American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"SREBP-mediated Signaling Restores Stem Cell Niche Properties in Human Lung Fibroblasts.","authors":"Grégoire Justeau, Marylène Toigo, Bruno Ribeiro Baptista, Danushki Herath, Rojda Yilmaz, Laure Crépin, Perla Abou Atmeh, Thalles De Freitas Castro, Hussa Alshehhi, Nicolas Poté, Denis Debrosse, Pierre Mordant, Marin Truchi, Bernard Mari, Frederic Gagnadoux, Etienne Audureau, Denise Al Alam, Karim El Mernissi, Justine Bertrand-Michel, Geneviève Derumeaux, Jorge Boczkowski, Maylis Dagouassat, Laurent Boyer","doi":"10.1165/rcmb.2024-0541OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0541OC","url":null,"abstract":"<p><p>Emphysema is characterized by chronic alveolar destruction. Lipofibroblasts (LIF) are crucial in the stem cell niche surrounding alveolar type II (AT2) cells and may contribute to alveolar regeneration. We aim to determine whether emphysema is associated with LIF reduction and whether Sterol regulatory binding protein (SREBP) activation promotes LIF differentiation and fibroblast stem cell niche properties. We quantified LIF in the lungs of patients with emphysema compared to controls by co-staining Vimentin/Adipose differentiation-related protein (ADFP). Using available datasets, we explored the expression level of lipogenic pathways in mesenchymal cells. Fibroblasts from patients were isolated and SREBP-mediated signaling was activated with a Liver X receptor (LXR) agonist T0901317, and compared with Rosiglitazone, a Peroxisome proliferator-activated receptor gamma (PPARγ) agonist (gene expression and lipidomic analysis). The stem cell niche properties of fibroblasts were evaluated through coculture with the H441 cell line or primary AT2 in organoid assays. Patients with emphysema had two times fewer LIF compared to controls. T0901317 induced lipogenic differentiation of human lung fibroblasts and increased triglycerides contents and several phosphatidylcholine forms, particularly Dipalmitoylphosphatidylcholine (PC32_0), one of the main surfactant components. Rosiglitazone only increased ADFP expression with minor effects on lipid components. SREBP mediated signalling in fibroblasts, and to a lesser extent PPARγ activation, increased their stem cell niche properties through the increase of organoid number. LIF are decreased in the alveoli of emphysematous patients. Activation of SREBP-mediated signaling promotes lipogenic differentiation of fibroblasts and enhances their stem cell niche properties.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022663","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":"Protective Role of Apelin in a Mouse Model of Post-Intensive Care Syndrome.","authors":"Yumiko Imai, Yasuha Kinugasa, Ryota Nukiwa, Mara Anais Llamas Covarrubias, Khin Kyaemon Thwin, Kumiko Yonezaki, Takashi Shimizu, Sho Yamasaki, Yusuke Shintani, Hitoshi Hashimoto, Yutaka Suzuki, Yuji Fujino, Kota Kubodera, Toru Kotani, Tomoyuki Furuyashiki, Josef Penninger, Arthur S Slutsky","doi":"10.1165/rcmb.2025-0028OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0028OC","url":null,"abstract":"<p><p>Post-Intensive Care Syndrome (PICS) is a serious condition involving physical weakness, depression, and cognitive impairment that develop during or after an intensive care unit (ICU) stay, often resulting in long-term declines in quality of life. Patients with acute respiratory distress syndrome (ARDS) and severe COVID-19 are at particularly high risk, yet the molecular mechanisms underlying PICS remain poorly understood. Here, we identify impaired Apelin-APJ signaling as a potential contributor to PICS pathogenesis via disruption of inter-organ homeostasis. Using a mouse model combining acute lung injury and hindlimb immobilization, we observed PICS-like features including muscle atrophy, lung inflammation, and neurobehavioral abnormalities such as anxiety-like behavior and special working memory. Single-cell RNA sequencing in brain revealed upregulation of gene programs associated with Alzheimer disease, depression, and neuroinflammation, particularly in endothelial cells and microglia. Concurrently, Apelin-APJ signaling was downregulated in skeletal muscle. These changes were exacerbated in Apelin-deficient mice and attenuated by muscle-specific Apelin overexpression, which also reduced systemic IL-6 and restored circulating Apelin levels. In ARDS survivors with severe COVID-19, ICU-acquired weakness (ICU-AW) was associated with reduced plasma Apelin and elevated IL-6 levels. Transcriptomic profiling of peripheral blood mononuclear cells from ICU-AW patients showed gene expression signatures linked to depression and neurodegeneration, mirroring murine findings. These data suggest that impaired Apelin-APJ signaling may play a role in PICS pathophysiology. While skeletal muscle appears to contribute to systemic Apelin levels, further studies are needed to clarify tissue-specific roles. Modulating this pathway could offer a therapeutic strategy to mitigate long-term outcomes in ICU survivors.