American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"An Old Dog Performing the Same Old Tricks: The Role of TGF-β Receptor in Tissue Factor Release and Extracellular Vesicle Formation.","authors":"R Chad Wade, Jessy S Deshane","doi":"10.1165/rcmb.2024-0627ED","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0627ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027815","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 Functional Variant <i>rs2122031</i> in <i>ATG7</i> Is Associated with the Risk of Radiation Pneumonitis.","authors":"Bo Liu, Yulong Yu, Wan Qin, Li Yang, Minxiao Yi, Lingyan Xiao, Yongbiao Huang, Xiao Zhou, Shiying Yu, Yihua Wang, Cong-Yi Wang, Yang Tang, Xianglin Yuan","doi":"10.1165/rcmb.2024-0238OC","DOIUrl":"10.1165/rcmb.2024-0238OC","url":null,"abstract":"<p><p>Radiation pneumonitis (RP) is characterized by inflammation and is associated with autophagy. However, the relationship between functional genetic variants of autophagy-related genes and radiation pneumonitis remains unknow. In this study we aimed to investigate whether genetic variants of genes involved in autophagy are associated with radiation pneumonitis. Genotyping was conducted on a total of 301 patients for thirteen single nucleotide polymorphisms (SNPs) of 5 genes in the autophagy pathway using MassArray and Sanger sequencing. Two radiation oncologists independently measured the degree of RP by chest X-ray or CT. The multivariate Cox hazard analysis and multiple testing showed that <i>ATG7: rs2122031 GA/GG</i> significantly decreased the risk of RP ≥ grade 3 (HR=0.369, 95% CI: 0.189-0.720, <i>P</i>=0.003, <i>Pc</i>=0.039). Furthermore, qRT-PCR and immunohistochemical analysis demonstrated that the <i>ATG7: rs2122031 AA</i> genotypes were related to decreased expression of ATG7. Loss of autophagy by deletion of ATG7 in fibroblasts or conditional <i>ATG7</i> knockout mice was proven to increase radiation pneumonitis. Single-cell RNA-seq revealed regulation of autophagy related genes enriched after irradiation stress in conditional <i>ATG7</i> knockout mice. Our findings indicated that genetic variants of <i>ATG7</i> were associated with RP and may therefore be used to predict RP before radiotherapy. Loss of ATG7 was also shown to promote RP, which suggested that ATG7 may be an intervention target for RP. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027900","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 Art(ery) of Contraction: Using Precision Cut Lung Slices to Model Pulmonary Hypertension in ARDS.","authors":"Maria L Ford, Anushka Ruwanpathirana, Rodney D Britt","doi":"10.1165/rcmb.2024-0603ED","DOIUrl":"10.1165/rcmb.2024-0603ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027906","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":"COPD Airway Epithelial Cell-derived Extracellular Vesicles Spread Cellular Senescence via MicroRNA-34a.","authors":"Justine V Devulder, Jonathan R Baker, Peter S Fenwick, Lina Odqvist, Louise E Donnelly, Peter J Barnes","doi":"10.1165/rcmb.2024-0183OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0183OC","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is associated with the acceleration of lung aging, and the accumulation of senescent cells in lung tissue. MicroRNA (miR)-34a induces senescence by suppressing the anti-aging molecule, sirtuin-1 (SIRT1). Senescent cells spread senescence to neighbouring and distant cells, favouring COPD progression and its comorbidities. Mechanisms for spreading senescence remain undetermined but may be mediated by the transfer of microRNAs in extracellular vesicles. We analysed the miRNA content of extracellular vesicles in COPD and explored their effect on cellular senescence of healthy cells. EVs were isolated from small airway epithelial cells (SAEC) from healthy donors or COPD patients. Recipient healthy SAEC were cultured with EVs and the expression of miR-34a and markers of cellular senescence, p21^CIP1 and SIRT1, were measured. We have shown that EVs from COPD cells induce senescence in healthy recipient cells via the selective transfer of miR-34a. COPD SAEC produce increased numbers of EVs enriched with miR-34a. EVs are taken up by healthy cells, resulting in reduced expression of the anti-aging molecule sirtuin-1 and increased expression of markers of senescence, like p21^CIP1 and positive staining for senescence-associated β-galactosidase, which were blocked by a specific miR-34a antagomir. Our findings provide evidence of the mechanism by which EVs spread cellular senescence in human primary cells via miR-34a, rather than via soluble mediators. EVs enriched with miR-34a may spread senescence locally, accounting for disease progression, but also provide a mechanism for distant spread to account for comorbidities and multimorbidity of the elderly.