American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Extracellular Vesicle ASC: A Novel Mediator for Lung-Brain Axis in Preterm Brain Injury.","authors":"Natalie Starke, Naga Venkata Divya Challa, Huijun Yuan, Shaoyi Chen, Matthew R Duncan, Erika D L R M Cabrera Ranaldi, Juan Pablo de Rivero Vaccari, Alini Schott, Ana Cecilia Aguilar, Yee-Shuan Lee, Aisha Khan, Jo Duara, April Tan, Merline Benny, Augusto F Schmidt, Karen Young, Eduardo Bancalari, Nelson Claure, Shu Wu","doi":"10.1165/rcmb.2023-0402OC","DOIUrl":"10.1165/rcmb.2023-0402OC","url":null,"abstract":"<p><p>Bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment are among the most common morbidities affecting preterm infants. Although BPD is a predictor of poor neurodevelopmental outcomes, it is currently uncertain how BPD contributes to brain injury in preterm infants. Extracellular vesicles (EVs) are involved in interorgan communication in diverse pathological processes. ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain) is pivotal in inflammasome assembly and activation of inflammatory response. We assessed expression profiles of the alveolar macrophage (AM) markers CD11b, CD11c, and CD206 as well as ASC in EVs isolated from the plasma of preterm infants at risk for BPD at 1 week of age. We found that infants on higher fraction of inspired oxygen therapy (HO₂⩾30%) had increased concentrations of AM-derived EV-ASC compared with infants on lower fraction of inspired oxygen (LO₂<30%). To assess the function of these EVs, we performed adoptive transfer experiments by injecting them into the circulation of newborn mice. We discovered that mice that received EVs from infants on HO₂ had increased lung inflammation, decreased alveolarization, and disrupted vascular development, the hallmarks of BPD. Importantly, these EVs crossed the blood-brain barrier, and the EVs from infants on HO₂ caused inflammation, reduced cell survival, and increased cell death, with features of pyroptosis and necroptosis in the hippocampus. These results highlight a novel role for AM-derived EV-ASC in mediating the lung-to-brain cross-talk that is critical in the pathogenesis of BPD and brain injury and identify potential novel targets for preventing and treating BPD and brain injury in preterm infants.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496883","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":"Paving the ROCKy Path to Novel Antifibrotics.","authors":"Rachel S Knipe, Reinoud Gosens","doi":"10.1165/rcmb.2024-0224ED","DOIUrl":"10.1165/rcmb.2024-0224ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305179","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":"Novel Small-Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies.","authors":"Soyoung Hwang, Wongil Lee, Dashnamoorthy Ravi, William Devine, Miyong Yong, R Bruce Diebold, Sang-Ae Seung, Nicholas W Ng, Jaekyoo Lee, Anu Gupta, Jong Sung Koh","doi":"10.1165/rcmb.2023-0401OC","DOIUrl":"10.1165/rcmb.2023-0401OC","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various <i>in vitro</i> cellular models. GNS-3595 also prevented transforming growth factor β-induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305178","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":"HPS6 Deficiency Leads to Reduced Vacuolar-Type H⁺-ATPase and Impaired Biogenesis of Lamellar Bodies in Alveolar Type II Cells.","authors":"Zhenhua Hao, Huipeng Wang, Zixuan Zhou, Qingsong Yang, Beibei Zhang, Jing Ma, Wei Li","doi":"10.1165/rcmb.2022-0492OC","DOIUrl":"10.1165/rcmb.2022-0492OC","url":null,"abstract":"<p><p>Lamellar bodies (LBs) are tissue-specific lysosome-related organelles in type II alveolar cells that are the main site for the synthesis, storage, and secretion of pulmonary surfactants. Defects in pulmonary surfactants lead to a variety of respiratory and immune-related disorders. LB biogenesis is closely related to their function, but the underlying regulatory mechanism is largely unclear. Here, we found that deficiency of HPS6, a subunit of BLOC-2 (biogenesis of lysosome-related organelles complex-2), led to a reduction of the steady-state concentration of vacuolar-type H⁺-ATPase and an increase in the luminal pH of LBs. Furthermore, we observed increased LB size, accumulated surfactant proteins, and altered lipid profiling of lung tissue and BAL fluid due to HPS6 deficiency. These findings suggest that HPS6 regulates the distribution of vacuolar-type H⁺-ATPase on LBs to maintain its luminal acidity and LB homeostasis. This may provide new insights into the LB pathology.