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

{"title":"The effect of adrenalectomy on bleomycin-induced pulmonary fibrosis in mice.","authors":"John McGovern, Carrighan Perry, Alexander Ghincea, Erica L Herzog, Shuai Shao, Huanxing Sun","doi":"10.1152/ajplung.00062.2024","DOIUrl":"10.1152/ajplung.00062.2024","url":null,"abstract":"<p><p>Progressive lung fibrosis is often fatal and has limited treatment options. Though the mechanisms are poorly understood, fibrosis is increasingly linked with catecholamines such as adrenaline (AD) and noradrenaline (NA) and hormones such as aldosterone (ALD). The essential functions of the adrenal glands include the production of catecholamines and numerous hormones, but the contribution of adrenal glands to lung fibrosis remains less well studied. Here, we characterized the impact of surgical adrenal ablation in the bleomycin model of lung fibrosis. Wild-type mice underwent surgical adrenalectomy or sham surgery followed by bleomycin administration. We found that although bleomycin-induced collagen overdeposition in the lung was not affected by adrenalectomy, histologic indices of lung remodeling were ameliorated. These findings were accompanied by a decrease of lymphocytes in bronchoalveolar lavage (BAL) and macrophages in lung tissues, along with concomitant reductions in alpha-smooth muscle actin (αSMA) and fibronectin. Surgical adrenalectomy completely abrogated AD, not NA, detection in all compartments. Systemic ALD levels were reduced after adrenalectomy, whereas ALD levels in lung tissues remained unaffected. Taken together, these results support the presence of a pulmonary-adrenal axis in lung fibrosis and suggest that adrenalectomy is protective in this disease. Further investigation will be needed to better understand this observation and aid in the development of novel therapeutic strategies.<b>NEW & NOTEWORTHY</b> The lung-adrenal axis plays a significant role in pulmonary fibrosis. Adrenalectomy provides protection against lung fibrotic ECM remodeling and lung inflammation by reducing the levels of lymphocytes in BAL and macrophages in lung of bleomycin-treated mice. Although compared with sham surgery, adrenalectomy raised collagen concentration in uninjured mice, there was no discernible difference in bleomycin-induced collagen accumulation. However, adrenalectomy significantly reversed the enhanced expression and colocalization of αSMA and fibronectin induced by bleomycin.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L15-L29"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520719","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":"Leukocyte kinetics and bacterial clearance during <i>Streptococcus pneumoniae</i> pneumonia and contributions of ICAM-1.","authors":"Matthew K McPeek, John C Gomez, Jessica R Martin, Marie Anne Iannone, Hong Dang, Claire M Doerschuk","doi":"10.1152/ajplung.00039.2024","DOIUrl":"10.1152/ajplung.00039.2024","url":null,"abstract":"<p><p><i>Streptococcus pneumoniae</i> is a leading cause of community-acquired pneumonia. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is highly expressed on the pulmonary capillary endothelium, alveolar epithelium, and other cell types within the lung. ICAM-1 plays important roles in leukocyte adhesion, migration, and motility. To determine the contributions of ICAM-1 to bacterial clearance and leukocyte kinetics during pneumonia, mice were inoculated with <i>S. pneumoniae</i> and evaluated 1, 4, and 7 days later. Our results show that <i>Icam1</i>^-/- mice have a greater number of viable bacteria within the lung at each time point. The impaired clearance observed in <i>Icam1</i>^-/- mice was not due to an impediment in leukocyte recruitment. In fact, <i>Icam1</i>^-/- mice had a greater number of neutrophils and recruited inflammatory macrophages in the lung tissue and the alveoli/airways on <i>day 7</i>. In contrast, fewer alveolar macrophages were present in the bronchoalveolar lavage (BAL) of <i>Icam1^-/-</i> mice. The loss of body weight and the concentrations of inflammatory mediators in the BAL were also significantly greater in <i>Icam1</i>^-/- mice. Mechanistic studies to understand the defect in clearance show that neutrophils and macrophage subpopulations had no defect in phagocytosis or acidification of phagosomes. RNA sequencing reveals many differences in gene expression but no suggestion of a defect in phagocytosis or killing. Thus, ICAM-1 is necessary for the clearance of <i>S. pneumoniae</i> and for the resolution of pneumonia but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways during <i>S. pneumoniae-</i>induced pneumonia.