American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"The Role of Tuftelin-1 in Mesomesenchymal Transition of Pleural Mesothelial Cells and the Progression of Pleural Fibrosis.","authors":"Ann Jeffers, Shuzi Owens, Wenyi Qin, Olamipejo Durojaye, Matt Florence, Peace Okeke, Luis Destarac, Shiva Keshava, Mitsuo Ikebe, Steven Idell, Torry A Tucker","doi":"10.1165/rcmb.2024-0263OC","DOIUrl":"10.1165/rcmb.2024-0263OC","url":null,"abstract":"<p><p>Pleural conditions causing exudative effusions (empyema or complicated parapneumonia) can result in pathological pleural organization leading to pleural fibrosis (PF). Pleural mesothelial cells (PMCs) undergo mesenchymal transition (MesoMT) and acquire a profibrotic phenotype characterized by increased expression of ACTA2; collagen type I (Col-1); and phenotypic changes, including elongation, stress fiber formation, and contraction. Using RNA-sequencing analysis, we identified Tuftelin-1 (Tuft1) as a novel potential target. Although prior studies have shown that Tuft1 expression is associated with aggressive cellular phenotypes, its role in PF is unknown. Our prior studies show that inhibition of PI3K/Akt, mTORC2, or GSK-3β blocks MesoMT. In this study, we build on previous findings and suggest that Tuft1 plays a key role in promoting MesoMT. In human PMCs, various mediators that induce MesoMT result in upregulation of Tuft1 expression. Furthermore, we also found that Tuft1 was increased in human pleuritis tissues and in murine models of PF compared with normal lung. In our studies, TGF-β-mediated increase in Tuft1 was blocked by the GSK-3β inhibitor 9-ING-41. Knockdown of Tuft1 <i>in vitro</i> blocked TGF-β-mediated MesoMT. Conversely, Tuft1 overexpression induced mTORC2 signaling and promoted MesoMT in the absence of TGF-β. <i>In vivo</i> analyses showed that mesothelial cell-specific Tuft1 knockout mice (Tuft1PMC^-/-) were protected from <i>Streptococcus pneumoniae</i>-mediated pleural injury. Histological analysis showed that pleural thickening and profibrotic markers were significantly reduced in Tuft1PMC^-/- mice compared with wild-type control animals. These studies strongly support therapeutic targeting of Tuft1 as a novel means to mitigate PF.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"441-450"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell Surface RNA Expression Modulates Alveolar Epithelial Function.","authors":"Jubilant Kwame Abledu, Christopher J Herbst, Raphael Brandt, Alen Kocak, Pritam Ghosh, Jacob L Gorenflos López, Kevin Diestelhorst, Stephan Block, Christian Hackenberger, Oliver Seitz, Elena Lopez-Rodriguez, Cengiz Gökeri, Martin Witzenrath, Matthias Ochs, Wolfgang M Kuebler","doi":"10.1165/rcmb.2024-0284OC","DOIUrl":"10.1165/rcmb.2024-0284OC","url":null,"abstract":"<p><p>Glycosylated RNA (glycoRNA) has recently emerged as a novel constituent of the glycocalyx on cell surfaces, yet its biological functions remain largely unexplored. In this report, we present the first analysis of glycoRNA expression and functionality in alveolar epithelial cells. To this end, we optimized new techniques for the detection of glycoRNA on living cell surfaces and in cell membrane-associated RNA samples through in-gel imaging after labeling with fluorescent dye conjugates. Specifically, we used conjugation of Cy5-hydrazide after mild oxidation with sodium periodate for detection of total cell surface sialoglycoRNA. Conjugation of dibenzocyclooctyne-sulfo-Cy5 in cells fed with tetraacetylated <i>N</i>-azidoacetyl-mannosamine or 6-azido-L-fucose detected <i>de novo</i>-formed sialoglycoRNA or fucoglycoRNA, respectively. Finally, biotinylated lectins in combination with infrared dye-conjugated streptavidin were used to differentiate between specific glycosidic linkages. Comparisons across primary alveolar epithelial cells and different alveolar epithelial-like cell lines revealed a cell-type-specific variation in glycoRNA abundance. Treatment of primary alveolar epithelial cells with an RNase cocktail reduced epithelial surface glycoRNA and was associated with a reduction in transepithelial electrical resistance and influenza A viral particle abundance. As such, the present work identifies glycoRNA as a novel component of the alveolar epithelial glycocalyx with potential relevance in epithelial barrier regulation and viral infection.