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

{"title":"Reflections on the introduction of surfactant therapy for neonates with respiratory distress.","authors":"Fred Possmayer, Ruud A W Veldhuizen, Alan H Jobe","doi":"10.1152/ajplung.00355.2024","DOIUrl":"10.1152/ajplung.00355.2024","url":null,"abstract":"<p><p>When pulmonary surfactant was first detected in the 1950s by Pattle and Clements, many thousands of infants perished each year due to a respiratory illness termed hyaline membrane disease. Hyaline membranes are formed by plasma leaking through damaged endothelial barriers into the terminal bronchiolar: alveolar spaces. Since the leaking plasma lacks erythrocytes, these clots are opaque. Insightful research by Avery and Mead soon led to the suggestion that the neonatal respiratory distress syndrome (RDS) did not arise because of the presence of hyaline membranes, but rather was related to the lack of sufficient pulmonary surfactant, mainly as a result of immaturity. Unfortunately, initial attempts at treating RDS with aerosolized dipalmitoyl-phosphatidylcholine, the major single molecular component, proved unsuccessful. Almost 20 years later, it was demonstrated by Enhorning and Robertson that treating prematurely delivered rabbit pups with natural surfactant prevents respiratory failure. Initially, it appeared unlikely that animal surfactants could be used for therapy with human infants. However, in 1980, Fujiwara demonstrated that a modified bovine surfactant extract promoted gaseous exchange with infants suffering from RDS. Soon a number of bovine and porcine-modified surfactants and two wholly synthetic formulations were shown to alleviate RDS. The present review relates some of the key scientific findings and significant clinical contributions responsible for reducing the neonatal morbidity and mortality associated with RDS. It further describes some of the more recent findings on the biological, biophysical, and physiological significance of pulmonary surfactant in health and disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L554-L563"},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416929","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":"TRAPping the effects of tobacco smoking: the regulation and function of <i>Acp5</i> expression in lung macrophages.","authors":"Suzanne H Willems, Shilei Qian, Pernilla Lång, Bjarne E Overtoom, Sina Alimostafazadeh, Rocío Fuentes-Mateos, Gwenda F Vasse, T Anienke van der Veen, Jelmer Vlasma, Marina H de Jager, Victor Guryev, Gyorgy Fejer, Göran Andersson, Barbro N Melgert","doi":"10.1152/ajplung.00157.2024","DOIUrl":"10.1152/ajplung.00157.2024","url":null,"abstract":"<p><p>Tartrate-resistant acid phosphatase [TRAP, gene acid phosphatase 5 (<i>Acp5;</i> gene name for TRAP)] is highly expressed in alveolar macrophages with proposed roles in lung inflammation and lung fibrosis development. We previously showed that its expression and activity are higher in lung macrophages of smokers and patients with chronic obstructive pulmonary disease (COPD), suggesting involvement in smoke-induced lung damage. In this study, we explored the function of TRAP and regulation of its different mRNA transcripts (<i>Acp5 201-206</i>) in lung tissue exposed to cigarette smoke to elucidate its function in alveolar macrophages. In mice exposed to cigarette smoke or air for 4-6 wk, higher <i>Acp5</i> mRNA expression in lung tissue after smoking was mainly driven by transcript <i>Acp5-202</i>, which originates from macrophages. The expression of <i>Acp5-202</i> correlated with transcription factors previously found to drive proliferation of macrophages. Treating fetal liver progenitor-derived alveolar-like macrophages [Max Planck Institute (MPI; macrophages derived from fetal liver progenitors) macrophages] with cigarette smoke extract resulted in more proliferation compared with nontreated cells. In contrast, <i>Acp5</i>-deficient MPI macrophages and MPI macrophages treated with a TRAP inhibitor proliferated significantly less than control macrophages. Mechanistically, this lack of proliferation after TRAP inhibition was associated with higher presence of phosphorylated Beta-catenin (β-catenin; a signaling protein) compared with nontreated controls. Phosphorylation of β-catenin is known to mark it for ubiquitination and degradation by the proteasome, preventing its activity in promoting cell proliferation. In conclusion, our findings provide strong evidence for TRAP stimulating alveolar macrophage proliferation by dephosphorylating β-catenin. By driving proliferation, TRAP likely helps sustain alveolar macrophage populations during smoke exposure, either compensating for their loss due to smoking or increasing their numbers to better manage smoke-induced damage.