<b>NEW & NOTEWORTHY</b> <i>Streptococcus pneumoniae</i> is the leading cause of community-acquired pneumonia. Our study examined ICAM-1, an adhesion molecule that is expressed on most cell types and plays important roles in leukocyte adhesion, migration, and motility. The data demonstrate that ICAM-1 is necessary for the clearance of <i>S. pneumoniae</i> and for the resolution of pneumonia but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L41-L59"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492921","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":"Navigating the extravascular lung waters of pulmonary edema in COVID-19 ARDS.","authors":"Pranav Jain, Georgios D Kitsios","doi":"10.1152/ajplung.00383.2024","DOIUrl":"10.1152/ajplung.00383.2024","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L176-L178"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806068","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":"Dynamic driving pressure predicts ventilator-induced lung injury in mice with and without endotoxin-induced acute lung injury.","authors":"Alison Wallbank, Alexander Sosa, Andrew Colson, Huda Farooqi, Elizabeth Kaye, Katharine Warner, David J Albers, Peter D Sottile, Bradford J Smith","doi":"10.1152/ajplung.00176.2024","DOIUrl":"10.1152/ajplung.00176.2024","url":null,"abstract":"<p><p>Mechanical ventilation (MV) is a necessary lifesaving intervention for patients with acute respiratory distress syndrome (ARDS) but it can cause ventilator-induced lung injury (VILI), which contributes to the high ARDS mortality rate (∼40%). Bedside determination of optimally lung-protective ventilation settings is challenging because the evolution of VILI is not immediately reflected in clinically available, patient-level, data. The goal of this work was therefore to test ventilation waveform-derived parameters that represent the degree of ongoing VILI and can serve as targets for ventilator adjustments. VILI was generated at three different positive end-expiratory pressures in a murine inflammation-mediated (lipopolysaccharide, LPS) acute lung injury model and in initially healthy controls. LPS injury increased the expression of proinflammatory cytokines and caused widespread atelectasis, predisposing the lungs to VILI as measured in structure, mechanical function, and inflammation. Changes in lung function were used as response variables in an elastic net regression model that predicted VILI severity from tidal volume, dynamic driving pressure (PD_Dyn), mechanical power calculated by integration during inspiration or the entire respiratory cycle, and power calculated according to Gattinoni' s equation. Of these, PD_Dyn best predicted functional outcomes of injury using either data from the entire dataset or from 5-min time windows. The windowed data show higher predictive accuracy after an ∼1-h \"run in\" period and worse accuracy immediately following recruitment maneuvers. This analysis shows that low driving pressure is a computational biomarker associated with better experimental VILI outcomes and supports the use of driving pressure to guide ventilator adjustments to prevent VILI.<b>NEW & NOTEWORTHY</b> Elastic net regression analysis of ventilation waveforms recorded during mechanical ventilation of initially healthy and lung-injured mice shows that low driving pressure is a computational biomarker associated with better ventilator-induced lung injury (VILI) outcomes and supports the use of driving pressure to guide ventilator adjustments to prevent VILI.