁺ jugular neurons mediate cholinergic bronchoconstriction. In this study, we found that in addition to MrgprC11, several other Mrgpr family members including MrgprA3, MrgprB4, and MrgprD are also specifically expressed in the jugular sensory neurons. MrgprC11⁺ jugular neurons exhibit dense innervation in the respiratory tract including the larynx, trachea, proximal, and distal bronchus. We also found that receptors for IL-4 and oncostatin M, two critical cytokines promoting allergic airway inflammation, are mainly expressed in jugular sensory neurons. Both IL-4 and oncostatin M can sensitize the neuronal responses of MrgprC11+ jugular neurons. Moreover, ablation of MrgprC11⁺ neurons significantly inhibited airway hyperresponsiveness in the asthmatic lung, demonstrating the critical role of MrgprC11⁺ neurons in controlling airway constriction. Our results emphasize the critical role of jugular sensory neurons in respiratory diseases.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455964","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 Non-Pulmonary 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":"https://doi.org/10.1165/rcmb.2024-0192LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-15","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":"SOX17 Prevents Endothelial-Mesenchymal Transition of Pulmonary Arterial Endothelial Cells in Pulmonary Hypertension through Mediating TGF-β/Smad2/3 Signaling.","authors":"Xiaozhou Zou, Mengnan Yuan, Wei Zhou, Anqi Cai, Yili Cheng, Zibo Zhan, Yiwen Zhang, Zongfu Pan, Xiaoping Hu, Su Zhang, Shuilian Zheng, Ting Liu, Ping Huang","doi":"10.1165/rcmb.2023-0355OC","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0355OC","url":null,"abstract":"<p><p>Endothelial to mesenchymal transition (EndMT) has been reported to cause pulmonary vascular remodeling of pulmonary hypertension (PH). We have demonstrated that SOX17, a member of the SRY-Box (SOX) transcription factor family, affects pulmonary artery vascular homeostasis through exosomes in an autocrine and paracrine manner. However, the role of SOX17 in mediating EndMT of pulmonary arterial endothelial cells (PAECs) in PH and its underlying intracellular mechanisms are not yet clarified. Here, we show that in the remodeling pulmonary vascular of idiopathic PH patients and Sugen 5416/hypoxia (Sugen/hypoxia)-induced PH rats, the downregulation of SOX17 expression was accompanied by a significant pulmonary arterial EndMT and TGF-β/Smad2/3 signaling activation. In primary HPAECs, the expression of SOX17 was inhibited by canonical TGF-β signaling. SOX17 overexpression reversed TGF-β- and hypoxia-induced EndMT. It is suggested that SOX17 is required for HPAECs to acquire TGF-β-mediated EndMT. Mechanistically, SOX17 prevented TGF-β-induced EndMT of PAECs through trans-suppressing ROCK1 expression by binding to the specific promoter region of ROCK1, thereby inhibiting the phosphorylation of MYPT1 and MLC. Further, we found that Tie2-Cre rats with endothelial cell-specific SOX17 overexpression were prevented from Sugen/hypoxia-induced EndMT and pulmonary vascular remodeling. In keeping with the in vitro data, compared with the Tie2-Cre rats treated by Sugen/hypoxia, the rats with SOX17 overexpression showed decreased expression of ROCK1 as well as the MYPT1 and MLC phosphorylation. Overall, our studies demonstrate a novel TGF-β/SOX17/ROCK1 pathway regulating EndMT of PAECs and propose SOX17 as a potential target for exploring therapeutics to alleviate pulmonary vascular remodeling in PH.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399133","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":"Sputum Metabolomic Signature and Dynamic Change of Cough Variant Asthma.","authors":"Zhe Chen, Kehan Jin, Zhangfu Fang, Kangping Huang, Zhiyin Chen, Hankun Lu, Mingtong Lin, Li Long, Jiaxing Xie, Mengzhao Wang, Kefang Lai, Yuxi Wei, Fang Yi","doi":"10.1165/rcmb.2024-0219OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0219OC","url":null,"abstract":"<p><p>Cough variant asthma (CVA), a common reason for chronic cough, is a globally prevalent and burdensome condition. The heterogeneity of CVA and a lack of knowledge concerning the exact molecular pathogenesis has hampered its clinical management. This study presented the first sputum metabolome of CVA patients, revealed the dynamic change during treatment, and explored biomarkers related to the occurrence and treatment response of CVA. We found arginine biosynthesis, purine metabolism, and pyrimidine metabolism pathways were enriched in CVA compared to healthy controls. Part of metabolic disturbances could be reversed by anti-asthmatic medication. The levels of dipeptides/tripeptides (alanyltyrosine, Gly-Tyr-Ala, Ala-Leu, and Thr-Leu) were significantly associated with sputum Neu% or Eos% of CVA patients. Differential metabolites pre-treatment between effective and ineffective groups enriched in purine metabolism, thiamine metabolism, and arginine metabolism. 2-isopropylmalate was down-regulated in CVA patients and increased after treatment, and effective group had a lower 2-isopropylmalate level pre-treatment. Random forest and logistic regression models identified glutathione, thiamine phosphate, alanyltyrosine, and 2'-deoxyadenosine as markers for distinguishing CVA from healthy controls (all AUC > 0.8). Thiamine phosphate might also be promising for predicting therapy responsiveness (AUC = 0.684). These findings implied that disturbed mitochondrial energy metabolism and imbalanced oxidation-reduction homeostasis probably underlay the metabolic pathogenesis of CVA.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405832","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":"The Complex Immune Cell Composition and Cellular Interaction in the Alveolar Compartment of Patients with Acute Respiratory Distress Syndrome.","authors":"Shiqi Zhang, JanWillem Duitman, Antonio Artigas, Lieuwe D J Bos","doi":"10.1165/rcmb.2024-0176TR","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0176TR","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) is characterized by protein rich edema due to alveolar-capillary barrier dysfunction caused by inflammatory processes. Currently, our understanding of the inflammatory response in patients with ARDS is mainly based on assessment of the systemic compartment and preclinical studies. Investigations into the intricate network of immune cells and their critical functions in the alveolar compartment remain limited. However, with recent improvements in single cell analyses, our comprehensive understanding of the interactions between immune cells in the lungs has improved. In this review, we summarize the current knowledge about the cellular composition and interactions of different immune cell types within the alveolar space of patients with ARDS. Neutrophils and macrophages are the predominant immune cells in the alveolar space of ARDS patients. Yet, all immune cells present, including lymphocytes, participate in complex interactions, coordinate recruitment, modulate the lifespan and control apoptosis through various signaling pathways. Moreover, the cellular composition of alveolar immune cells is associated with clinical outcomes of ARDS patients. In conclusion, this synthesis advances our understanding of ARDS immunology, emphasizing the crucial role of immune cells within the alveolar space. Associations between cellular composition and clinical outcomes highlight the significance of exploring distinct alveolar immune cell subsets. Such exploration holds promise for uncovering novel therapeutic targets in ARDS pathophysiology, presenting avenues for enhancing clinical management and treatment strategies for ARDS patients. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387295","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 Single-Cell RNA Sequencing Atlas of the COPD Distal Lung to Predict Cell-Cell Communication.","authors":"Jessica B Blackburn, Tiffany S Tufenkjian, Yang Liu, David S Nichols, Timothy S Blackwell, Bradley W Richmond","doi":"10.1165/rcmb.2024-0232LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0232LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363998","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}