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

{"title":"Pulmonary vascular remodeling in Fra-2 transgenic mice is driven by type 2 inflammation and accompanied by pulmonary vascular hyperresponsiveness.","authors":"Anna Birnhuber, Valentina Biasin, Pritesh P Jain, Grzegorz Kwiatkowski, Ekaterina Boiarina, Jochen Wilhelm, Katharina Ahrens, Chandran Nagaraj, Andrea Olschewski, Martin Witzenrath, Stefan Chlopicki, Leigh M Marsh, Christoph Tabeling, Grazyna Kwapiszewska","doi":"10.1152/ajplung.00274.2024","DOIUrl":"10.1152/ajplung.00274.2024","url":null,"abstract":"<p><p>Lung vessel remodeling leads to increased pulmonary vascular resistance, causing pulmonary arterial hypertension (PAH), and consequently right ventricular hypertrophy and failure. In patients suffering from systemic sclerosis (SSc), PAH can occur and is a life-threatening complication. Dysregulation of immune processes plays a crucial role in pulmonary vascular remodeling, as has previously been shown in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH. Here, we investigate whether vascular remodeling in the Fra-2 TG model is driven by type 2 inflammation and is associated with vascular hyperresponsiveness, an important feature of PAH pathobiology. Basal pulmonary arterial pressure and pulmonary vascular responsiveness to hypoxic ventilation and serotonin were increased in isolated, perfused, and ventilated lungs of Fra-2 TG mice compared with wild-type (WT) littermates. Similarly, contractile responses of isolated intrapulmonary arteries were elevated in Fra-2 TG mice. We also observed increased expression of contractile genes in Fra-2 overexpressing human pulmonary arterial smooth muscle cells (PASMCs) with elevated intracellular calcium levels after interleukin (IL)-13 stimulation. These findings were corroborated by transcriptomic data highlighting dysregulation of vascular smooth muscle cell contraction and type 2 inflammation in Fra-2 TG mice. In vivo, type 2-specific anti-inflammatory treatment with IL-13 neutralizing antibodies improved vascular remodeling in Fra-2 TG mice, similar to corticosteroid treatment with budesonide. Our results underscore the importance of type 2 inflammation and its potential therapeutic value in PAH-associated pulmonary vascular remodeling and hyperresponsiveness in SSc-PAH.<b>NEW & NOTEWORTHY</b> In patients suffering from systemic sclerosis (SSc), pulmonary arterial hypertension (PAH) is a life-threatening complication linked to immune dysregulation. Preclinical analyses in Fos-related antigen-2 (Fra-2) transgenic (TG) mice, a model of SSc-PAH, identify type 2 inflammation as a key driver of vascular remodeling. Anti-inflammatory treatment targeting type 2 inflammation via IL-13 neutralizing antibodies improved pulmonary vascular remodeling. Thus, type 2-specific anti-inflammatory treatment may be a promising therapeutic approach in SSc-PAH.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L413-L429"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187746","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":"Effects of maternal edible THC consumption on offspring lung growth and function in a rhesus macaque model.","authors":"Lyndsey E Shorey-Kendrick, B Adam Crosland, Matthias C Schabel, Ilhem Messaoudi, Minzhe Guo, Matthew G Drake, Zhenying Nie, R Clayton Edenfield, Issac Cinco, Michael H Davies, Jason A Graham, Olivia L Hagen, Owen J T McCarty, Cindy T McEvoy, Eliot R Spindel, Jamie O Lo","doi":"10.1152/ajplung.00360.2024","DOIUrl":"10.1152/ajplung.00360.2024","url":null,"abstract":"<p><p>Prenatal cannabis use is rising, in part due to legalization and perceptions of safety. The impact of prenatal cannabis exposure on offspring development, especially respiratory health, remains largely unknown. The objective of this study was to determine whether in utero exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, is deleterious to offspring lung development and function using a rhesus macaque model. Female rhesus macaques received a daily edible containing either THC (2.5 mg/7 kg/day, equivalent to a heavy medical cannabis dose) or placebo during gestation and postnatally. Serial in utero magnetic resonance imaging (MRI) was performed during pregnancy at approximately gestational days (G)110 and G150. At 6 mo of age, infants underwent pulmonary function testing, followed by tissue collection for molecular analysis (bulk RNAseq, whole genome bisulfite sequencing, and spatial RNAseq). THC-exposed infants displayed significantly reduced forced residual capacity, which correlated with nonsignificant decreases in total lung capacity, lung diffusion capacity and lower fetal lung perfusion, oxygen availability, and lung volume measured by MRI. Consistent with these decreases in volume indices, levels of pulmonary growth factors were decreased in bronchial alveolar lavage at 6 mo. Molecular analysis of infant lungs revealed altered epigenetic regulation of gene expression, including at genes involved in extracellular matrix organization and lung development, and activation of immune signaling. Our study suggests that exposure to prenatal edible THC alters epigenetic regulation of lung gene expression and may negatively affect offspring lung development and function. Data from this study will help guide healthcare provider counseling on cannabis use in pregnancy.