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L159-L175"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724781","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":"Pulmonary-delivered Anticalin Jagged-1 antagonists reduce experimental airway mucus hyperproduction and obstruction.","authors":"Katharina Heinzelmann, Athanasios Fysikopoulos, Thomas J Jaquin, Janet K Peper-Gabriel, Eva-Maria Hansbauer, Stefan Grüner, Josef Prassler, Claudia Wurzenberger, Joseph G C Kennedy, Jazmin Y Snead, Joe A Wrennall, Kristina Heinig, Cornelia Wurzenberger, Rachida-Siham Bel Aiba, Robert Tarran, Alessandra Livraghi-Butrico, Mary F Fitzgerald, Gary P Anderson, Christine Rothe, Gabriele Matschiner, Shane A Olwill, Matthias Hagner","doi":"10.1152/ajplung.00059.2024","DOIUrl":"10.1152/ajplung.00059.2024","url":null,"abstract":"<p><p>Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs. Hence, pulmonary delivery of therapeutic agents is a promising approach to target this pathway while minimizing systemic exposure. Using Anticalin technology, Jagged-1 Anticalin binding proteins were generated and engineered to potent and selective inhalable Jagged-1 antagonists. Their therapeutic potential to reduce airway mucus hyperproduction and obstruction was investigated ex vivo and in vivo. In primary airway cell cultures grown at an air-liquid interface and stimulated with inflammatory cytokines, Jagged-1 Anticalin binding proteins reduced both mucin gene expression and mucous cell metaplasia. In vivo, prophylactic and therapeutic treatment with a pulmonary-delivered Jagged-1 Anticalin binding protein reduced mucous cell metaplasia, epithelial thickening, and airway mucus hyperproduction in IL-13 and house dust mite allergen-challenged mice, respectively. Furthermore, in a transgenic mouse model with pathophysiologic features of cystic fibrosis and chronic obstructive pulmonary disease (COPD), pulmonary-delivered Jagged-1 Anticalin binding protein reduced hallmarks of airway mucus obstruction. In all in vivo models, a reduction of mucous cells with a concomitant increase of ciliated cells was observed. Collectively, these findings support Jagged-1 antagonists' therapeutic potential for patients with muco-obstructive lung diseases and the feasibility of targeting the Jagged-1/Notch pathway by inhalation.<b>NEW & NOTEWORTHY</b> Airway mucus drives severity and mortality in diverse chronic lung diseases. The Jagged-1/Notch pathway controls the balance of ciliated versus mucous cells, but targeting the pathway systemically carries the risk of side effects. Here we developed novel, Anticalin-derived, pulmonary-delivered Jagged-1 antagonists, to inhibit airway mucus hyperproduction and obstruction in chronic lung diseases. Our preclinical data demonstrate the effectiveness of these antagonists in diminishing secretory cell and mucus levels and alleviating hallmarks of mucus obstruction.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L75-L92"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581450","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":"Antenatal steroids enhance long-term neonatal lung outcomes and are associated with placental alterations in experimental chorioamnionitis.","authors":"Adom Netsanet, Gregory J Seedorf, Steven H Abman, Elizabeth S Taglauer","doi":"10.1152/ajplung.00204.2024","DOIUrl":"10.1152/ajplung.00204.2024","url":null,"abstract":"<p><p>Intrauterine inflammation from chorioamnionitis (CA) is associated with placental dysfunction and increased risk of bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity. Antenatal steroid (ANS) treatment improves early respiratory outcomes for premature infants. However, it remains unclear whether ANS improves long-term respiratory outcomes, and whether these effects are mediated through the improvement of placental dysfunction and/or direct impact on the fetal lung. We hypothesized that maternal ANS therapy preserves long-term lung development and impacts placental structural changes and gene expression in experimental CA with features of BPD. Pregnant rat dams were administered either saline (CTL), intra-amniotic (IA) endotoxin (ETX), ETX plus intramuscular (IM) betamethasone (ETX + BETA), or IM BM alone (BETA) on <i>embryonic day 20</i> (E20). We collected placental tissue at delivery (E22) and infant lung tissue on the <i>day of life</i> (DOL) <i>14</i>. In comparison with controls, IA ETX had impaired infant lung growth and function. Maternal BM treatment of ETX-exposed pregnant dams reduced infant total lung