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022632","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":"IGFBP7 Contributes to EndMT and Serves as Biomarker for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension.","authors":"Lin Deng, Ziping Wang, Olivier Boucherat, Bin Leng, Chengrui Cao, Muhua He, Zongye Cai, Zhen Chen, Guifu Wu, Sebastien Bonnet, Wenbin Wei, Jin-Song Bian","doi":"10.1165/rcmb.2025-0004LE","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0004LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022665","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":"Airway Goblet Metaplasia Resulting from YAP/TAZ Deletion Drives Pulmonary Inflammatory Responses.","authors":"Nan Cheng, Konstantinos Kontodimas, Adeline Matschulat, Julia Hicks-Berthet, Xaralabos Varelas","doi":"10.1165/rcmb.2025-0169OC","DOIUrl":"https://doi.org/10.1165/rcmb.2025-0169OC","url":null,"abstract":"<p><p>The increased presence of goblet epithelial cells in conducting airways of the respiratory system is common in pulmonary disorders and is often accompanied by disrupted immune and alveolar responses. Signaling effectors that restrict goblet cell production include YAP and TAZ, transcriptional regulators of Hippo signaling, which repress goblet cell differentiation in the airway epithelium. Here, we investigated the acute responses to goblet cell metaplasia that are induced by the conditional loss of YAP/TAZ in club epithelial cells of adult mouse lungs. We found that the increased production of goblet epithelial cells drives inflammatory states broadly throughout airway and alveolar epithelial cells, including in distal alveolar type II (AT2) epithelial cells. We demonstrate that goblet cells produce factors that rapidly activate alveolar macrophages, which stimulate AT2 inflammatory responses, and that depletion of alveolar macrophages rescues AT2 responses to aberrant goblet cell production. These findings demonstrate direct roles for goblet cells in triggering inflammatory signals and reveal a circuitry of cellular communication that is initiated by mucus-producing cells in the lung.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.3,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022661","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":"September Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.73i3RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.73i3RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"73 3","pages":"iii-iv"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939159","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":"GPIIb/IIIa-ICAM-1-Mediated Platelet-Endothelial Adhesion Exacerbates Pulmonary Hypertension.","authors":"Lingdan Chen, Qianwen Bai, Ruidi Tang, Cheng Hong, Chunxian Cen, Qiao Luo, Heying Li, Wenju Lu, Chunli Liu, Shangwei Ding, Jian Wang, Tao Wang","doi":"10.1165/rcmb.2024-0438OC","DOIUrl":"10.1165/rcmb.2024-0438OC","url":null,"abstract":"<p><p>Patients with pulmonary hypertension (PH) typically present with a diminished platelet count, but the role of platelets in the development and progression of PH remains unclear. Our research has uncovered that, within animal models of PH, platelet depletion or transfusion of platelets from healthy donors reduced pulmonary vascular thickening. In contrast, the transfusion of platelets from PH-affected subjects into healthy animals led to an augmentation of pulmonary vascular thickening. Transcriptomic analysis revealed that platelets from patients with PH exhibited an upregulation of genes associated with cellular adhesion, platelet activation, and adhesion. Notably, the hub genes, glycoprotein IIb/IIIa, were implicated in mediating platelet-endothelium adhesion through their interaction with intercellular adhesion molecule-1 (ICAM-1) on pulmonary arterial endothelial cells, triggering platelet activation and the subsequent release of platelet-derived growth factor BB. This release increased the proliferation and migration of pulmonary arterial smooth muscle cells. The pharmacological targeting of ICAM-1 has been shown to mitigate PH in a murine model under hypoxic conditions; however, this ameliorative effect was not observed in thrombocytopenic mice under analogous conditions. In summary, the adhesion of platelets to the endothelium, facilitated by glycoprotein IIb/IIIa and ICAM-1, exacerbates PH by intensifying the thickening of the pulmonary vascular wall through platelet activation and secretion of platelet-derived growth factor BB.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"383-395"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527810","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":"Stub1 Acetylation by CBP/p300 Attenuates Chronic Hypoxic-Driven Pulmonary Hypertension by Suppressing HIF-2α.","authors":"Amanda Czerwinski, Paul Sidlowski, Emily Mooers, Yong Liu, Ru-Jeng Teng, Kirkwood Pritchard, Xigang Jing, Suresh Kumar, Amy Y Pan, Pengyuan Liu, Girija G Konduri, Adeleye J Afolayan","doi":"10.1165/rcmb.2024-0353OC","DOIUrl":"10.1165/rcmb.2024-0353OC","url":null,"abstract":"<p><p>HIF-1/2 (Hypoxia-Inducible Factors 1/2) are fundamental to the development of pulmonary hypertension (PH). Prolonged hypoxia can trigger the shift from HIF-1 to HIF-2 activity, which is critical in PH progression. Ubiquitin ligases regulate HIF activity through protein degradation. However, little is known about if or how these ligases control the HIF-1/2 switch associated with PH progression. We demonstrate that Stub1 (STIP1 homology and U-box containing protein1), an E3 ubiquitin ligase, influences HIF response to hypoxia by suppressing