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

{"title":"Mechanical stretch promotes sustained proliferation and inflammation in developing human airway smooth muscle.","authors":"Li Y Drake, Daniel Pfeffer-Kleemann, Emily Y Zhang, Maunick Lefin Koloko Ngassie, Christina M Pabelick, Y S Prakash","doi":"10.1152/ajplung.00070.2025","DOIUrl":"10.1152/ajplung.00070.2025","url":null,"abstract":"<p><p>Preterm infants frequently require respiratory support, including continuous positive airway pressure (CPAP), that imposes mechanical stretch on highly compliant perinatal airways. How this excess stress impacts airway development and function is not completely understood. Using human fetal airway smooth muscle (fASM), a key cell type in airway contractility and remodeling, as a model, we investigated the effects of stretch, focusing on the role of mechanosensitive ion channels Piezo1 and Piezo2. We found that CPAP-like static stretch did not alter Piezo1 and Piezo2 protein expression per se and had a minimal effect on fASM cell proliferation or IL-6 production during the stretch period. However, CPAP-like stretch produces long-term effects in fASM, leading to increased cell proliferation and IL-6 production during the poststretch period, though interestingly, it does not enhance extracellular matrix deposition. The role of Piezo channels appears context-dependent in that the Piezo1 antagonist GsMTx4 reduced baseline proliferation in nonstretched cells but slightly increased proliferation in stretched cells. Piezo1 and Piezo2 inhibition did not alter IL-6 production. These results suggest that stretch induces a sustained increase in cell proliferation and inflammatory responses, which may contribute to long-term remodeling in former preterm infants initially exposed to CPAP.<b>NEW & NOTEWORTHY</b> Mechanical stretch associated with respiratory support can impair airway development and function in neonates, but the mechanisms are not fully understood. Using developing human airway smooth muscle cells exposed to cyclic forces with static stretch to mimic continuous positive airway pressure, we found that stretch dysregulates long-term cell proliferation and inflammatory cytokine production, and mechanosensitive Piezo ion channels may play a role in the proliferation response.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L296-L306"},"PeriodicalIF":3.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648212","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":"Degradation of oxidized phospholipids by lysosomal phospholipase A2 regulates pulmonary fibrosis.","authors":"Doyun Kwak, Song Ling, Natalya Subbotina, James A Shayman, Tomas H Sisson, Kevin K Kim","doi":"10.1152/ajplung.00038.2025","DOIUrl":"10.1152/ajplung.00038.2025","url":null,"abstract":"<p><p>Recent evidence suggests that oxidized phospholipids (oxPLs) play a critical role in the pathogenesis of pulmonary fibrosis. The precise mechanism by which oxPL contributes to fibrosis remains unknown and likely involves complex interactions between epithelial cell injury, phospholipid accumulation, and macrophage activation. We have previously identified lysosomal phospholipase A2 (LPLA2, PLAG15) as a critical enzyme involved in the catabolism of oxPL, especially within alveolar macrophages. We hypothesized that LPLA2 activity would mitigate the accumulation of oxPL within macrophages and thereby influence the development of pulmonary fibrosis. Using wild-type (WT) and LPLA2-null mice, we induced lung injury with bleomycin and assessed lung fibrosis severity, bronchoalveolar lavage (BAL) cell lipid accumulation, and monocyte/macrophage profibrotic activation. Our results show that LPLA2-null mice accumulated significantly more intracellular lipid within their alveolar cells, exhibited higher transforming growth factor-β (TGFβ) levels in their BAL fluid, and developed more severe fibrosis after bleomycin injury compared with WT mice. In vitro studies confirmed that LPLA2 expression in WT bone marrow-derived macrophages limits oxPL accumulation and thereby mitigates their profibrotic activation. Overexpression of LPLA2 in WT mice reduced alveolar cell lipid accumulation, decreased BAL fluid (BALF) TGFβ levels, and attenuated fibrosis. These findings underscore the critical role that LPLA2 plays in regulating lipid accumulation and suggest that enhancing LPLA2 activity within alveolar cells (or the alveolar compartment) could attenuate the fibrotic response following lung injury. By identifying LPLA2 as a key regulator in this pathway, we propose that targeting LPLA2 and related lipid metabolic processes offers a promising therapeutic strategy.