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"466-478"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555583","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":"MOTS-c Promotes Glycolysis via AMPK-HIF-1α-PFKFB3 Pathway to Ameliorate Cardiopulmonary Bypass-induced Lung Injury.","authors":"Zihao Shen, Peng Lu, Wanjun Jin, Ziang Wen, Yuanpu Qi, Xiangyu Li, Mingyu Chu, Xin Yao, Minchao Wu, Ao Wang, Xiao Zhang, Wei Wang, Meijuan Song, Xiaowei Wang","doi":"10.1165/rcmb.2024-0533OC","DOIUrl":"10.1165/rcmb.2024-0533OC","url":null,"abstract":"<p><p>Cardiopulmonary bypass (CPB) is essential during cardiac surgery but frequently leads to lung ischemia-reperfusion injury (LIRI), a significant contributor to postoperative complications. We investigated the protective effects of mitochondrial open reading frame of the 12S ribosomal RNA type C (MOTS-c), a mitochondrial-derived peptide, against LIRI-induced acute lung injury (ALI), emphasizing glycolytic reprogramming and ferroptosis in pulmonary microvascular endothelial cells. We hypothesized that MOTS-c exerts its protective effects by regulating glycolysis and suppressing ferroptosis via metabolic signaling pathways. We conducted a prospective, controlled trial involving 107 patients undergoing CPB, evaluating plasma concentrations of MOTS-c and inflammatory markers. MOTS-c concentrations were significantly reduced in patients with ALI. <i>In vivo</i> and <i>in vitro</i> experiments demonstrated that MOTS-c pretreatment alleviated LIRI by enhancing glycolytic flux, reducing oxidative stress, and suppressing ferroptosis in pulmonary microvascular endothelial cells. In particular, MOTS-c reinstated the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), an essential glycolytic enzyme, thus preserving cellular energy homeostasis and diminishing lipid peroxidation. The findings further emphasize the involvement of the AMPK (AMP-activated protein kinase)-hypoxia inducible factor-1α (HIF-1α) signaling pathway in the protective benefits facilitated by MOTS-c. MOTS-c elevated phosphorylated AMPKα and HIF-1α expression, indicating a vital function for these pathways in enhancing glycolysis and antioxidant defenses. Genetic and pharmacological inhibition of PFKFB3 abrogated the protective effects of MOTS-c, thereby confirming the essential role of PFKFB3-mediated glycolysis in alleviating LIRI. Our research indicates that MOTS-c could serve as a potential therapeutic agent for the prevention or treatment of LIRI-induced ALI by enhancing glycolysis, suppressing ferroptosis, and activating the AMPK-HIF-1α pathway. Future study should explore the clinical application of MOTS-c, potentially improving outcomes for patients undergoing high-risk cardiac operations.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"353-368"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539910","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 Cross-Species and Sex-Specific Meta-Analysis of Transcriptomic Studies of Pulmonary Hypertension.","authors":"Lan Zhao, Christine M Cunningham, Jason Hong, Stuti Agarwal, Ke Yuan, Vinicio A de Jesus Perez, Mark R Nicolls","doi":"10.1165/rcmb.2024-0410OC","DOIUrl":"10.1165/rcmb.2024-0410OC","url":null,"abstract":"<p><p>Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling and right ventricle dysfunction. Among the five PH groups, group 1 pulmonary arterial hypertension (PAH) is a particularly serious condition characterized by a poor prognosis. PAH can occur in idiopathic, associated, and heritable forms, and has a notable female predominance. A number of <i>in vivo</i> PH models in rodents, together with <i>in vitro</i> cultured vascular cells such as pulmonary arterial pulmonary arterial (PA) endothelial cells and PA smooth muscle cells derived from patients with PAH, have been widely used to reproduce the pathological disease features. To systematically evaluate the <i>in vivo</i> and <i>in vitro</i> efficacy of the existing PH model systems, publicly available whole-transcriptome data from humans and rodents were collected and analyzed. Subgroups of the <i>Schistosoma</i>-induced female PH model in mice and the male chronic hypoxia PH model in rats correlated well with human heritable PAH and idiopathic PAH lungs, respectively. An SU5416 chronic hypoxia PH model is well connected to the decompensated right ventricles of human PAH. Sex dimorphisms have been observed in PAH-derived PA endothelial cells and PA smooth muscle cells, independent of gonadal hormones. We conducted, for the first time, a meta-cohort and cross-species comparative study and identified optimal <i>in vivo</i> and <i>in vitro</i> PH model systems that recapitulate certain aspects of human PH, which could provide novel insights into new therapeutic avenues in PH.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"427-440"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Will Stub1 Be the Next Target for Pulmonary Hypertension Therapy Development?","authors":"Yuanjun Shen","doi":"10.1165/rcmb.2025-0034ED","DOIUrl":"10.1165/rcmb.2025-0034ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"329-331"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering HMGB1-derived Peptides to Unravel Sex-Specific Mechanisms in Pulmonary Arterial Hypertension.","authors":"Qi Zheng, Zhiyu Dai","doi":"10.1165/rcmb.2025-0070ED","DOIUrl":"10.1165/rcmb.2025-0070ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"337-339"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Acrolein-Lipopolysaccharide Mouse Model for Frequent Exacerbations in Chronic Obstructive Pulmonary Disease.","authors":"Bernhard