HIF-2 and enhancing HIF-1 mRNA, protein stability, and activity. Stub1 transgenic mice exposed to prolonged hypoxia exhibited significant decreases in pulmonary vessel and right ventricular remodeling, resulting from a failure of chronic hypoxia to trigger the transition from HIF-1α to HIF-2α and activate HIF-2α. Specifically, acute hypoxia induced the acetylation of Stub1 at lysine 287, promoting its translocation into the nucleus and selectively suppressing HIF-2 activity. Despite the decreased total Stub1 expression, the marginal increase in Stub1^K287Ac in the nucleus was sufficient for suppressing chronic hypoxia-induced HIF-2 activity in Stub1 transgenic mice. Our findings established that Stub1 acetylation regulates the putative HIF-1/2α switch driving PH progression in hypoxic and pseudohypoxic conditions.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"369-382"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143527814","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 Critical Role of HMGB1Cys106 in Regulating Sex-Specific p53 Signaling in Pulmonary Arterial Hypertension.","authors":"Odunayo Susan Lawal, Maki Niihori, Joel James, A J Hinkle, Takanori Sano, Nolan McClain, Ruslan Rafikov, Olga Rafikova","doi":"10.1165/rcmb.2024-0296OC","DOIUrl":"10.1165/rcmb.2024-0296OC","url":null,"abstract":"<p><p>HMGB1 (High Mobility Group Box 1) is a nuclear protein released from damaged cells and implicated in the pathogenesis of pulmonary arterial hypertension (PAH) through activation of proinflammatory and prosurvival responses. However, the role of intracellular HMGB1 signaling, particularly its interactions with DNA and transcriptional regulation, remains underexplored. In this study, we investigated the role of intracellular HMGB1 and its critical residue Cys106 by engineering cell-penetrating peptide (αHMGB1Cys106) that mimics part of the HMGB1 dimeric interface surrounding Cys106. The peptide's effects on HMGB1 intracellular distribution, DNA-binding affinity, and p53 expression and signaling were assessed in cell culture and <i>in vivo</i> using the Sugen/Hypoxia rat model of severe PAH. Our findings demonstrate that αHMGB1Cys106 significantly altered HMGB1 intracellular dynamics, prompting its nuclear exit and subsequent degradation. This effect was associated with a decreased HMGB1-DNA binding and reduced p53 expression both <i>in vitro</i> and <i>in vivo</i>. Remarkably, preventive and therapeutic administration of αHMGB1Cys106 mitigated Sugen/Hypoxia-induced PAH development and progression in a sex-specific manner. In females, the peptide therapy reduced pulmonary apoptosis, senescence, and genotoxic stress, providing significant protection in earlier PAH and effectively reversing the PAH phenotype at advanced stages. Conversely, in males, the treatment yielded only partial benefits, primarily through attenuated genotoxic signaling. These results establish Cys106 as a critical regulator of intracellular HMGB1 signaling, which mediates p53-mediated downstream effects and PAH progression in a sex-specific manner.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"396-414"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630011","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":"TBX4 in Pulmonary Hypertension: Linking Lung Development to Precision Therapy.","authors":"Wadih El Khoury, Stephen Y Chan","doi":"10.1165/rcmb.2025-0164ED","DOIUrl":"10.1165/rcmb.2025-0164ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"340-342"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12416304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061941","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":"Transcription Factor EB SUMOylation in Airway Epithelial Cells Impairs Lysosomal Biogenesis to Promote Asthma Development.","authors":"Qianying Yu, Yao Zhou, Jing Wang, Meng Zhang, Caixia Di, Yujiao Wu, Qun Wu, Wen Su, Jinke Cheng, Jiajia Lv, Min Wu, Zhenwei Xia","doi":"10.1165/rcmb.2024-0191OC","DOIUrl":"10.1165/rcmb.2024-0191OC","url":null,"abstract":"<p><p>Lysosomal dysfunction is the primary cause of various immune disorders. Transcription factor EB (TFEB) SUMOylation is critically involved in lysosomal biogenesis. Whether TFEB SUMOylation-associated lysosomal dysfunction contributes to asthma pathogenesis remains to be determined. Here, we observed that ovalbumin stimulation impaired lysosomal function through TFEB SUMOylation, which leads to increased NLRP3 and inflammatory factors. Mechanistically, mutation of the TFEB SUMOylation site did not abolish the ability of its nuclear translocation but increased TFEB stability and binding capability with target genes' promoters, thereby promoting lysosomal biogenesis and bioactivity through liquid-liquid phase separation and thus inhibiting the production of inflammatory factors and alleviating allergic airway inflammation. Our observations demonstrate that TFEB SUMOylation interferes with lysosomal biogenesis, contributing to asthma pathogenesis and lending mechanistic insight into asthmatic disease and improving our understanding of the transcriptional regulation of host immune responses.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"451-465"},"PeriodicalIF":5.3,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490568","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}