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997833","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 Early Life Acetaminophen Exposure Causes Persistent Abnormalities in the Murine Lung.","authors":"Maya R Grayck, Bradford J Smith, Alexander Sosa, Emma Golden, William C McCarthy, Mack Solar, Natarajan Balasubramaniyan, Lijun Zheng, Evgenia Dobrinskikh, Mercedes Rincon, David J McCulley, David J Orlicky, Clyde J Wright","doi":"10.1165/rcmb.2024-0452OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0452OC","url":null,"abstract":"<p><p>Whether early life acetaminophen (APAP) exposures injure the developing lung is controversial. We sought to correlate murine pulmonary developmental expression profiles of <i>Cyp2e1</i> to susceptibility to APAP exposure. P14 C57BL/6 mice were exposed to APAP (140 mg/kg x 1, IP) and assessed for evidence of a histologic, metabolic, functional, and/or transcriptional pulmonary response. Similar experiments were performed in P14 IL6^-/- mice given the controversial role of IL6 in APAP-induced tissue injury. No evidence of hepatic injury was noted in APAP exposed P14 mice. In contrast, within 6 hours of exposure pulmonary tissue demonstrated histologic and functional evidence of injury and increased mitochondrial load by fluorescent lifetime imaging microscopy (FLIM). The pulmonary transcriptional response was marked by increased expression of <i>Cyp2e1</i>, Nrf2 targets, and pro-inflammatory genes. Specifically, APAP exposure increased pulmonary IL6 mRNA, protein and associated STAT3 signaling. In contrast, IL6^-/- demonstrated attenuated STAT3 signaling and injury at 6 hours of exposure. At P28, functional and stereologic assessment of both WT and IL6^-/- mice exposed to a single dose of APAP at P14 revealed persistent abnormalities consistent with lung enlargement and alveolar simplification. Developmentally regulated surges in pulmonary <i>Cyp2e1</i> expression correlate with sensitivity to APAP exposures that do not cause recognizable hepatic injury. A single exposure during this developmental window is enough to cause persistent functional and stereological abnormalities. These results highlight the need to further study the relationship between developmentally-regulated pulmonary <i>Cyp2e1</i> expression, APAP exposures and long-term pulmonary dysfunction.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142997709","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 Sound of Silence: Suppressing Cbx5 Decreases Fibrosis by Inhibiting Fibroblasts.","authors":"Mauricio Rojas, Ana L Mora","doi":"10.1165/rcmb.2024-0618ED","DOIUrl":"10.1165/rcmb.2024-0618ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998373","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":"Optimizing Neutrophil Recruitment to Tackle Bacterial Infections?","authors":"Rosemary Bayless, Yogesh Saini","doi":"10.1165/rcmb.2024-0575ED","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0575ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998358","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 Sarcoidosis Epitope Augments MHCII, CD80/CD86 Expression, Promotes B-Cell Differentiation and IgG Production.","authors":"Jaya Talreja, Changya Peng, Kezhong Zhang, Lobelia Samavati","doi":"10.1165/rcmb.2024-0428OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0428OC","url":null,"abstract":"<p><p>Numerous chronic human disorders are associated with immune activation by obscure antigen(s). We identified a novel sarcoidosis-epitope (ChainA) by immunoscreening of a novel T7 phage library and confirmed an abundance of ChainA IgG-antibody in sarcoidosis. We tested whether ChainA epitope elicits immune responses through B-cell activation, plasma cell differentiation and antibody production. PBMCs from healthy controls and sarcoidosis patients were challenged by chemically synthesized ChainA epitope, and assessed cellular activation markers of B-cells, T-cells, MHC classes, plasma cell differentiation and Unfolded Protein Response (UPR) transcription factors. Chain A increased expression of MHCII class and CD80/CD86 costimulatory molecules. ChainA significantly augmented the transition of naïve B-cells to memory B-cells and plasma cells in sarcoidosis PBMCs compared to healthy PBMCs. B-Cells differentiation to antibody-secreting plasma cells requires activation of UPR, B lymphocyte-induced maturation protein 1 (Blimp-1) and X-box binding protein 1 (XBP-1). ChainA treatment upregulated the expression of Blimp-1 and spliced form of XBP-1, a transcriptional activator of endoplasmic reticulum (ER) stress response. Furthermore, the transition of B cells to plasma cells in response to ChainA induced the production of anti-ChainA IgG. In parallel to human PBMCs, utilizing murine splenocytes, we validated our observations that ChainA challenge augments MHCII expression, a robust UPR responses, and an increased production of IgG specific antibody against ChainA. These results indicate ChainA epitope may be involved in the pathogenesis of sarcoidosis, as it activates MHCII, memory B-cells, plasma cell differentiation and production of ChainA specific IgG.