<b>NEW & NOTEWORTHY</b> In a translational rhesus macaque model, chronic prenatal delta-9-tetrahydrocannabinol exposure resulted in decreased lung volumes in offspring measured at 6 mo of age. These decreases correlated with altered DNA methylation in the lung, including at genes involved in extracellular matrix organization, lung development, and activation of immune signaling, and changes in lung cell composition as measured by spatial transcriptomics. These findings add to the growing evidence that prenatal cannabis exposure may adversely affect offspring development.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L463-L477"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187682","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":"Surfactant protein levels and genetic variants as biomarkers for COVID-19 severity in children.","authors":"Natalie Sicher, Brycen Aldrich, Shaoyi Zhang, Lauren Mazur, Susan Juarez, Erik Lehman, Dajiang Liu, Chintan K Gandhi","doi":"10.1152/ajplung.00318.2024","DOIUrl":"10.1152/ajplung.00318.2024","url":null,"abstract":"<p><p>Since its outbreak, the novel coronavirus (COVID-19) has significantly impacted the pediatric population. Pulmonary surfactant dysfunction has been linked to other respiratory diseases in children and COVID-19 in adults, but its role in COVID-19 severity remains unclear. We hypothesized that elevated surfactant protein (SP) levels and single nucleotide polymorphisms (SNPs) of SP genes are associated with severe COVID-19 in children. We enrolled 325 COVID-19 positive children and categorized them as having mild or severe disease. Plasma SP-A, SP-B, and SP-D levels were measured. DNA was extracted and genotyped for SNPs in five SP genes, <i>SFTPA1</i>, <i>SFTPA2</i>, <i>SFTPB</i>, <i>SFTPC</i>, and <i>SFTPD</i>. Quantile regression was used to compare SP levels between groups, and receiver operating curve analysis determined an optimal cutoff value of SP level for predicting severe COVID-19. Logistic regression evaluated the odds ratio (OR) for severe disease and associations between SNPs and COVID-19 severity. We found that increased plasma SP-A levels, but not SP-B or SP-D, were significantly associated with severe COVID-19. No significant correlation was observed between age and SP levels. A plasma SP-A level of 10 ng/mL was identified as the optimal cutoff for predicting severe COVID-19, with an OR of 5.9, indicating that children with SP-A levels above this threshold are nearly six times more likely to develop severe COVID-19 disease. In addition, the rs8192340 of <i>SFTPC</i> was associated with decreased risk of severe COVID-19 before, but not after, Bonferroni correction. These findings suggest that plasma SP-A may serve as a potential biomarker for severe COVID-19 in children.<b>NEW & NOTEWORTHY</b> Surfactant dysfunction is linked to other pulmonary diseases, but its role in pediatric coronavirus (COVID-19) is unclear. We found elevated plasma surfactant protein (SP)-A levels, but not SP-B or SP-D, significantly associated with severe COVID-19. A plasma SP-A threshold of 10 ng/mL predicted severe COVID-19. The rs8192340 of <i>SFTPC</i> was associated with decreased risk of severe COVID-19 before, but not after, Bonferroni correction. These findings suggest plasma SP-A may serve as a potential biomarker for pediatric COVID-19 severity.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L350-L356"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998497","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":"Every breath you take: exploring macrophages and environmental exposures in the lung-a tribute to Dr. Joseph Brain's legacy.","authors":"Larissa A Shimoda, Julie A Bastarache, Rodney D Britt, Wolfgang M Kuebler","doi":"10.1152/ajplung.00407.2024","DOIUrl":"10.1152/ajplung.00407.2024","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L321-L323"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998421","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":"Shear stress-induced restoration of pulmonary microvascular endothelial barrier function following ischemia reperfusion injury requires VEGFR2 signaling.","authors":"Don Walsh, Daria S Kostyunina, Aoife Blake, John Boylan, Paul McLoughlin","doi":"10.1152/ajplung.00200.2024","DOIUrl":"10.1152/ajplung.00200.2024","url":null,"abstract":"<p><p>Normal shear stress produced by blood flow is sensed by the vascular endothelium and required for maintenance of the homeostatic functions of the endothelium