American journal of physiology. Lung cellular and molecular physiology最新文献

{"title":"Endothelial PHD2 deficiency induces apoptosis resistance and inflammation via AKT activation and AIP1 loss independent of HIF2α.","authors":"Shuibang Wang, Keytam S Awad, Li-Yuan Chen, Mohammad A H Siddique, Gabriela A Ferreyra, Caroline L Wang, Thea Joseph, Zu-Xi Yu, Kazuyo Takeda, Cumhur Y Demirkale, You-Yang Zhao, Jason M Elinoff, Robert L Danner","doi":"10.1152/ajplung.00077.2024","DOIUrl":"10.1152/ajplung.00077.2024","url":null,"abstract":"<p><p>In hypoxic and pseudohypoxic rodent models of pulmonary hypertension (PH), hypoxia-inducible factor (HIF) inhibition attenuates disease initiation. However, HIF activation alone, due to genetic alterations or use of inhibitors of prolyl hydroxylase domain (PHD) enzymes, has not been definitively shown to cause PH in humans, indicating the involvement of other mechanisms. Given the association between endothelial cell dysfunction and PH, the effects of pseudohypoxia and its underlying pathways were investigated in primary human lung endothelial cells. <i>PHD2</i> silencing or inhibition, while activating HIF2α, induced apoptosis-resistance and IFN/STAT activation in endothelial cells, independent of HIF signaling. Mechanistically, PHD2 deficiency activated AKT and ERK, inhibited JNK, and reduced AIP1 (ASK1-interacting protein 1), all independent of HIF2α. Like PHD2, <i>AIP1</i> silencing affected these same kinase pathways and produced a similar dysfunctional endothelial cell phenotype, which was partially reversed by AKT inhibition. Consistent with these in vitro findings, AIP1 protein levels in lung endothelial cells were decreased in <i>Tie2-Cre</i>/<i>Phd2</i> knockout mice compared with wild-type controls. Lung vascular endothelial cells from patients with pulmonary arterial hypertension (PAH) showed IFN/STAT activation. Lung tissue from both SU5416/hypoxia PAH rats and patients with PAH all showed AKT activation and dysregulated AIP1 expression. In conclusion, PHD2 deficiency in lung vascular endothelial cells drives an apoptosis-resistant and inflammatory phenotype, mediated by AKT activation and AIP1 loss independent of HIF signaling. Targeting these pathways, including PHD2, AKT, and AIP1, holds the potential for developing new treatments for endothelial dysfunction in PH.<b>NEW & NOTEWORTHY</b> HIF activation alone does not conclusively lead to human PH, suggesting that HIF-independent signaling may also contribute to hypoxia-induced PH. This study demonstrated that <i>PHD2</i> silencing-induced pseudohypoxia in human lung endothelial cells suppresses apoptosis and activates STAT, effects that persist despite HIF2α inhibition or knockdown and are attributed to AKT and ERK activation, JNK inhibition, and AIP1 loss. These findings align with observations in lung endothelial cells and tissues from PAH rodent models and patients.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L503-L519"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003398","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":"Circulating free heme induces cytokine storm and pulmonary hypertension through the MKK3/p38 axis.","authors":"Mathews Valuparampil Varghese, Joel James, Dinesh Bharti, Franz Rischard, Olga Rafikova, Ruslan Rafikov","doi":"10.1152/ajplung.00422.2022","DOIUrl":"10.1152/ajplung.00422.2022","url":null,"abstract":"<p><p>Hemolysis is associated with pulmonary hypertension (PH), but the direct contribution of circulating free heme to the PH pathogenesis remains unclear. Here, we show that the elevated levels of circulating free heme are sufficient to induce PH and inflammatory response in mice and confirm the critical role of mitogen-activated protein kinase kinase-3 (MKK3)-mediated pathway in free heme signaling. Following the continuous infusion of heme for 2 wk, wild-type (WT) but not MKK3 knockout (KO) mice develop PH, as evidenced by a significantly elevated right ventricular (RV) systolic pressure, RV hypertrophy, and pulmonary vascular remodeling. The MKK3/p38 axis, markedly activated by heme infusion in WTs, results in upregulated proliferative/cytokine signaling targets Akt, ERK1/2, and STAT3, which were abrogated in MKK3 KO mice. Moreover, the MKK3 KOs were protected against heme-mediated endothelial barrier dysfunction by restoring the tight junction protein zonula occludens-1 expression and diminishing the inflammatory cell infiltration in the lungs. Plasma cytokine multiplex analysis revealed a severe cytokine storm already 24 h after initiation of heme infusion, with a significant increase of 19 cytokines, including IL-1b, IL-2, IL-6, IL-9, and TNF-a, in WT animals and complete attenuation of cytokine production in MKK3 KO mice. Together, these findings reveal a causative role of circulating free heme in PH through activating inflammatory and proliferative responses. The central role of MKK3 in orchestrating the heme-mediated pathogenic response supports MKK3 as an attractive therapeutic target for PH and other lung inflammatory diseases linked to hemolytic anemia.