resistance by 15.3% (<i>P</i> < 0.05), improved infant lung compliance by 9.5% (<i>P</i> < 0.05), preserved alveolar and vascular growth (<i>P</i> < 0.05), and improved right ventricular hypertrophy (RVH) by 42.4% (<i>P</i> < 0.05). ETX + BETA pregnancies were also associated with normalization of placental spiral artery modification and altered placental gene expression. These included the upregulation of placental prolactin, which has regulatory effects on pregnancy homeostasis and has been clinically associated with decreased BPD risk. The current study identifies parallel lung and placental changes associated with ANS treatment, providing a foundation for future studies to identify alternate antenatal therapies with more specific efficacy for BPD prevention.<b>NEW & NOTEWORTHY</b> We performed parallel neonatal lung and placental analyses in a preclinical model to characterize the impact of antenatal betamethasone in experimental chorioamnionitis. Antenatal steroids improved long-term respiratory outcomes and were associated with concurrent structural and molecular changes in the placenta. This study establishes an important model system for future analyses to evaluate mechanistic links determining whether the long-term impact of antenatal steroids on lung development may be through alteration of placental function.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L197-L205"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862998","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":"Citrullinated and malondialdehyde-acetaldehyde-modified fibrinogen activates macrophages and promotes profibrotic responses in human lung fibroblasts.","authors":"Nozima Aripova, Michael J Duryee, Wenxian Zhou, Bryant R England, Carlos D Hunter, Lauren E Klingemann, Nigina Aripova, Amy J Nelson, Dawn Katafiasz, Kristina L Bailey, Jill A Poole, Geoffrey M Thiele, Ted R Mikuls","doi":"10.1152/ajplung.00153.2024","DOIUrl":"10.1152/ajplung.00153.2024","url":null,"abstract":"<p><p>The objective of this study was to assess fibrinogen (FIB) comodified with citrulline (CIT) and/or malondialdehyde-acetaldehyde (MAA) initiates macrophage-fibroblast interactions, leading to extracellular matrix (ECM) deposition that characterizes rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Macrophages (Mϕ) were stimulated with native-FIB, FIB-CIT, FIB-MAA, or FIB-MAA-CIT. Supernatants (SNs) [Mϕ-SN (U-937-derived) or MϕP-SN (PBMC-derived)] or direct antigens were coincubated with human lung fibroblasts (HLFs). Gene expression was examined using RT-PCR. ECM deposition was quantified using immunohistochemistry and Western blot; cell signaling mechanisms were delineated. Platelet-derived growth factor (PDGF)-BB and TGF-β were measured in macrophage supernatants, and inhibition studies were performed using Su16f and SB431542, respectively. HLF gene expression of <i>CD36</i>, <i>COL6A3</i>, <i>MMP-9</i>, <i>MMP-10</i>, and <i>MMP-12</i> was increased following stimulations with Mϕ-SN generated from modified FIB but not from direct antigens. HLF stimulated with MϕP-SN^FIB-MAA-CIT derived from patients with RA-ILD resulted in 4- to 30-fold increases in <i>COL6A3</i> and <i>MMP12</i> expression; upregulation was greater in HLFs stimulated with MϕP-SN derived from RA-ILD versus controls. HLF exposure to Mϕ-SN^FIB-MAA-CIT increased types I/VI collagen deposition versus all other Mϕ-SN groups and was greater than FIB-MAA-CIT stimulation. PDGF-BB and TGF-β signaling had the highest concentrations identified in Mϕ-SN^FIB-MAA-CIT and MϕP-SN^FIB-MAA-CIT, particularly from RA-ILD-derived cells. PDGF-BB and TGF-β inhibitors, alone and in combination, significantly reduced HLF-mediated ECM deposition from Mϕ-SN stimulations. These results show that comodified fibrinogen activates macrophages to produce PDGF-BB and TGF-β that promotes an aggressive HLF phenotype characterized by increased ECM deposition. These results suggest that targeting CIT and/or MAA modifications or downstream cellular signals could represent novel approaches to RA-ILD treatment.