in systemic conduit and resistance vessels. Many critical illnesses are characterized by periods of abnormally reduced or absent shear stress in the lung (e.g., hemorrhagic shock, embolism, ischemia reperfusion injury, and lung transplantation) and are complicated by pulmonary edema following reperfusion due to microvascular leak. The role of shear stress in regulating the pulmonary microvascular endothelial barrier in the intact vascular bed has not been previously examined. We tested the hypothesis that, in lungs injured by a period of ischemia and reperfusion (IRI), reduced shear stress contributes to increased pulmonary microvascular endothelial barrier permeability and edema formation. Furthermore, we examined the role of vascular endothelial-derived growth factor receptor 2 (VEGFR2) as a mechanosensor mediating the endothelial response to this altered shear stress. Following IRI, we perfused isolated ventilated mouse lungs with a low viscosity solution (LVS) or a higher, physiological viscosity solution (PVS) at constant flow to produce differing endothelial shear stresses in the intact microcirculation. Lungs perfused with LVS developed pulmonary edema due to increased endothelial permeability whereas those perfused with PVS were protected from edema formation by reduced endothelial permeability. This effect of PVS required normal VEGFR2 mechanoreceptor function. These data show for the first time that shear stress has an important role in restoring endothelial barrier function in the intact pulmonary microcirculation following injury and have important implications for the treatment of pulmonary edema in critically ill patients.<b>NEW & NOTEWORTHY</b> Critical illnesses are frequently complicated by noncardiogenic pulmonary edema. Many such illnesses include periods of reduced blood flow, often accompanied by hemodilution, which together reduce endothelial shear stress. We report that in ischemia-reperfusion injury reduced shear stress contributes to increased permeability of the in situ pulmonary microvascular endothelium and worsens alveolar edema. Restoring shear stress toward normal reduces endothelial permeability and edema formation, an effect that requires the normal mechanoreceptor function of VEGFR2.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L389-L404"},"PeriodicalIF":3.6,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863000","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 mysterious case of missing lymphocytes: a cautionary tale of interinstitutional variability in outcomes of lung dissociation protocols.","authors":"Olivia S Harlow, Vijay Raaj Ravi, Fang Ke, Nathan L Sanders, Elise Armstrong, Joseph P Mizgerd, Anukul T Shenoy","doi":"10.1152/ajplung.00323.2024","DOIUrl":"10.1152/ajplung.00323.2024","url":null,"abstract":"<p><p>Rigor and reproducibility are vital to scientific advancement. It is unclear whether a protocol optimized for tissue dissociation in one institution performs well universally. Here, we share our brand-new lab's experience with interinstitutional variability that led to the discovery that a protocol optimized for murine lung dissociation at Boston University (BU) fails to reproduce similar CD4⁺ T cell, CD8⁺ T cell, and B cell outcomes at the University of Michigan at Ann Arbor (U-M). We report that the type 2 collagenase-based protocol from BU yields reduced numbers of lung lymphocytes at U-M, and this appeared to be a result of harsher collagenase activity despite using identical protocols, reagents, and vendors at both institutions. This variability could not be explained by higher Ca²⁺ levels in Ann Arbor water (which we posited may heighten the collagenase activity) but instead appeared to be due to technical details within the protocol that led to the protocols behaving in an institution-specific manner. Indeed, we find that merely switching between the protocol from BU and a newly optimized protocol at U-M was sufficient to improve (or worsen) lymphocyte yields from murine lungs when synchronously performed at both institutions. Taken together, although the reason(s) for the interinstitutional variability in lymphocyte outcomes remains unknown, this report serves as a cautionary tale against directly adopting lung dissociation protocols across institutions without reoptimization, and calls for careful inspection of cross-institutional reproducibility of previously described protocols.<b>NEW & NOTEWORTHY</b> Rigor and reproducibility are vital to scientific advancement. It is unclear whether a protocol optimized for tissue dissociation in one institution performs well universally. Here, the authors share their experience with interinstitutional variability that led to the discovery that a protocol optimized for murine lung dissociation in one institution failed to reproduce similar lymphocyte outcomes elsewhere. This report, thus, serves as a cautionary tale against directly adopting tissue dissociation protocols across institutions without reoptimization.