<b>NEW & NOTEWORTHY</b> During lung injury and fibrosis, there is accumulation of oxidized phospholipid within macrophages in the alveolar space. This promotes profibrotic macrophage activation, resulting in pulmonary fibrosis. We find that degradation of oxidized phospholipid by lysosomal phospholipase A2 is important in preventing fibrosis. This offers a potential therapeutic target.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L214-L223"},"PeriodicalIF":3.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493413","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":"Understanding and manipulating morphogenetic processes to generate in vitro models of airways.","authors":"Katharina Raasch, Pauline Henrot, Alice Hadchouel-Duvergé, Maeva Zysman, Isabelle Dupin","doi":"10.1152/ajplung.00015.2025","DOIUrl":"10.1152/ajplung.00015.2025","url":null,"abstract":"<p><p>Branching morphogenesis, the process by which cells and tissues organize into complex branched tubular structures, is fundamental to the development of functional organs, including the respiratory airways in mammalian lungs. Advances in understanding the molecular and cellular mechanisms driving morphogenetic processes have enabled the development of sophisticated in vitro models that mimic the structure and function of airways. This review recapitulates developmental principles guiding airway morphogenesis, including the key signaling pathways, cellular interactions, and the different biochemical and mechanical cues. We discuss how these principles have been harnessed to engineer in vitro models of airways, providing a comprehensive overview of current artificial lung culture systems. We consider fully morphogenetic-mimicking strategies such as organoid modeling to more reductionist strategies, such as airway-on-chip systems. By examining both the breakthroughs and current limitations, we highlight the potential of these models to reproduce airway physiology and diseases, such as congenital pulmonary airway malformation and chronic obstructive pulmonary disease. Furthermore, we consider future directions in the field, emphasizing the need for controlling complex environmental cues and integrating multiple cellular components to create increasingly accurate and functional airway models.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L234-L254"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511426","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":"CFTR-Independent Prostaglandin E₂-Stimulated Chloride Secretion in Human Airway.","authors":"Shayda M Abazari, Ghazal Masarweh, Jesse Gammons, Jessica B Sarthi, Beate Illek, Zachary M Sellers","doi":"10.1152/ajplung.00279.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00279.2024","url":null,"abstract":"<p><p><b>Background:</b> Prostaglandin E₂ (PGE₂) is a potent stimulator of airway epithelial Cl^- secretion. PGE₂ can stimulate CFTR-independent Cl^- secretion from Calu-3 submucosal gland cells, whereas human bronchial epithelial (HBE) cells require CFTR. <b>Aim:</b> Determine the mechanism(s) driving CFTR-independent PGE₂-stimulated Cl^- secretion in Calu-3 cells. <b>Methods:</b> Short-circuit current (I_sc) was measured in Calu-3, HBE, and duodenal enteroids in Ussing Chambers. mRNA expression and intracellular Ca²⁺ (Ca²⁺_i) was determined by qPCR and Fura-Red imaging, respectively. <b>Results:</b> In Calu-3 and HBE cells, PGE₂-stimulated I_sc was reduced by bilateral and basolateral-only removal of extracellular Ca²⁺ (Ca²⁺_e), but not by inhibition of protein kinase A (PKA), inositol 1,4,5-triphosphate (IP₃), or Ca²⁺_i stores. Duodenal enteroids utilized PKA, IP₃, Ca²⁺_i and Ca²⁺_e. EP receptor mRNA expression and functional measurements indicated EP4 receptor dominance in Calu-3 cells. EP4 receptor agonist CAY-10598 (CFTR_inh-172, glibenclamide) increased Ca²⁺_i and I_sc was driven by Ca²⁺-activated Cl^- secretion. I_sc was inhibited by