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998349","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":"Improved Annotation of Asthma Gene Variants with Cell Type Deconvolution of Nasal and Lung Expression-Quantitative Trait Loci.","authors":"Zaid W El-Husseini, Tatiana Karp, Andy Lan, Tessa E Gillett, Cancan Qi, Dmitry Khalenkow, Thys van der Molen, Chris Brightling, Alberto Papi, Klaus F Rabe, Salman Siddiqui, Dave Singh, Monica Kraft, Bianca Beghé, Philippe Joubert, Yohan Bossé, Don Sin, Ana H Cordero, Wim Timens, Corry-Anke Brandsma, Ke Hao, David C Nickle, Judith M Vonk, Martijn C Nawijn, Maarten van den Berge, Reinoud Gosens, Alen Faiz, Gerard H Koppelman","doi":"10.1165/rcmb.2024-0251MA","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0251MA","url":null,"abstract":"<p><p>Asthma is a genetically complex inflammatory airway disease associated with over 200 Single nucleotide polymorphisms (SNPs). However, the functional effects of many asthma-associated SNPs in lung and airway epithelial samples are unknown. Here, we aimed to conduct expression quantitative trait loci (eQTL) analysis using a meta-analysis of nasal and lung samples. We hypothesize that incorporating cell-type proportions of airway and lung samples enhances eQTL analysis outcomes. Nasal brush (n=792) and lung tissue (n=1087) samples were investigated separately. Initially, a general eQTL analysis identified genetic variants associated with gene expression levels. Estimated cell-type proportions were adjusted based on the Human Lung Cell Atlas. Additionally, the presence of significant interaction effects between asthma-associated SNPs and each cell type proportion was explored and considered evidence for cell-type associated eQTL. In nasal brush and lung parenchyma samples, 44 and 116 asthma-associated SNPs were identified as eQTLs. Adjusting for cell-type proportions revealed eQTLs for an additional 17 genes (e.g., <i>FCER1G</i>, <i>CD200R1</i>, and <i>GABBR2</i>) and 16 Genes (e.g., <i>CYP2C8</i>, <i>SLC9A2</i>, and <i>SGCD</i>) in nose and lung, respectively. Moreover, we identified eQTLs for 9 SNPs annotated to genes such as <i>VASP</i>, <i>FOXA3</i>, <i>PCDHB12</i> displayed significant interactions with cell type proportions of Club, Goblet, and alveolar macrophages. Our findings demonstrate increased power for identifying eQTLs among asthma-associated SNPs by considering cell-type proportion of the bulk-RNA-seq data from nasal and lung tissues. Integration of cell-type deconvolution and eQTL analysis enhances our understanding of asthma genetics and cellular mechanisms, uncovering potential therapeutic targets for personalized interventions.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998045","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 Immune Response Evasion Strategy to Redose Adeno-associated Viral Vectors and Prolong Survival in Surfactant Protein-B Deficient Mice.","authors":"Martin H Kang, Sylvia P Thomas, Caralyn Westley, Thomas Blouin, Liqun Xu, Ying Kai Chan, Erin Lisk, Sarah Allen, Arul Vadivel, Kennedy Nangle, Janani Ramamurthy, Yanlong Pei, Lunndon Lewis, Jessica J Chiang, Marty J Romeo, Silvia Vaena, Elizabeth C O'Quinn, Henry D Schrecker, Casey G Langdon, Paul J Nietert, George M Church, Jeffrey A Whitsett, Sarah K Wootton, Bernard Thébaud","doi":"10.1165/rcmb.2024-0247OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0247OC","url":null,"abstract":"<p><p>Surfactant protein-B (SP-B) deficiency is a lethal neonatal respiratory disease with few therapeutic options. Gene therapy using adeno-associated viruses (AAV) to deliver human <i>SFTPB</i> cDNA (AAV-hSPB) can improve survival in a mouse model of SP-B deficiency. However, the effect of this gene therapy wanes. Gene therapy efficacy could be prolonged if AAV vectors were able to be redosed, but readministering vectors is hindered by an immune response which includes toll like receptor 9 (TLR9) recognition of unmethylated CpG DNA motifs in the AAV genome. One strategy to mitigate TLR9 recognition of AAV is to incorporate decoy nucleotide sequences within the AAV genome. This work examined if AAV containing these TLR9 inhibitory oligonucleotide sequences (AAV-hSPB_TLR9i) could mitigate the immune response sufficiently to redose AAV in the lungs and prolong the survival of SP-B deficient mice. Indeed, AAV-hSPB_TLR9i was able to be redosed multiple times which significantly improved survival in our mouse model. This was partially a result of long-term increased <i>SFTPB</i> RNA and SP-B protein expression. Conversely, redosing AAV-hSPB resulted in the rapid death of SP-B deficient mice after the second AAV dose. TLR9 inhibition enabled readministration by avoiding the broad stimulation of genes belonging to multiple pathways in the host immune and inflammatory responses, including components of the interferon pathways. Thus, redosing of AAV vectors in the lungs using TLR9 inhibitory sequences is a promising strategy for prolonging gene therapy efficacy, with a proof-of-concept for AAV readministration in a clinically relevant mouse model of SP-B deficiency.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142976956","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}