<b>NEW & NOTEWORTHY</b> This study has uncovered that the enzyme tartrate-resistant acid phosphatase (TRAP) is crucial for alveolar macrophage proliferation through a β-catenin-dependent pathway. Importantly, TRAP influences this important ability of alveolar macrophages through the <i>Acp5</i>-202 mRNA transcript. The increase in TRAP expression following smoke exposure suggests that it plays a key role in promoting cell renewal, potentially helping to mitigate smoke-induced lung damage.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L497-L511"},"PeriodicalIF":3.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490531","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":"Fibrotic and emphysematous murine lung mechanics under negative-pressure ventilation.","authors":"K A M Quiros, T M Nelson, A Ulu, E C Dominguez, T M Nordgren, M Eskandari","doi":"10.1152/ajplung.00087.2024","DOIUrl":"10.1152/ajplung.00087.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide, and the progressive nature heightens the calamity of the disease. In existing COPD studies, lung mechanics are often reported under positive-pressure ventilation (PPV) and extrapolations made from these studies pose restrictions as recent works have divulged disparate elastic and energetic results between PPV and more physiological negative-pressure ventilation (NPV) counterparts. This nonequivalence of PPV and NPV must be investigated under diseased states to augment our understanding of disease mechanics. To assess the comparability of diseased pulmonary mechanics in PPV and NPV, we pose a novel study to parse out the currently entangled contributions of ventilation mode and diseased state by analyzing murine PV curves from porcine pancreatic elastase (PPE) and hog dust extract (HDE) induced COPD models under positive and negative pressures. We find that, for PPE-exposed, under NPV, volume, compliance (<i>C, C_start</i>, and <i>C_def</i>), and hysteresis are increased in diseased states and that under PPV, only compliance (<i>C</i> and <i>C_start</i>) is increased. For HDE-exposed, under NPV, volume, compliance (<i>C, C_inf</i>, <i>C_def</i>, and <i>K</i>), and hysteresis are decreased, whereas, under PPV, only volume and static compliance decreased. All significant mechanical variations due to disease were observed solely at higher pressures (40 cmH₂O) under both PPV and NPV. Our nuanced conclusions indicate the detection capabilities of multiple mechanics-based biomarkers are sensitive to the ventilation mode, where NPV exhibits more altered mechanics metrics in PPE-exposed and HDE-exposed groups compared with PPV counterparts, suggesting the resolution of biomarkers when applied under NPV research considerations may offer greater versatility.<b>NEW & NOTEWORTHY</b> We evaluate whether ubiquitous pressure-volume (PV) curve biomarkers depend on the ventilation mode under which they were collected (i.e., positive- or negative-pressure ventilation). This is a significant investigation considering recent works have revealed PV curves are distinct and noninterchangeable under the two ventilation modes. Multiple biomarkers noted under negative-pressure ventilation are lacking from positive-pressure counterparts, albeit for small-scale species considerations. Future investigations should confirm the applicability of these findings for large-scale specimens for clinical considerations.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L443-L455"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982362","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":"Engineered hydrogel biomaterials facilitate lung progenitor cell differentiation from induced pluripotent stem cells.","authors":"Alicia E Tanneberger, Rachel Blomberg, Ganna Bilousova, Amy L Ryan, Chelsea M Magin","doi":"10.1152/ajplung.00419.2024","DOIUrl":"10.1152/ajplung.00419.2024","url":null,"abstract":"<p><p>Lung progenitor (LP) cells identified by the expression of transcription factor NK2 homeobox 1 (NKX2.1) are essential for the development of all lung epithelial cell types and hold tremendous potential for pulmonary research and translational regenerative medicine applications. Here, we present engineered hydrogels as a promising alternative to the naturally derived materials that are often used to differentiate human-induced pluripotent stem cells (iPSCs) into LP cells. Poly(ethylene glycol) norbornene (PEGNB) hydrogels with defined composition were used to systematically investigate the role of microenvironmental stiffness, cell origin, and splitting during the differentiation process. Results demonstrated that each factor impacted LP differentiation efficiency and that the soft hydrogels replicating healthy lung stiffness [elastic modulus (<i>E</i>) = 4.00 ± 0.25 kPa] produced the highest proportion of LP cells based on flow cytometric analysis results (54%) relative to the stiff hydrogels (48%) and Matrigel controls (32%) at the end of the nonsplit differentiation protocol. Collectively, these results showed that engineered hydrogels provide a well-defined microenvironment for iPSC-to-LP differentiation and perform as effectively as the current gold standard Matrigel-coated tissue culture plastic. Adopting engineered biomaterials in cell culture protocols may enable greater control over differentiation parameters and has the potential to enhance the clinical translation of iPSC-derived LP cells.<b>NEW & NOTEWORTHY</b> Standard iPSC differentiation protocols rely on Matrigel, a basement membrane extract from mouse sarcoma cells that is poorly defined and exhibits significant batch-to-batch variation. Due to these limitations, Matrigel-derived products have never been approved by the Food and Drug Administration. This study introduces a novel method for differentiating iPSCs into lung progenitor cells using well-defined hydrogel substrates. These biomaterials not only enhance differentiation efficiency but also streamline the regulatory pathway, facilitating their potential therapeutic application.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L379-L388"},"PeriodicalIF":3.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143062986","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":"Parenchymal and inflammatory responses to ozone exposure in the aging healthy and surfactant protein C mutant lung.","authors":"Jenna R Cheminant, Cassandra E Deering-Rice, Christopher B Massa, Ujjwal Adhikari, Jessica Noll, Christopher A Reilly, Alessandro Venosa","doi":"10.1152/ajplung.00261.2024","DOIUrl":"10.1152/ajplung.00261.2024","url":null,"abstract":"<p><p>Ozone (O₃) is a ubiquitous pollutant known to produce acute, transient inflammation through oxidative injury and inflammation. These effects are exacerbated in susceptible populations, such as the elderly and those exhibiting genetic mutations in central nodes of pulmonary function. To comprehend the impact of these predisposing factors, the present study examines structural, mechanical, and immunological responses to single acute O₃ exposure (0.8 ppm, 3 h) in young (8-14-wk old), middle-aged (44-52-wk old), and old (>80-wk old) mice. Furthermore, this work compares the impact of a clinically relevant mutation in the gene encoding for the alveolar epithelial type 2 specific surfactant protein C. Aging was associated with reduced lung resistance and increases in respiratory elastic properties, the latter of which was exacerbated in SP-C mutant mice. Ozone exposure produced focal injury localized at the terminal bronchiole-to-alveolar junctions and enlarged alveoli in aged SP-C mutant lungs. Flow cytometric analysis revealed increases in mononuclear myeloid abundance in aged SP-C mutant lungs, paired with a contraction in CD8⁺ expressing cells. Expansion of tertiary lymphoid tissues was also noted in aged groups, more evident in the mutant mice. Spatial transcriptomics of CD68⁺ macrophages and CD45^- nonimmune parenchymal cells highlighted age-dependent shifts in inflammatory and extracellular matrix organization signaling, and enrichment in senescence and chromatin remodeling pathways. These results illustrate the structural and immunological impact of O₃ in the aging wild-type and mutant lung and emphasize the significance of modeling environmental exposure in at-risk populations.<b>NEW & NOTEWORTHY</b> Environmental stress and genetic mutations in key functional nodes are linked to the pathogenesis and exacerbation of respiratory pathologies. These responses are exacerbated by aging, though the impact of these factors in combination is not clearly defined. Using a surfactant protein-C mutant line, our studies describe structural changes and phenotypic responses triggered by acute ozone exposure in the young/middle-aged/old lung. Spatial transcriptomics also found regionally distinct and enhanced activation in the aged lung.