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L260-L266"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941552","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":"Vitamin D as an add-on therapy to phosphodiesterase-5 inhibitor in experimental pulmonary arterial hypertension.","authors":"Rui Adão, Bianca Barreira, Elena Paternoster, Daniel Morales-Cano, Miguel A Olivencia, Begoña Quintana-Villamandos, Diego A Rodríguez-Chiaradía, Angel Cogolludo, Francisco Perez-Vizcaino","doi":"10.1152/ajplung.00319.2024","DOIUrl":"10.1152/ajplung.00319.2024","url":null,"abstract":"<p><p>Severe vitamin D (vitD) deficiency is a very common condition in patients with pulmonary arterial hypertension (PAH), and it is a predictor of poor prognosis. There is emerging evidence suggesting a connection between the insufficient response to phosphodiesterase-5 inhibitors (PDE5i) and vitD deficiency in patients with PAH. In the present translational study, vitD deficiency was induced in Wistar rats by exposure to vitD-free diet for 5 wk and followed by Su5416 administration and hypoxia (10%) for 3 wk, a standard experimental model of PAH. Then, rats were randomized to either <i>1</i>) the PDE5i tadalafil and continuing vitD-free diet or <i>2</i>) tadalafil plus a single dose of vitD and standard diet for 4 wk. VitD supplementation improved exercise capacity and right ventricular function and decreased systolic right ventricular pressure, right atrial hypertrophy, right ventricular hypertrophy, and pulmonary arterial remodeling. VitD improved the ex vivo endothelium-dependent response to acetylcholine, indicating an improvement in NO bioavailability, which also resulted in an acute ex vivo response to sildenafil. Thus, the restoration of vitD, by rescuing endothelial function and PDE5i effectiveness, significantly improved the histological, hemodynamic, and functional features of rats with PAH. VitD may be especially beneficial for PDE5i-treated patients with PAH.<b>NEW & NOTEWORTHY</b> Severe vitamin D deficiency is very prevalent in patients with pulmonary arterial hypertension. We show that addition of vitamin D to the standard PDE5 inhibitor tadalafil increases its therapeutic efficacy in pulmonary hypertensive rats that were deficient in vitamin D.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L253-L259"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942641","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":"Caspase inhibition restores collagen Iα1 and fibronectin release in cigarette smoke extract-exposed human lung fibroblasts.","authors":"Agnese La Mensa, Marco Buscetta, Roy R Woldhuis, Maura Cimino, Maria Rita Giuffrè, Marta Cristaldi, Paola Dino, Luigi Fiore, Alberto Fucarino, Giovanna Lo Iacono, Alessandro Bertani, Corry-Anke Brandsma, Fabio Bucchieri, Chiara Cipollina","doi":"10.1152/ajplung.00214.2024","DOIUrl":"10.1152/ajplung.00214.2024","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by obstructed airflow, airway remodeling, and inflammation, with cigarette smoke (CS) exposure being the main risk factor. Although CS extract (CSE) has been shown to activate caspases in various cell types, the role of caspases in human lung fibroblasts (hLFs) in COPD remains poorly understood. Recent studies have linked caspases to extracellular matrix (ECM) remodeling in skin and kidney fibrosis. Caspase activation can be triggered by oxidative stress, with active caspase-3 executing the pore-forming protein gasdermin E (GSDME) in the cleaved N-terminal form GSDME-NT. We investigated whether CSE activates caspases and GSDME in hLFs and their role in ECM remodeling. MRC-5 lung fibroblasts were treated with CSE with or without the antioxidant <i>N</i>-acetyl-cysteine (NAC) and the caspase-8 inhibitor z-IETD-fmk. We measured the effects on caspase-1-8-3/7 activation, GSDME cleavage, ECM remodeling (procollagen Iα1, COLIα1, and fibronectin, FN), and mitochondrial superoxide (mSOX) generation. Key findings were validated in patient-derived hLFs (phLFs). Our results showed that CSE induced caspase-1-8-3/7 activation, mSOX generation, and decreased COLIα1 and FN levels in MRC-5. CSE caused caspase-8-dependent activation of caspase-3, leading to GSDME cleavage. Treatment with NAC inhibited mSOX and caspase activation. Inhibition of caspase-8 and mSOX restored FN and COLIα1 levels. In phLFs, we confirmed caspase-1 and -8 activation, mSOX increase, COLIα1/FN decrease, and the effects of NAC. Our findings highlight the role of the axis caspase-8-3/7-GSDME and mSOX in regulating ECM protein, suggesting that these pathways may contribute to remodeling in COPD.