<b>NEW & NOTEWORTHY</b> This study demonstrates that elevated levels of circulating free heme can induce pulmonary hypertension (PH) and inflammation in mice. Continuous heme infusion activated the MKK3/p38 pathway, leading to increased right ventricular pressure, right ventricular hypertrophy, and vascular remodeling. This activation upregulated signaling cascades such as Akt, ERK1/2, and STAT3, whereas MKK3 knockout mice were protected against these changes and had reduced inflammatory responses, highlighting MKK3's potential as a therapeutic target for PH.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L574-L586"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142085857","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":"Comparative biophysical study of clinical surfactants using constrained drop surfactometry.","authors":"Yi Y Zuo","doi":"10.1152/ajplung.00058.2024","DOIUrl":"10.1152/ajplung.00058.2024","url":null,"abstract":"<p><p>Surfactant replacement therapy is crucial in managing neonatal respiratory distress syndrome (RDS). Currently licensed clinical surfactants in the United States and Europe, including Survanta, Infasurf, Curosurf, and Alveofact, are all derived from bovine or porcine sources. We conducted a comprehensive examination of the biophysical properties of these four clinical surfactant preparations under physiologically relevant conditions, using constrained drop surfactometry (CDS). The assessed biophysical properties included the adsorption rate, quasi-static and dynamic surface activity, resistance to surfactant inhibition by meconium, and the morphology of the adsorbed surfactant films. This comparative study unveiled distinct in vitro biophysical properties of these clinical surfactants and revealed correlations between their chemical composition, lateral film structure, and biophysical functionality. Notably, at 1 mg/mL, Survanta exhibited a significantly lower adsorption rate compared with the other preparations at the same surfactant concentration. At 10 mg/mL, Infasurf, Curosurf, and Survanta all demonstrated excellent dynamic surface activity, whereas Alveofact exhibited the poorest quasi-static and dynamic surface activity. The suboptimal surface activity of Alveofact is found to be correlated with its unique monolayer-predominant morphology, in contrast to other surfactants forming multilayers. Curosurf, in particular, showcased superior resistance to biophysical inhibition by meconium compared with other preparations. Understanding the diverse biophysical behaviors of clinical surfactants provides crucial insights for precision and personalized design in treating RDS and other respiratory conditions. The findings from this study contribute valuable perspectives for the development of more efficacious and fully synthetic surfactant preparations.<b>NEW & NOTEWORTHY</b> A thorough investigation into the biophysical properties of four animal-derived clinical surfactant preparations was conducted through constrained drop surfactometry under physiologically relevant conditions. This comparative study unveiled unique in vitro biophysical characteristics among these clinical surfactants, establishing correlations between their chemical composition, lateral film structure, and biophysical functionality. The acquired knowledge offers essential insights for the precise and personalized design of clinical surfactant for the treatment of respiratory distress syndrome and other respiratory conditions.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L535-L546"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003397","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":"Dissecting the lung transcriptome of pulmonary fibrosis-associated pulmonary hypertension.","authors":"Adam J Brownstein, Marco Mura, Gregoire Ruffenach, Richard N Channick, Rajan Saggar, Airie Kim, Soban Umar, Mansoureh Eghbali, Xia Yang, Jason Hong","doi":"10.1152/ajplung.00166.2024","DOIUrl":"10.1152/ajplung.00166.2024","url":null,"abstract":"<p><p>Integrative multiomics can help elucidate the pathophysiology of pulmonary fibrosis (PF)-associated pulmonary hypertension (PH) (PF-PH). Weighted gene coexpression network analysis (WGCNA) was performed on a transcriptomic dataset of explanted lung tissue from 116 patients with PF. Patients were stratified by pulmonary vascular resistance (PVR), and differential gene expression analysis was conducted. Gene modules were correlated with hemodynamics at the time of transplantation and tested for enrichment in the lung transcriptomics signature of an independent pulmonary arterial hypertension (PAH) cohort. We found 1,250 differentially expressed genes between high and low PVR groups. WGCNA identified that black and yellowgreen modules negatively correlated with PVR, whereas the tan and darkgrey modules are positively correlated with PVR in PF-PH. In addition, the tan module showed the strongest enrichment for an independent PAH gene signature, suggesting shared gene expression patterns between PAH and PF-PH. Pharmacotranscriptomic analysis using the Connectivity Map implicated the tan and darkgrey modules as potentially pathogenic in PF-PH, given their combined module signature demonstrated a high negative connectivity score for treprostinil, a medication used in the treatment of PF-PH, and a high positive connectivity score for bone morphogenetic protein (BMP) loss of function. Pathway enrichment analysis revealed that inflammatory pathways and oxidative phosphorylation were downregulated, whereas epithelial-mesenchymal transition was upregulated in modules associated with increased PVR. Our integrative systems biology approach to the lung transcriptome of PF with and without PH identified several PH-associated coexpression modules and gene targets with shared molecular features with PAH warranting further investigation to uncover potential new therapies for PF-PH.