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L334-L349"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998422","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":"Carotid bodies mediate glial cell activation and neuroinflammation in the NTS following long-term intermittent hypoxia: role in cardiorespiratory dysfunction.","authors":"Katherin Pereyra, Esteban Diaz-Jara, Ignacio Bernal-Santander, Sinay Vicencio, Rodrigo Del Rio, Rodrigo Iturriaga","doi":"10.1152/ajplung.00280.2024","DOIUrl":"10.1152/ajplung.00280.2024","url":null,"abstract":"<p><p>Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, heightened chemosensory discharges of the carotid body (CB), which contributes to potentiate the ventilatory hypoxic response and elicits hypertension. We aimed to determine <i>1</i>) whether the persistence of cardiorespiratory alterations found in long-term CIH depends on the inputs from the CB and <i>2</i>) in what extension the activation of glial cells and neuroinflammation in the caudal region of the nucleus of the solitary tract (NTS) require functional CB chemosensory activity. To evaluate these hypotheses, we exposed male mice to CIH for 60 days. At 50 days of CIH, CBs were denervated and animals were kept in CIH for 10 additional days. At the end of the experiments, we measured arterial blood pressure, breathing regularity, and hypoxic ventilatory response (HVR) and assessed astrocyte and microglia cell activation. Compared to sham treatment, CIH induced hypertension [mean arterial blood pressure (MABP): 83.47 ± 1.39 vs. 95.00 ± 2.18 mmHg] and disordered breathing [irregularity score (IS): 7.77 ± 0.49 vs. 12.56 ± 1.66], increased the HVR [1.69 ± 0.17 vs. 4.31 ± 0.87 change in minute ventilation (ΔV̇e)/min], and produced an early transient activation of astrocytes followed by a late and persistent activation of microglia in the NTS. In addition, CIH increased IL-1β, IL-6, and TNF-α levels in the NTS. Bilateral CB denervation after 50 days of CIH results in the restoration of normal glial cell activation in the NTS, lower levels of IL-6 and TNF-α, and reductions in arterial blood pressure (83.47 ± 1.38 mmHg) and HVR (1.63 ± 0.43 ΔV̇e/min). The present results suggest that CB inputs to the NTS during long-term CIH contribute to maintain the cardiorespiratory alterations and the formation of a neuroinflammatory niche at the NTS by modifying glial cell activity.<b>NEW & NOTEWORTHY</b> Chronic intermittent hypoxia (CIH), a feature of obstructive sleep apnea, causes cardiorespiratory alterations (i.e. hypertension) linked to oxidative stress, inflammation, and sympathoexcitation. In the present study, we highlight the role of enhanced carotid body (CB) chemosensory afferent discharges to the nucleus of the solitary tract (NTS) in long-term CIH-induced cardiorespiratory disorders. Indeed, we provide evidence that supports the notion that increased CB afferent activity contributes to persistent CIH-induced hypertension, likely triggering neuroinflammation in the NTS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L357-L371"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942647","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":"Secondhand vape exposure regulation of CFTR and immune function in cystic fibrosis.","authors":"Benjamin L Wisniewski, Mahesh Shrestha, Dinesh Bojja, Chandra L Shrestha, Chris S Lee, Hazel Ozuna, Rachael E Rayner, Shasha Bai, Estelle Cormet-Boyaka, Susan D Reynolds, Benjamin T Kopp","doi":"10.1152/ajplung.00328.2024","DOIUrl":"10.1152/ajplung.00328.2024","url":null,"abstract":"<p><p>Secondhand smoke exposure (SHSe) is a public health threat for people with cystic fibrosis (CF) and other lung diseases. Primary smoking reduces CF transmembrane conductance regulator (CFTR) channel function, the causative defect in CF. We reported that SHSe worsens respiratory and nutritional outcomes in CF by disrupting immune responses and metabolic signaling. Recently, electronic cigarette (e-cigs) usage by caregivers and peers has increased rapidly, causing new secondhand e-cig vape exposures. Primary vaping is associated with immunologic deficits in healthy people, but it is unknown whether e-cigs similarly impacts CF immune function or how it differs from SHSe. Human CF and non-CF blood monocyte-derived macrophages (MDMs) and bronchial epithelial cells (HBECs) were exposed to flavored and unflavored e-cigs. The effect of e-cigs on CFTR expression and function, bacterial killing, cytokine signaling, lipid mediators, and metabolism was measured during treatment with CFTR modulators. E-cigs decreased CFTR expression and function