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

{"title":"Effects of patient pleural effusion fluids on the BBSome components expression of human benign mesothelial cells.","authors":"Rajesh M Jagirdar, Erasmia Rouka, Eleanna Pitaraki, Ioannis Sarrigeorgiou, Ourania S Kotsiou, Sotiris I Sinis, Eleftherios D Papazoglou, Periklis Marnas, Zoi Malami, Peggy Lymberi, Anastasios D Giannou, Chrissi Hatzoglou, Konstantinos I Gourgoulianis, Sotirios G Zarogiannis","doi":"10.1152/ajplung.00373.2023","DOIUrl":"10.1152/ajplung.00373.2023","url":null,"abstract":"<p><p>Malignant pleural mesothelial cells are affected by the extracellular milieu although such data on benign cells are scarce. Benign cells sense the extracellular environment with the primary cilium (PC) and its molecular complex, the Bardet-Biedl syndrome family of proteins (BBSome), is critical for this process. Here we aimed to assess the changes in BBSome gene expression in ordinary two-dimensional (2-D) and spheroid three-dimensional (3-D) cell cultures after incubation with pleural effusion fluids (PFs) of several etiologies. The benign human mesothelial cells (MeT-5A) were incubated with PF from patients with mesothelioma (Meso-PF), breast cancer (BrCa-PF), hemothorax (Hemo-PF), and congestive heart failure (CHF-PF). Gene expression of <i>BBS1, 2, 4, 5, 7, 9,</i> and <i>18</i> was assessed by quantitative real-time PCR (qRT-PCR) to monitor PF-induced gene expression changes. MeT-5A cell migration using the PC-modulating drugs ammonium sulfate (AS) and lithium chloride (LC) during PF incubation was also determined. BBSome gene expression upon influence of BrCa-PF and Hemo-PF was more pronounced in 2-D compared with 3-D, inducing global changes in 2-D. CHF-PF and Meso-PF also induced changes in 2-D but not as many, while in all cases, MeT-5A grown in 3-D were more resistant to the effects of the PF. Meso-PF decreased 2-D cell migration, while the disturbance of PC in all PF cases resulted in decreased cell migration. These data suggest distinct BBSome molecular profile changes in benign mesothelial cells exposed to malignant and benign PF that is different in each case, in both 2-D and 3-D. Cell migration is sensitive to drug disturbance with PC modulators in PF-exposed cells.<b>NEW & NOTEWORTHY</b> Studying mesothelial PC in pleural physiology and pathophysiology is at an early stage. Previously, we have highlighted the role of the PC in mesothelial cell phenotypes as well as the role of BBSome components in the context of benign and malignant mesothelial cell physiology. Here we extended our contributions by providing evidence on the BBSome changes induced in benign mesothelial cells by their exposure to different etiology PFs.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L105-L112"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520717","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-A and its immunomodulatory roles in infant respiratory syncytial virus infection: a potential for therapeutic intervention?","authors":"Muhammad Pradhika Mapindra, Tania Castillo-Hernandez, Howard Clark, Jens Madsen","doi":"10.1152/ajplung.00199.2024","DOIUrl":"10.1152/ajplung.00199.2024","url":null,"abstract":"<p><p>The vast majority of early-life hospital admissions globally highlight respiratory syncytial virus (RSV), the leading cause of neonatal lower respiratory tract infections, as the major culprit behind the poor neonatal outcomes following respiratory infections. Unlike those of older children and adults, the immune system of neonates looks rather unique, therefore mostly counting on the innate immune system and antibodies of maternal origins. The collaborations between cells and immune compartments during infancy inclines bias toward a T-helper 2 (Th2) immune profile and thereby away from a T-helper 1 (Th1) immune response. What makes it more problematic is that RSV infection also tends to elicit a stronger Th2-biased immune response and drive an aberrant allergy-like inflammation. It is thus evident how RSV infections potentially pave the way for wheezing recurrences and childhood asthma later in life. Surfactant, the essential lung substance for normal breathing processes in mammals, has immunomodulatory properties including lung collectins such as Surfactant Protein-A (SP-A), which is the most abundant protein component of surfactant, and also Surfactant Protein-D (SP-D). Deficiency of SP-A and SP-D has been found to be associated with impaired pathogen clearance and exacerbated immune responses during infections. We therefore conducted a review of the literature to describe pathomechanisms of RSV infections during blunted neonatal immunity potentially facilitating allergy-like inflammatory events within the developing lungs and highlight the potential protective role of the humoral collectin SP-A to mitigate these in the \"early in life\" pulmonary immune system.