dasatinib, wortmannin, and GSK650394, indicating involvement of Src, phosphoinositol phosphate (PI3K), serum glucocorticoid kinase 1 (SGK1). CFTR-independent CAY-10598-stimulated I_sc was mediated by apical Ca²⁺ release-activated Ca²⁺ channels (CRAC), P2X receptors, and basolateral TRPV channels. <b>Conclusions:</b> Calu-3 and HBE cells predominantly utilize EP4 receptors and Ca²⁺_e-mediated signaling for PGE₂-stimulated Cl^- secretion. However, Calu-3 cells leverage apical Ca²⁺ entry through CRAC and P2X receptors, together with basolateral TRPV activation, Src, PI3K, and SGK1 signaling, for CFTR-independent Cl^- secretion. Gaining insights into means to increase CFTR-independent airway Cl^- secretion may identify novel therapies to help ameliorate lung diseases with compromised CFTR function.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599123","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":"Leveraging intrinsic non-sinusoidal patterns to infer search behavior to predict exposure to respiratory stressors.","authors":"Anju Bimal, Szilard L Beres, Victoria Ribeiro Rodrigues, Barbara K Smith, Paul W Davenport, Nicholas J Napoli","doi":"10.1152/ajplung.00379.2024","DOIUrl":"10.1152/ajplung.00379.2024","url":null,"abstract":"<p><p>This study introduces a novel entropy-based methodology to quantitatively characterize nonlinear transient breathing dynamics under respiratory stress. Environmental and pathophysiological stressors can disrupt the respiratory system's gas exchange, leading to compromise and compensatory mechanisms. We present a data-driven approach that systematically evaluates classical respiratory features alongside novel entropic features as key indicators under respiratory stress. We demonstrate that conventional metrics like breathing rate (<i>B</i>_R), time of inspiration (<i>T</i>_I), and expiration (<i>T</i>_E) fail to capture discriminating features needed to detect early ventilatory instability and predict intervention needs. An exhaustive analysis of key respiratory fiducial points using entropic methods led to novel features for understanding respiratory mechanics and classifying respiratory states. We found that the nonlinear dynamics of the transition times between inspiratory and expiratory phases (interphases) are crucial for assessing adaptability to respiratory challenges. This metric quantifies the complexity of transition duration (acceleration and deceleration between phases) and is essential for predicting declining breathing states. Our predictive model incorporating these novel approaches showed superior discriminating ability over models using classical features, achieving a 50.76% increase in predictive power as measured by the area under the curve (AUC). These findings underscore the effectiveness of this entropy-based approach for early detection of respiratory compromise, with the best model achieving an AUC of 0.784. The results have significant implications for improving clinical monitoring of acute respiratory failure and managing chronic respiratory conditions.<b>NEW & NOTEWORTHY</b> Entropy-based metrics analyzing respiratory phase transitions (inspiration-to-expiration and expiration-to-inspiration) detect respiratory compromise under hypoxic conditions better than standard breathing rate measurements. Analysis of nonlinear dynamics during these transitions reveals key ventilatory adaptations during exposure to respiratory stressors. Measuring timing variations at phase transitions improves predictive model performance in detecting exposure to hypoxic environments by a 50.76% increase in area under the curve (AUC) vs. classical methods.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L134-L160"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148848","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":"Maternal diabetes and lung health: an unexplored risk factor for COPD?","authors":"Sriyani Ranatunga, Christopher D Pascoe","doi":"10.1152/ajplung.00046.2025","DOIUrl":"10.1152/ajplung.00046.2025","url":null,"abstract":"<p><p>Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death worldwide, is traditionally considered a disease of smoking. However, <20% of people who smoke develop COPD, indicating the disease is complex, resulting from the interplay of genetic and environmental