<b>NEW & NOTEWORTHY</b> This report demonstrates that fibrinogen simultaneously harboring two common posttranslational modifications activates macrophages to secrete platelet-derived growth factor (PDGF)-BB and transforming growth factor (TGF)-β. Resulting cross talk between activated macrophages and human lung fibroblasts leads to marked increases in extracellular matrix deposition. These protein modifications are abundant and colocalize in lung tissues from patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD), and the results suggest that agents targeting citrullination and/or malondialdehyde-acetaldehyde (MAA) adduct formation could represent novel therapeutic strategies.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L134-L147"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905797/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666782","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":"Hypoxic effects of heroin and fentanyl and their basic physiological mechanisms.","authors":"Eugene A Kiyatkin","doi":"10.1152/ajplung.00251.2024","DOIUrl":"10.1152/ajplung.00251.2024","url":null,"abstract":"<p><p>Respiratory depression that diminishes oxygen delivery to the brain is the most dangerous effect of opioid drugs. Although plethysmography is a valuable tool to examine drug-induced changes in respiration, the primary cause of brain abnormalities induced by opioids is the global decrease in brain oxygen levels. The primary goal of this review is to provide an overview and discussion on fluctuations in brain oxygen levels induced by opioids, with a focus on heroin and fentanyl. To evaluate fluctuations in brain oxygen levels, we used oxygen sensors coupled with high-speed amperometry in awake, freely moving rats. First, we provide an overview of brain oxygen responses induced by natural physiological stimuli and discuss the mechanisms regulating oxygen entry into brain tissue. Then, we present data on brain oxygen responses induced by heroin and fentanyl and review their underlying mechanisms. These data allowed us to compare the effects of these drugs on brain oxygen regarding their latency, potency, time-dependency, and potential lethality at high doses as well as their relationships with peripheral oxygen responses. We also discuss data on the effects of naloxone on brain oxygen responses induced by heroin and fentanyl in the paradigms of both the pretreatment and treatment, when naloxone is administered at different times after the primary opioid drug. Although most data discussed were obtained in rats, they may have clinical relevance for understanding the mechanisms underlying the physiological effects of opioids and developing rational treatment strategies to decrease acute lethality and long-term health complications of opioid misuse.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L930-L948"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455990","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":"Disruption of immune responses by type 1 diabetes exacerbates SARS-CoV-2 mediated lung injury.","authors":"Sara Kass-Gergi, Gan Zhao, Joanna Wong, Aaron I Weiner, Stephanie Adams Tzivelekidis, Maria E Gentile, Meryl Mendoza, Nicolas P Holcomb, Xinyuan Li, Madeline Singh, Yuru Huang, Alena Klochkova, Andrew E Vaughan","doi":"10.1152/ajplung.00250.2024","DOIUrl":"10.1152/ajplung.00250.2024","url":null,"abstract":"<p><p>COVID-19 commonly presents as pneumonia, with those most severely affected progressing to respiratory failure. Patient responses to SARS-CoV-2 infection are varied, with comorbidities acting as major contributors to varied outcomes. Focusing on one such major comorbidity, we assessed whether pharmacological induction of type 1 diabetes mellitus (T1DM) would increase the severity of lung injury in a murine model of COVID-19 pneumonia utilizing wild-type mice infected with mouse-adapted SARS-CoV-2. Hyperglycemic mice exhibited increased weight loss and reduced blood oxygen saturation in comparison with their euglycemic counterparts, suggesting that these animals indeed experienced more severe lung injury. Transcriptomic analysis revealed a significant impairment of the adaptive immune response in the lungs of diabetic mice compared with those of control. To expand the limited options available for tissue analysis due to biosafety restrictions, we also employed a new technique to digest highly fixed tissue into a