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305176","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":"Novel Hemodynamic, Vascular Lesion, and Cytokine/Chemokine Differences Regarding Sex in a Pulmonary Arterial Hypertension Model.","authors":"Jenny L Hewes, Aritra Bhadra, Erin Schreck, John Thomas Goodman, Mita Patel, Chun Zhou, Ji Young Lee, Natalie R Bauer","doi":"10.1165/rcmb.2023-0378OC","DOIUrl":"10.1165/rcmb.2023-0378OC","url":null,"abstract":"<p><p>Sex differences are recognized in pulmonary hypertension. However, the progression of disease with regard to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics, and alterations in circulating chemokines/cytokines differ between males and females, we used a progressive model of pulmonary arterial hypertension (PAH), Sugen/hypoxia, and analyzed cohorts of male and female rats at time points suggested to indicate worsening disease. Our analysis included echocardiography for hemodynamics, morphometry, immunofluoresecence, and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index, compared with those for females at each time point, as well as increased medial artery thickening at 8 weeks of PAH. Furthermore, females exhibited fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, granulocyte-macrophage colony-stimulating factor, IL-10, and macrophage interacting protein-1α that were not observed in females, whereas females were observed to have increased RANTES (whose name derives from Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) and CXCL-10 that were not found in males. Males also have increased infiltrating macrophages in vascular lesions, compared with females. We found that development of progressive PAH in hemodynamics, morphology, and chemokine/cytokine circulation differs significantly between males and females. These data suggest a macrophage-driven pathology in males, whereas there may be T cell protection from vascular damage in females with PAH.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305177","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":"Distinct Responses of Cystic Fibrosis Epithelial Cells to SARS-CoV-2 and Influenza A Virus.","authors":"Isabel Pagani, Arianna Venturini, Valeria Capurro, Alessandro Nonis, Silvia Ghezzi, Mariateresa Lena, Beatriz Alcalá-Franco, Fabrizio Gianferro, Daniela Guidone, Carla Colombo, Nicoletta Pedemonte, Alessandra Bragonzi, Cristina Cigana, Luis J V Galietta, Elisa Vicenzi","doi":"10.1165/rcmb.2024-0213OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0213OC","url":null,"abstract":"<p><p>The COVID-19 pandemic has underscored the impact of viral infections on individuals with cystic fibrosis (CF). Initial observations suggested lower COVID-19 rates among CF populations; however, subsequent clinical data have presented a more complex scenario. This study aimed to investigate how bronchial epithelial cells from CF and non-CF individuals, including various CF transmembrane conductance regulator (CFTR) mutations, respond to <i>in vitro</i> infection with SARS-CoV-2 variants and SARS-CoV. Comparisons with the Influenza A virus (IAV) were included based on evidence that CF patients experience heightened morbidity from IAV infection. Our findings showed that CF epithelial cells exhibited reduced replication of SARS-CoV-2, regardless of the type of CFTR mutation or SARS-CoV-2 variant, as well as the original 2003 SARS-Cove. In contrast, these cells displayed more efficient IAV replication compared to non-CF cells. Interestingly, the reduced susceptibility to SARS-CoV-2 in CF was not linked to the expression of angiotensin converting enzyme 2 (ACE2) receptor nor to CFTR dysfunction, as pharmacological treatments to restore CFTR function did not normalize the viral response. Both SARS-CoV-2 infection and CFTR function influenced the levels of certain cytokines and chemokines, although these effects were not correlated. Overall, this study reveals a unique viral response in CF epithelial cells, characterized by reduced replication for some viruses like SARS-CoV-2, while showing increased susceptibility to others such as IAV. This research offers a new perspective on CF and viral interactions, emphasizing the need for further investigation into the mechanisms underlying these differences. 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":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142279100","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":"Piecing Together the Role of IL-4 Receptor Alpha in Allergic Asthma One Cell at a Time.","authors":"Miranda L Curtiss,Paul B Rothman","doi":"10.1165/rcmb.2024-0309ed","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0309ed","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264345","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":"Cav1 Scaffolding Domain Peptide (CSP7): A Novel Target for Idiopathic Pulmonary Fibrosis.","authors":"Sadiya Bi Shaikh,Irfan Rahman","doi":"10.1165/rcmb.2024-0314ed","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0314ed","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264344","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":"Emerging Role of CircRNA-Cacna1d in Sepsis-Induced Lung Injury: A Potential Therapeutic Target and Biomarker.","authors":"Nargis Shaheen,Jing Zhao","doi":"10.1165/rcmb.2024-0424ed","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0424ed","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264348","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":"From Data Mining to Discovery: SNHG11 as a Therapeutic Target in Pulmonary Hypertension.","authors":"Yann Grobs,François Potus","doi":"10.1165/rcmb.2024-0415ed","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0415ed","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":6.4,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264346","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}