<b>NEW & NOTEWORTHY</b> This research investigates the connection between caspases, gasdermins, and extracellular matrix (ECM) remodeling in the context of cigarette smoke-associated lung diseases. The study found that cigarette smoke extract (CSE) activates caspases and gasdermin E in human lung fibroblasts, leading to decreased ECM protein expression and release. Findings herein reported suggest that targeting the caspase-8-3/7-gasdermin axis and mitochondrial reactive oxygen species may help restore ECM remodeling in chronic lung diseases associated with cigarette smoke exposure.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L239-L252"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942649","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":"Evidence of sex differences in ozone-induced oxysterol and cytokine levels in differentiated human nasal epithelial cells.","authors":"Dre'Von A Dobson, Alexia Perryman, Erin McNell, Hye-Young H Kim, Ned A Porter, Meghan E Rebuli, Ilona Jaspers","doi":"10.1152/ajplung.00332.2024","DOIUrl":"10.1152/ajplung.00332.2024","url":null,"abstract":"<p><p>Acute exposure to ozone (O₃) causes upper and lower airway inflammation. We and others have previously demonstrated that O₃ oxidizes lipids, particularly cholesterol, into electrophilic oxysterols, such as secosterol B (SecoB), which can adduct proteins, thus altering cellular signaling pathways. To investigate how O₃-derived oxysterols influence cytokine and chemokine release, nasal epithelial cells (HNECs) from healthy donors (<i>n</i> = 18 donors) were exposed to 0.4 ppm O₃ for 4 h. Afterward, immune mediators in apical washes and basolateral supernatants were analyzed using ELISAs, whereas sterol and oxysterol levels were examined using liquid-chromatography mass spectrometry (LC-MS). O₃ exposure increased SecoB, 7-ketocholesterol (7Keto-Chol), 27-hydroxycholesterol (27OH-Chol), and epoxycholesterols in a sex-dependent manner. Female-derived HNECs had significant increases in SecoB, 27OH-Chol, and β-epoxycholesterol, whereas male-derived cells showed increases in 7Keto-Chol only. O₃ decreased the release of granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-7 but increased interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), VEGF, and Eotaxin. Females exhibited O₃-induced IL-1β and VEGF increases, whereas males showed increased Eotaxin and reduced GM-CSF. Basolaterally, O₃ exposure decreased GM-CSF and thymus and activation-regulated chemokine (TARC) while raising IL-6, IL-13, IL-1β, IL-8, and TNFα. Females showed higher TNFα and IL-1β, but males did not. Oxysterols correlated differently with cytokines by sex. Females showed positive correlations between oxysterols and proinflammatory cytokines like IL-6 and IL-1β, whereas males displayed negative correlations with IL-6, IL-8, and TNFα. In conclusion, O₃-induced cytokine/chemokine responses and sterol/oxysterol levels in HNECs vary by sex, with donor-specific oxysterols associated with O₃-triggered inflammatory mediator release.<b>NEW & NOTEWORTHY</b> It is increasingly recognized that lung biology and responses to pollutant exposures differ in males and females. Using a model of differentiated nasal epithelial cells from male and female donors, our data demonstrate that pollutant-induced cytokine/chemokine responses and oxidized lipid levels vary by sex, with donor-specific oxidized lipids linked to inflammatory mediator release.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L207-L214"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881075","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":"mTOR signaling regulates multiple metabolic pathways in human lung fibroblasts after TGF-β and in pulmonary fibrosis.","authors":"Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka","doi":"10.1152/ajplung.00189.2024","DOIUrl":"10.1152/ajplung.00189.2024","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis is a fatal disease characterized by the transforming growth factor (TGF-β)-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lungs with scar tissue. We and others have shown that TGF-β-mediated activation of the mechanistic target of rapamycin complex 1 (mTORC1) and downstream upregulation of activating transcription factor 4 (ATF4) promotes metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts, whereas mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq datasets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of patients with IPF. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.<b>NEW & NOTEWORTHY</b> Here, we used transcriptomic and metabolomic approaches to develop a more complete understanding of the role that mTOR, and its downstream effector ATF4, play in promoting metabolic reprogramming in lung fibroblasts. We identify novel metabolic pathways that may promote pathologic phenotypes, and we provide evidence from single-cell RNA-seq datasets that similar metabolic reprogramming occurs in patient lungs.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L215-L228"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913182","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}