single-cell suspension, originally designed for scRNA-Seq, which we then adapted for flow cytometric analysis. Flow immunophenotyping and scRNA-Seq confirmed impaired recruitment of T-cells into the lungs of T1DM animals. In addition, scRNA-Seq revealed a distinct, highly inflammatory macrophage profile in the diabetic cohort that correlates with the more severe infection these mice experienced clinically, allowing insight into a possible mechanism for this phenomenon. Recognizing the near certainty that respiratory viruses will continue to present significant public health concerns for the foreseeable future, our study provides key insights into how T1DM results in a much more severe infection and identifies possible targets to ameliorate comorbidity-associated severe disease.<b>NEW & NOTEWORTHY</b> We define the exacerbating effects of type 1 diabetes mellitus (T1DM) on COVID-19 pneumonia severity in mice. Hyperglycemic mice experienced increased weight loss and reduced oxygen saturation. Transcriptomic analysis revealed impaired immune responses in diabetic mice, while flow cytometry and single-cell RNA sequencing confirmed reduced T-cell recruitment and an inflammatory macrophage profile. In addition, we introduced a novel technique for tissue analysis, enabling flow cytometric analysis on highly fixed tissue samples.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L839-L851"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339327","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":"Identification of FGFR4 as a regulator of myofibroblast differentiation in pulmonary fibrosis.","authors":"Mada Ghanem, Aurélien Justet, Madeleine Jaillet, Eirini Vasarmidi, Tiara Boghanim, Mouna Hachem, Aurélie Vadel, Audrey Joannes, Pierre Mordant, Agshin Balayev, Taylor Adams, Hervé Mal, Aurélie Cazes, Nicolas Poté, Arnaud Mailleux, Bruno Crestani","doi":"10.1152/ajplung.00184.2023","DOIUrl":"10.1152/ajplung.00184.2023","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with limited therapeutic options. Fibroblast growth factor receptor-4 (FGFR4) is a known receptor for several paracrine fibroblast growth factors (FGFs). FGFR4 is also the main receptor for FGF19, an endocrine FGF that was demonstrated by our group to have antifibrotic properties in the lung. We aimed to determine whether FGFR4 could modulate pulmonary fibrogenesis. We assessed FGFR4 mRNA and protein levels in IPF and control lungs. In vitro, we determined the effect of transforming growth factor-β (TGF-β), endothelin-1, and platelet-derived growth factor (PDGF) on FGFR4 expression in human lung fibroblasts. We determined the effect of FGFR4 inhibition, using a specific pharmacological inhibitor (FGF401), or genetic deletion in murine embryonic fibroblasts (MEFs) on TGF-β-induced myofibroblastic differentiation. In vivo, we evaluated the development of bleomycin-induced lung fibrosis in <i>Fgfr4</i>-deficient (<i>Fgfr4^-</i>^/-) mice compared with wild-type littermates (WT) and after FGF401 treatment in WT mice compared with a control group receiving the solvent only. FGFR4 was decreased in IPF lungs, as compared with control lungs, at mRNA and protein levels. In vitro, FGFR4 was downregulated after treatment with TGF-β, endothelin-1, and PDGF. In vitro, FGFR4 inhibition by FGF401 prevented TGF-β1-induced collagen and ACTA2 increase in lung fibroblasts. Similar results were observed in <i>Fgfr4^-</i>^/- MEFs. In vivo, FGFR4 genetic deficiency or FGFR4 pharmacological inhibition did not modulate bleomycin-induced pulmonary fibrosis. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo.<b>NEW & NOTEWORTHY</b> FGFR4 has been reported to have antifibrotic effects in the liver. We aimed to determine the involvement of FGFR4 during IPF. Our data suggest that FGFR4 exerts profibrotic properties by enhancing TGF-β signaling in vitro. However, the inhibition of FGFR4 is not sufficient to prevent the development of pulmonary fibrosis in vivo. To our knowledge, this is the first study to assess the profibrotic action of FGFR4 during pulmonary fibrosis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L818-L830"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339331","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}