factors. Emerging evidence highlights the importance of exposure in early life to environmental irritants that impair fetal lung development and subsequent lung function trajectories, increasing risk for future COPD. Specifically, childhood asthma, preterm birth, and surfactant deficiency have been associated with lung function impairments and an increased COPD risk later in life. Furthermore, prenatal exposure to cigarettes influences sensitivity of individuals to smoking in their later life. A mounting body of evidence now indicates that diabetes exposure during pregnancy increases the risk for several childhood conditions linked to COPD risk, suggesting that maternal diabetes may be an unexplored risk factor for COPD. This article reviews the current literature on the influence of maternal diabetes on known early-life COPD risk factors (asthma and preterm birth), and identifies knowledge gaps that need to be addressed to pindown a potential association with COPD. Specifically, whether exposure to maternal diabetes influences offspring risk for COPD through already identified risk modifiers, or directly by altering lung function trajectories or sensitivity to cigarettes. Maternal diabetes rates are rising worldwide, with type 2 diabetes mellitus (T2DM) during pregnancy and gestational diabetes mellitus (GDM) nearly doubling over the last 15 years. Understanding how prenatal diabetes influences COPD risk is imperative to establishing whether intervening early can prevent COPD in this population.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L126-L133"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214664","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":"Activated factor X inhibition ameliorates NF-κB-IL-6-mediated perivascular inflammation and pulmonary hypertension.","authors":"Satomi Imakiire, Keiji Kimuro, Keimei Yoshida, Kohei Masaki, Ryo Izumi, Misaki Imabayashi, Takanori Watanabe, Tomohito Ishikawa, Kazuya Hosokawa, Shouji Matsushima, Toru Hashimoto, Keisuke Shinohara, Shunsuke Katsuki, Tetsuya Matoba, Kazufumi Nakamura, Katsuya Hirano, Hiroyuki Tsutsui, Kohtaro Abe","doi":"10.1152/ajplung.00303.2024","DOIUrl":"10.1152/ajplung.00303.2024","url":null,"abstract":"<p><p>Activated factor X (FXa) induces inflammatory response and cell proliferation in various cell types via activation of proteinase-activated receptor-1 (PAR₁) and/or PAR₂. We thus aimed to investigate the impact of FXa on the development of pulmonary arterial hypertension (PAH) and the mechanisms involved. The effects of edoxaban, a selective FXa inhibitor, on hemodynamic, right ventricular (RV) hypertrophy, and vascular remodeling were evaluated in a monocrotaline (MCT)-exposed pulmonary hypertension (PH) rat model. At 21 days after a single subcutaneous injection of MCT of 60 mg/kg, right ventricular systolic pressure (RVSP) and total pulmonary vascular resistance index (TPRI) were elevated concomitant with the increased plasma FXa and lung interleukin-6 (<i>IL-6</i>) mRNA. Daily administration of edoxaban (10 mg/kg/day, by gavage) starting from the day of MCT injection for 21 days ameliorated RVSP, TPRI, RV hypertrophy, pulmonary vascular remodeling, and macrophage accumulation. Edoxaban reduced nuclear factor-kappa B (NF-κB) activity and <i>IL-6</i> mRNA level in the lungs of MCT-exposed rats. mRNA levels of <i>FXa</i>, <i>PAR₁,</i> and <i>PAR₂</i> in cultured pulmonary arterial smooth muscle cells (PASMCs) isolated from patients with PAH were higher than those seen in normal PASMCs. FXa stimulation increased cell proliferation and mRNA level of <i>IL-6</i> in normal PASMCs, both of which were blunted by edoxaban and PAR₁ antagonist. Moreover, FXa stimulation activated extracellularly regulated kinases 1/2 in a PAR₁-dependent manner. Inhibition of FXa ameliorates NF-κB-IL-6-mediated perivascular inflammation, pulmonary vascular remodeling, and the development of PH in MCT-exposed rats, suggesting that FXa may be a potential target for the treatment of PAH.