F E Reiter, Natalie Bordag, Diana Schnoegl, Martina Delbeck, Tobias Madl, Hansjörg Habisch, Grazyna Kwapiszewska, Jörg Meding, Leigh M Marsh","doi":"10.1165/rcmb.2024-0507MA","DOIUrl":"10.1165/rcmb.2024-0507MA","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a severe progressive lung disease, often caused by prolonged exposure to cigarette smoke and environmental factors. Preclinical COPD research predominately relies on chronic smoke or elastase animal models, each with their own advantages and limitations, such as limited pathophysiological insights or long treatment times. Here we describe a novel and time-efficient mouse model of COPD based on bacterial LPS and the reactive aldehyde acrolein (Acro). Mice were treated once per week for 4 weeks with a combination of both LPS and Acro. Histological, inflammatory, and metabolomic alterations were analyzed by histological quantification, multicolor flow cytometry, and nuclear magnetic resonance. Acro/LPS treatment induced moderate airspace enlargement and bronchial remodeling. These structural changes were associated with a distinct inflammatory profile marked by an increase in macrophages and T-helper cells, as well as increased cytokines, including CXCL11, IL-17a, and TNF-α. Strong inflammation, consisting of T-helper and B cells, was detected in the perivascular and peribronchial spaces and increased macrophages in the alveolar regions. In addition, intervention with the steroid dexamethasone induced a strong reduction in T cells and macrophages and partially ameliorated histological alterations. Furthermore, we could detect alterations in the metabolome of serum and tissue, including an increase in COPD-associated metabolites like trimethylamine N-oxide, as well as a misbalance in energy-related metabolites and several amino acids. In summary, we can describe a practical, representative, and time-efficient mouse model of COPD, with the potential to study the immunological and pathophysiological development of the disease.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"343-352"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955903","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 Mighty Mitochondrial Microprotein: The Protective Role of MOTS-c in Acute Lung Injury.","authors":"Corrine Kliment","doi":"10.1165/rcmb.2025-0062ED","DOIUrl":"10.1165/rcmb.2025-0062ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"335-336"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Role for Platelet-Endothelial Crosstalk in Pulmonary Hypertension.","authors":"Li Hu, Feng Chen","doi":"10.1165/rcmb.2025-0044ED","DOIUrl":"10.1165/rcmb.2025-0044ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"332-334"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143555579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of <i>Tbx4</i> Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension.","authors":"Gabriel Maldonado-Velez, Elizabeth A Mickler, Todd G Cook, Micheala A Aldred","doi":"10.1165/rcmb.2024-0459OC","DOIUrl":"10.1165/rcmb.2024-0459OC","url":null,"abstract":"<p><p>Pulmonary arterial hypertension is a progressive vascular disease characterized by remodeling of the precapillary pulmonary arteries. Genomic variation within the T-box 4 (TBX4) transcription factor is the second most common genetic cause of pulmonary arterial hypertension and can also cause severe lung developmental disorders with neonatal pulmonary hypertension (PH). Currently, the effect of TBX4 loss of function on later stages of lung development and predisposition to lung disease, including PH, is not well understood. Therefore, we generated <i>Tbx4</i> conditional knockout (<i>Tbx4-</i>CKO) mice in which <i>Cre</i> recombinase deletes exon 5 of <i>Tbx4</i> within the embryonic lung mesenchyme to create a null allele. We harvested lungs from these mice at various time points to examine alveologenesis, vascularization, vascular remodeling, lung cellular composition, and disruption of transcriptional activity compared with control lungs. Right ventricular systolic pressure was measured in 6-month-old mice to evaluate for PH. <i>Tbx4-</i>CKO lungs show enlargement of airspaces, as confirmed by an increase in mean linear intercept at Postnatal Day (P)14 (24.9%), P36 (31.5%), and P180 (49.6%). These lungs also show a 39.3% decrease in von Willebrand factor-positive vessels and a 14.2% increase in vessel wall thickness. Consistent with these results, <i>Tbx4-</i>CKO mice show a statistically significant increase of 15.7% in right ventricular systolic pressure and 16.3% in the Fulton index. Bulk RNA-sequencing analysis revealed enrichment of pathways and genes relevant to lung alveologenesis, angiogenesis, and PH. Our results show that disruption of <i>Tbx4</i> expression during early lung development is sufficient to disrupt postnatal lung development and circulation.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"415-426"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}