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

{"title":"Allergic airway inflammation amplifies mast cell responses in isolated guinea pig intralobular bronchi.","authors":"Mu Nie, Jielu Liu, Yujiao Xiang, Anthony Wong, Emma Hendriks, Gunnar Nilsson, Jesper Säfholm, Mikael Adner","doi":"10.1152/ajplung.00422.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00422.2024","url":null,"abstract":"<p><p>Excessive uncontrolled airway narrowing is the main cause of the symptoms in asthma, yet the reasons behind this problem are still elusive. As mechanistic studies of isolated airways from asthmatic individuals are almost impossible to perform, the aim of this study was to investigate the contractile responses in intralobular bronchi (ILB) isolated from a guinea asthma model. These distal airways are surrounded by parenchymal tissue and resemble functional characteristics of human bronchi. Isolated ILB were mounted in myographs to measure smooth muscle reactions. To avoid the irreversible post-mortem bronchoconstriction, lungs were filled with ice-cold buffer solution containing 1 µM salbutamol followed by 48 hours incubation of the isolated ILB. Pharmacological characterization of ILB from naïve guinea pigs showed that prostaglandin E₂ induced mild relaxation, whereas histamine, carbachol, leukotriene D₄, and the thromboxane A₂ mimetic U46619 caused robust contractions. Although the responses to contractile agonists (histamine, carbachol and leukotriene D₄ ) were similar, the contractile responses to house dust mite (HDM) in ILB from HDM sensitized and challenged guinea pigs were significantly greater than those from sensitized-only control guinea pigs. Similarly to isolated human small airways, the antigen response was abolished by inhibitors to mast cell mediators such as histamine, leukotrienes and prostanoids. This study presents, for the first time, an investigation of bronchial responses using a guinea pig asthma model, examining airways with pathophysiological features similar to those of asthmatic individuals and comparing them to matched controls. Moreover, the results suggest the potential of mast cells in the development of asthma.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656116","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 cystathionine-γ-lyase inhibitor DL-propargylglycine augments the ability of L-cysteine ethyl ester to overcome the adverse effects of morphine on breathing.","authors":"Paulina M Getsy, Gregory A Coffee, Santhosh M Baby, Walter J May, Fraser Henderson, Zackery T Knauss, Stephen J Lewis","doi":"10.1152/ajplung.00003.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00003.2025","url":null,"abstract":"<p><p>L-cysteine ethyl ester (L-CYSee) overcomes adverse effects elicited by systemic injection of morphine on ventilatory parameters and arterial blood-gas chemistry in rats. L-CYSee or L-cysteine, resulting from the de-esterification of L-CYSee, may enter enzymatic cascades that produce the ventilatory stimulant, hydrogen sulfide (H₂S). DL-propargylglycine (DL-PROP) is an inhibitor of cystathionine-γ-lyase (CSE)-mediated conversion of L-cysteine to H₂S and has been widely used <i>in vivo</i>. Here, we examined whether L-CYSee (2 injections x 500 μmmol/kg, IV)-induced reversal of the changes in ventilation elicited by morphine (10 mg/kg, IV) in freely-moving male Sprague Dawley rats was altered by prior administration of DL-PROP (25 mg/kg, IV). The major findings were (1) the effects of morphine on ventilatory parameters were not affected by subsequent injection of DL-PROP, (2) injection of L-CYSee elicited a prompt reversal of the adverse effects of morphine that was more pronounced in DL-PROP-treated than vehicle-treated rats, and (3) the actions of the second injection of L-CYSee were dramatically augmented in DL-PROP-treated rats. In addition, the changes in many of the ventilatory parameters during a subsequent hypoxic-hypercapnic (HH) gas challenge were augmented substantially by DL-PROP. This study demonstrates that (1) inhibition of CSE with DL-PROP does not affect the ventilatory actions of morphine, (2) reversal effects of L-CYSee were augmented by blockade of CSE, and (3) blockade of CSE augments the ventilatory responses to HH gas challenge in morphine-treated rats. These unexpected findings suggest that the CSE-dependent production of H₂S from L-CYSee countermands L-CYSee reversal of morphine-induced respiratory depression in rats.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656035","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":"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":"","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":"","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":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"","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":"","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":"","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":"","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":"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":"","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":"","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":"","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":"","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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}