in CF and non-CF MDMs and negated CFTR functional restoration by elexacaftor/tezacaftor/ivacaftor (ETI). E-cigs also negated the restoration of anti-inflammatory PGD₂ expression in CF MDMs treated with ETI compared with controls. Flavored but not unflavored e-cigs increased proinflammatory cytokine expression in CF MDMs and e-cigs promoted glycolytic metabolism. E-cigs did not impact bacterial killing. Overall, HBECs were less impacted by e-cigs compared with MDMs. E-cigs reduced macrophage CFTR expression and hindered functional CFTR restoration by CFTR modulators, promoting a glycolytic, proinflammatory state. E-cigs are an emerging public health threat that may limit the efficacy of CFTR modulators in people with CF.<b>NEW & NOTEWORTHY</b> New research reveals that e-cigarettes pose a serious health risk for individuals with cystic fibrosis (CF). Exposure to electronic cigarette (e-cig) vapors decreases CF transmembrane conductance regulator (CFTR) function and undermines the effectiveness of CFTR modulators, potentially worsening inflammation and metabolic responses. This highlights an urgent need for awareness around e-cig use, especially among caregivers and peers of those with CF. E-cigarettes may further complicate the management of this chronic lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L324-L333"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12164564/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998424","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":"Enhanced lung endothelial glycolysis is implicated in the development of severe pulmonary hypertension in type 2 diabetes.","authors":"Qiuyu Zheng, Jody Tori O Cabrera, Atsumi Tsuji-Hosokawa, Francisco J Ramirez, Hua Cai, Jason X-J Yuan, Jian Wang, Ayako Makino","doi":"10.1152/ajplung.00305.2023","DOIUrl":"10.1152/ajplung.00305.2023","url":null,"abstract":"<p><p>Metabolic abnormalities in pulmonary endothelial cells are implicated in pulmonary hypertension (PH) while increasing evidence shows the influence of diabetes on progressing PH. In this study, we examined the effect of type 2 diabetes on hypoxia-induced PH and investigated its molecular mechanisms using hypoxia-induced diabetic male mice. Chronic hypoxia led to a more severe PH in type 2 diabetic mice than in control mice. Next, we compared gene expression patterns in isolated pulmonary endothelial cells (MPECs) from control mice in normoxia (CN), diabetic mice in normoxia (DN), control mice exposed to hypoxia (CH), and diabetic mice exposed to hypoxia (DH). The results showed that expression levels of 27 mRNAs, out of 92 mRNAs, were significantly different among the four groups. Two glycolysis-related proteins, GAPDH and HK2, were increased in MPECs of DH mice compared with those in DN or CH mice. In addition, the levels of pyruvate and lactate (glycolysis end products) were significantly increased in MPECs of DH mice, but not in CH mice, compared with MPECs of CN mice. Augmentation of glycolysis by terazosin exacerbated hypoxia-induced PH in CH mice but not in DH mice. On the contrary, inhibiting GAPDH (a key enzyme of the glycolytic pathway) by koningic acid ameliorated hypoxia-induced PH in DH mice but had no effect in CH mice. These data suggest that enhanced glycolysis in diabetic mice is involved in severe hypoxia-induced PH, and glycolysis inhibition is a potential target to reduce the severe progression of PH in patients with diabetes.<b>NEW & NOTEWORTHY</b> Increasing evidence shows that diabetes exacerbates the progression of pulmonary hypertension; however, its molecular mechanisms are understudied. In this study, we revealed that augmented glycolysis in diabetic pulmonary endothelial cells is involved in the development of severe PH in diabetes. Inhibition of glycolysis could be a therapeutic strategy for treating pulmonary hypertension in patients with diabetes.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L430-L442"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492919","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":"Epigenetic age acceleration in idiopathic pulmonary fibrosis revealed by DNA methylation clocks.","authors":"Daniel B Kurbanov, Farida Ahangari, Taylor Adams, Ruben De Man, Jessica Tang, Marianne Carlon, Nebal Abu Hussein, Emmanuela Cortesi, Marta Zapata, Laurens De Sadelaar, Wim Wuyts, Bart Vanaudenaerde, Naftali Kaminski, John E McDonough","doi":"10.1152/ajplung.00171.2024","DOIUrl":"10.1152/ajplung.00171.2024","url":null,"abstract":"<p><p>In this research, we delve into the association between epigenetic