<b>NEW & NOTEWORTHY</b> This study demonstrated that chronic treatment with activated factor X (FXa) inhibitor ameliorated NF-κB-IL-6-mediated perivascular inflammation in a rat model with pulmonary arterial hypertension, which is associated with elevated FXa activity. FXa may act on pulmonary arterial smooth muscle cells, inducing cell proliferation and inflammatory response via upregulated PAR₁, thereby contributing to pulmonary vascular remodeling. Understanding the patient-specific pathophysiology is a prerequisite for applying FXa-targeted therapy to the treatment of pulmonary arterial hypertension.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L183-L196"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293202","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":"PMN recruitment in inflammatory lung injury models follows classical transendothelial migration paradigms requiring PECAM-1 and CD99.","authors":"Maureen E Haynes, Erika Arias, David P Sullivan, William A Muller","doi":"10.1152/ajplung.00069.2025","DOIUrl":"10.1152/ajplung.00069.2025","url":null,"abstract":"<p><p>Immune cells are recruited to sites of inflammation in a stepwise process involving a symphony of signals and receptors. In the systemic circulation, the step at which immune cells migrate out of the blood and across the endothelium, transendothelial migration, occurs via homophilic interactions between leukocyte PECAM-1 and CD99 and endothelial cell PECAM-1 and CD99. Previous work showed that rolling and adhesion of immune cells in the lung vasculature does not follow the classical paradigm of inflammatory recruitment; however, the transmigration step of this process has largely gone understudied. In this study, we demonstrate that polymorphonuclear cells (PMNs) use PECAM-1 and CD99 when transmigrating in response to murine chemical, bacterial, and ischemia/reperfusion lung injury (IRI). We demonstrate that recruitment of PMNs in response to both Gram-positive and Gram-negative bacteria is PECAM-1- and CD99-dependent. We implemented a method of intravital microscopy (IVM) of the pulmonary vasculature after IRI, with which we directly visualized and quantified transmigration. We demonstrate, in real time, that PMN enter the alveoli by crossing alveolar capillaries. Because PMNs are known to be independent mediators of both tissue damage and resolution of inflammation, we tested these effective blocking antibodies for survival effects in models of 50-60% mortality, but found none. In summary, our study shows that the classical transmigration protein interactions are necessary for the transmigration of PMNs into the airspace during response to four distinct inflammatory stimuli.<b>NEW & NOTEWORTHY</b> Previous studies have shown that neutrophil extravasation in the lung was selectin-independent and the requirement for leukocyte integrins was stimulus-dependent. This study demonstrates that PECAM-1 and CD99 are required for PMN transmigration during chemical, bacterial, and ischemia/reperfusion lung inflammation. We show directly in real time, using intravital microscopy, that neutrophils extravasate from alveolar capillaries. Blocking antibodies against PECAM-1 or CD99 prevented transmigration into the lung airspace, just as they prevent transmigration in the systemic circulation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L112-L125"},"PeriodicalIF":3.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The nitrofen/bisdiamine murine model of congenital diaphragmatic hernia has a pulmonary hypertension vascular phenotype consistent with human CDH.","authors":"Cailin R Gonyea, Yuanjun Shen, Katherine M Nelson, Rylie N Bird, Rachel M Gilbert, Oluyinka O Olutoye, Sundeep G Keswani, Jason P Gleghorn","doi":"10.1152/ajplung.00233.2024","DOIUrl":"10.1152/ajplung.00233.2024","url":null,"abstract":"<p><p>Congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (CDH-PH) has severe implications for the survival of patients with CDH; however, CDH-PH is often refractory to pulmonary vasodilators, rendering it difficult to treat. As such, models are necessary to study the etiology, mechanism, onset, and progression of pulmonary vascular remodeling in CDH. Despite several established murine models of CDH, no characterized CDH-PH or CDH-associated pulmonary vascular remodeling murine model exists. In this work, we assessed the nitrofen/bisdiamine (N/B) murine CDH model for pulmonary hypertension (PH) hallmarks to establish its usefulness as a model for studying mechanisms leading to CDH-PH. To do so, we evaluated key metrics of vascular PH at two different