<b>NEW & NOTEWORTHY</b> An integrative systems biology approach that included transcriptomic analysis of explanted lung tissue from patients with pulmonary fibrosis (PF) with and without pulmonary hypertension (PH) undergoing lung transplantation, combined with hemodynamic correlation and pharmacotranscriptomics, identified modules of genes associated with pulmonary vascular disease severity. Comparison with an independent pulmonary arterial hypertension (PAH) dataset identified shared gene expression patterns between PAH and PF-PH.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L520-L534"},"PeriodicalIF":3.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974843","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":"Descending motor drive does not interact with muscle metaboreflex for ventilation regulation during rhythmic exercise in healthy humans","authors":"Felipe S. Gomes, Thiago R. Lopes, Richard M. Bruce, Bruno M. Silva","doi":"10.1152/ajplung.00183.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00183.2024","url":null,"abstract":"American Journal of Physiology-Lung Cellular and Molecular Physiology, Ahead of Print. <br/>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"84 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180023","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":"Cigarette smoking prolongs inflammation associated with influenza infection and delays its clearance in mice","authors":"Jelmer R. Vlasma, Tineke Anienke van der Veen, Marina H. De Jager, Martijn C. Nawijn, Corry-Anke Brandsma, Barbro N. Melgert","doi":"10.1152/ajplung.00369.2023","DOIUrl":"https://doi.org/10.1152/ajplung.00369.2023","url":null,"abstract":"American Journal of Physiology-Lung Cellular and Molecular Physiology, Ahead of Print. <br/>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"6 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180022","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 pH-sensitive translocation of V-ATPase in the small airway of cystic fibrosis pigs","authors":"Raul Villacreses, Ian M. Thornell, Xiaopeng Li, Steven E. Mather, Jimena Urbano, David A. Stoltz, Joseph Zabner","doi":"10.1152/ajplung.00147.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00147.2024","url":null,"abstract":"American Journal of Physiology-Lung Cellular and Molecular Physiology, Ahead of Print. <br/>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"111 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180026","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":"Magnitude of Obesity Alone does not Alter the Alveolar Lipidome","authors":"William G. Tharp, Carolyn R. Morris, Yulica Santos-Ortega, Calvin P. Vary, S. Patrick Bender, Anne E. Dixon","doi":"10.1152/ajplung.00112.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00112.2024","url":null,"abstract":"American Journal of Physiology-Lung Cellular and Molecular Physiology, Ahead of Print. <br/>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"14 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180027","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":"Activation of Platelets and the Complement System in Mice with Schistosoma-Induced Pulmonary Hypertension","authors":"Claudia Mickael, Mariah Jordan, Janelle N. Posey, Rubin M. Tuder, Eva Nozik, Joshua M. Thurman, Kurt R. Stenmark, Brian B. Graham, Cassidy Delaney","doi":"10.1152/ajplung.00165.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00165.2024","url":null,"abstract":"American Journal of Physiology-Lung Cellular and Molecular Physiology, Ahead of Print. <br/>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"21 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180024","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 miRNA transfection for screening in precision cut lung slices","authors":"Joanna Nowakowska, Nika Gvazava, Wojciech Langwinski, Kamil Ziarniak, Iran Augusto N Silva, John Stegmayr, Darcy E. Wagner, Aleksandra Szczepankiewicz","doi":"10.1152/ajplung.00138.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00138.2024","url":null,"abstract":"American Journal of Physiology-Lung Cellular and Molecular Physiology, Ahead of Print. <br/>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":"31 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180025","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}