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L179-L196"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811593","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":"Impaired antiviral immunity in frequent exacerbators of chronic obstructive pulmonary disease.","authors":"Lydia J Finney, Peter Fenwick, Samuel V Kemp, Aran Singanayagam, Michael R Edwards, Kylie B R Belchamber, Tatiana Kebadze, Eteri Regis, Gavin D Donaldson, Patrick Mallia, Louise E Donnelly, Sebastian L Johnston, Jadwiga A Wedzicha","doi":"10.1152/ajplung.00118.2024","DOIUrl":"10.1152/ajplung.00118.2024","url":null,"abstract":"<p><p>Respiratory viruses cause chronic obstructive pulmonary disease (COPD) exacerbations. Rhinoviruses (RVs) are the most frequently detected. Some patients with COPD experience frequent exacerbations (≥2 exacerbations/yr). The relationship between exacerbation frequency and antiviral immunity remains poorly understood. The objective of this study was to investigate the relationship between exacerbation frequency and antiviral immunity in COPD. Alveolar macrophages and bronchial epithelial cells (BECs) were obtained from patients with COPD and healthy participants. Alveolar macrophages were infected with RV-A16 multiplicity of infection (MOI) 5 and BECs infected with RV-A16 MOI 1 for 24. Interferons (IFNs) and proinflammatory cytokines IL-1β, IL-6, C-X-C motif chemokine ligand (CXCL)-8, and TNF were measured in cell supernatants using a mesoscale discovery platform. Viral load and interferon-stimulated genes were measured in cell lysates using quantitative PCR. Spontaneous and RV-induced IFN-β, IFN-γ, and CXCL-11 release were significantly reduced in alveolar macrophages from patients with COPD compared with healthy subjects. IFN-β was further impaired in uninfected alveolar macrophages from patients with COPD with frequent exacerbations 82.0 pg/mL versus infrequent exacerbators 234.7 pg/mL, <i>P</i> = 0.008 and RV-infected alveolar macrophages from frequent exacerbators 158.1 pg/mL versus infrequent exacerbators 279.5 pg/mL, <i>P</i> = 0.022. Release of proinflammatory cytokines CXCL-8, IL-6, TNF, and IL-1β was higher in uninfected BECs from patients with COPD compared with healthy subjects but there was no difference in proinflammatory response to RV between groups. IFN responses to RV were impaired in alveolar macrophages from patients with COPD and further reduced in patients with frequent exacerbations.<b>NEW & NOTEWORTHY</b> COPD exacerbations are commonly triggered by viral infections. Some patients with COPD have frequent exacerbations leading to rapid lung function decline and increased mortality. In this study, antiviral responses (interferons) from bronchial epithelial cells and alveolar macrophages were reduced in patients with COPD compared with healthy participants and further reduced in patients with COPD with frequent exacerbations. Impaired antiviral immunity may lead to frequent COPD exacerbations. Targeted vaccinations and antiviral therapy may reduce exacerbations in COPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L120-L133"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666783","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":"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":"","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":"","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":"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":"","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":"","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":"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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shear stress-induced restoration of pulmonary microvascular endothelial barrier function following ischaemia reperfusion injury requires VEGFR2 signalling.","authors":"Don Walsh, Daria Kostyunina, Aoife Blake, John Boylan, Paul McLoughlin","doi":"10.1152/ajplung.00200.2024","DOIUrl":"https://doi.org/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 characterised by periods of abnormally reduced or absent shear stress in the lung (e.g. haemorrhagic shock, embolism, ischaemia reperfusion injury and lung transplantation) and are complicated by pulmonary oedema 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 ischaemia and reperfusion (IRI), reduced shear stress contributes to increased pulmonary microvascular endothelial barrier permeability and oedema formation. Furthermore, we examined the role of 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 of the intact microcirculation. Lungs perfused with LVS developed pulmonary oedema due to increased endothelial permeability whereas those perfused with PVS were protected from oedema 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 oedema in critically ill patients.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-19","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}