gestational time points and compared the results to sex- and age-matched human CDH tissue sections and results from a meta-analysis of published data of human CDH samples. We found that vessel rarefaction, smooth muscle hypertrophy, and adventitial extracellular matrix deposition were present in the N/B CDH murine model at <i>E18.5</i> in late gestation. In addition, this same vascular PH phenotype was present much earlier in development at <i>E16.5</i>, after normal diaphragmatic development and closure, but still within the pseudoglandular phase of lung development. Finally, comparisons with human CDH data confirm that the N/B CDH murine model recapitulates the pulmonary hypertension vascular phenotype seen in human CDH lung sections. Together, these data validate a mouse CDH-PH model with the ability to genetically perturb pathways that may exacerbate or improve CDH-PH outcomes, which could, in turn, lead to therapies or diagnostic markers of CDH-PH severity in utero.<b>NEW & NOTEWORTHY</b> Pulmonary hypertension (PH) is a severe complication of congenital diaphragmatic hernia (CDH), yet mechanisms and potential interventions remain poorly understood, partly due to the lack of animal models. This study validated that the nitrofen/bisdiamine (N/B) CDH mouse model recapitulates a PH vascular phenotype, including vessel rarefaction, smooth muscle hypertrophy, and remodeling that is benchmarked to human CDH tissues. These findings suggest that this model is a robust in vivo tool for the mechanistic study of CDH-PH.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L48-L60"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12235656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186295","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":"Olfactomedin-4 elevation in pediatric acute respiratory distress syndrome.","authors":"Ryan O'Sullivan, Matthew N Alder, Celeste G Dixon, Donglan Zhang, Nishi Srivastava, Nadir Yehya","doi":"10.1152/ajplung.00040.2025","DOIUrl":"10.1152/ajplung.00040.2025","url":null,"abstract":"<p><p>Neutrophils play a key role in acute respiratory distress syndrome (ARDS). The neutrophil marker olfactomedin-4 (OLFM4) has been implicated with worse outcomes in pediatric sepsis; however, OLFM4 has not been studied in pediatric ARDS. Therefore, we performed a secondary analysis of a prospective cohort of children with Berlin-defined ARDS with plasma collected on <i>day 0</i> of ARDS, testing for an association between OLFM4 and 28-day mortality, 7-day dialysis-free survival, and 28-day ventilator-free days (VFDs), adjusting for age, ARDS etiology, immunocompromised status, and arterial partial pressure of oxygen ([Formula: see text])/fraction of inspired oxygen ([Formula: see text]). We also tested the ability of LPS and histones to affect OLFM4 expression in vitro. In 333 children with ARDS (21% nonsurvivors), OLFM4 was higher in nonsurvivors, in severe ARDS, in hyperinflammatory ARDS, and in those with multiple organ failures. In multivariable regression, OLFM4 was associated with higher mortality, higher probability of dialysis by <i>day 7</i>, and fewer VFDs. In stratified analyses, the association between OLFM4 and worse outcomes did not differ between infectious and noninfectious ARDS. In vitro, OLFM4 expression increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. Overall, OLFM4 was associated with worse outcomes in pediatric ARDS. Histone H3 could induce OLFM4 expression in neutrophils, thus linking damage-associated molecular patterns to neutrophil polarization, which may represent a possible targetable pathway in pediatric ARDS.<b>NEW & NOTEWORTHY</b> Olfactomedin-4 (OLFM4) was associated with higher mortality, higher probability of dialysis by <i>day 7</i>, and fewer ventilator-free days (VFDs) in a pediatric acute respiratory distress syndrome (ARDS) cohort. In vitro, OLFM4 increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. OLFM4 appears to be a marker, and potentially a mediator, of pathological inflammation and end-organ damage in ARDS.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L172-L182"},"PeriodicalIF":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12213118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273980","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}