aging and idiopathic pulmonary fibrosis (IPF), a debilitating lung disease that progresses over time. Utilizing the Illumina MethylationEPIC array, we assessed DNA methylation levels in donated human lung tissue from patients with IPF, categorizing the disease into mild, moderate, and severe stages based on clinical assessments. We used seven epigenetic clocks to determine age acceleration, which is the discrepancy between biological (epigenetic) and chronological age. Our findings revealed a notable acceleration of biological aging in IPF tissues compared with healthy controls, with four clocks-Horvath's, Hannum's, PhenoAge, and DunedinPACE-showing significant correlations. DunedinPACE, in particular, indicated a more rapid aging process in the more severe regions within the lungs of IPF cases. These results suggest that the biological aging process in IPF is expedited and closely tied to the severity of the disease. The study underscores the potential of DNA methylation as a biomarker for IPF, providing valuable insights into the underlying methylation patterns and the dynamics of epigenetic aging in affected lung tissue. This research supports the broader application of epigenetic clocks in clinical prognosis and highlights the critical role of biological age in the context of medical research and healthcare.<b>NEW & NOTEWORTHY</b> Using epigenetic clocks, we found a notable acceleration of biological aging in IPF tissues, particularly in DunedinPACE, suggesting that the biological aging process in IPF is accelerated and closely related to the severity of the disease. The study also underscores DNA methylation's potential as a biomarker for IPF, as well as the dynamics of epigenetic aging and the need to consider biological age in medical research and healthcare.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L456-L462"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456823","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 circulating renin-angiotensin system and mortality among patients hospitalized for COVID-19: a mechanistic substudy of the ACTIV-4 Host Tissue trials.","authors":"Christopher L Schaich, Mark C Chappell, Matthew S Shotwell, Meghan M Joly, Kevin W Gibbs, Aaron Barksdale, Ivor S Douglas, Peter Chen, Joseph E Levitt, Michael A Puskarich, Todd W Rice, Michelle S Harkins, Kristin M Hudock, Michael J Lanspa, Adit A Ginde, Wesley H Self, Sean P Collins, D Clark Files","doi":"10.1152/ajplung.00372.2024","DOIUrl":"10.1152/ajplung.00372.2024","url":null,"abstract":"<p><p>SARS-CoV-2 targets angiotensin-converting enzyme-2 (ACE2), a key peptidase of the renin-angiotensin system (RAS), which regulates the balance of the vasoconstrictor/inflammatory peptide Ang II and the vasodilator/anti-inflammatory peptide Ang-(1-7). Few studies have quantified the circulating elements of the RAS longitudinally in SARS-CoV-2 infection and their association with COVID-19 outcomes. Thus, we evaluated the association of circulating RAS enzymes and peptides with mortality among patients with COVID-19. Blood samples were collected from 111 patients with COVID-19 and new-onset hypoxemia during the delta and omicron waves at 19 hospitals in the United States. Circulating RAS components were quantified via radioimmunoassay or ELISA at 0 (baseline), 1, 3, and 5 days after randomization. We used multivariable Cox regression to estimate the association of baseline and longitudinal RAS concentrations with 90-day mortality. Participants were aged 18-90 (means [SD]: 55 [14]) yr and 62% were male. There were 22 (20%) deaths over 90 days of follow-up. ACE2 levels above the sample median (≥4.9 pM; adjusted HR [95% CI]: 0.10 [0.02, 0.43]) and ACE2/ACE ratio (≥6.0 × 10^-3; adjusted HR: 0.08 [0.02, 0.39]) were associated with significantly lower mortality. Similarly, when analyzed as continuous, log₂-normalized, time-varying predictors from <i>day 0</i> to <i>day 5</i>, twofold increments of ACE2 and ACE2/ACE ratio over this period were associated with lower mortality (adjusted HR: 0.79 [0.65, 0.97] and 0.78 [0.63, 0.97], respectively). Circulating Ang II, Ang-(1-7), and ACE levels were not associated with mortality. These results suggest higher circulating ACE2 protein in hospitalized patients with COVID-19 is associated with reduced mortality.<b>NEW & NOTEWORTHY</b> We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L405-L412"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12101116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063094","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}