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

{"title":"Opportunity Knocks: The 4^th cohort of the <i>American Journal of Physiology-Lung Cellular and Molecular Physiology</i> Early Career Editorial Fellowship Program.","authors":"Larissa A Shimoda, Cristina M Alvira, Julie A Bastarache, Rodney D Britt, Rachel S Knipe, Wolfgang M Kuebler, Thiago S Moreira, Eric P Schmidt","doi":"10.1152/ajplung.00238.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00238.2025","url":null,"abstract":"","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697384","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":"High fat diet obesity exacerbates acute lung injury induced dysregulation of fatty acid oxidation in alveolar epithelial type 2 cells.","authors":"Eleni Kallinos, Kuei-Pin Chung, Lisa K Torres, Divya Bhatia, Baran Ersoy, Peter Carmeliet, William Zhang, Heather W Stout-Delgado, Augustine M K Choi, Maria Plataki","doi":"10.1152/ajplung.00406.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00406.2024","url":null,"abstract":"<p><p>Obesity is a risk factor for acute respiratory distress syndrome (ARDS). We previously showed obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic model of ARDS. We sought to expand our understanding of this association and examined the effect of obesity on β-oxidation (FAO), the mitochondrial process of breaking down fatty acids, in alveolar epithelial type 2 cells (AEC2) in hyperoxia-induced ARDS. AEC2 were isolated from mice receiving 60% versus 10% fat diet. Carnitine palmitoyltransferase 1A (CPT1A) mediates the transport of fatty acids into mitochondria for subsequent FAO. Cpt1a^loxp/loxpSftpc^CreERT2+/- mice were generated with AEC2 specific CPT1A downregulation. Obesity was associated with intracellular lipid accumulation and increased expression of CPT1A in AEC2 after hyperoxia. Mitochondrial FAO however was significantly transcriptionally downregulated in AEC2 of obese compared to lean mice after hyperoxia. AEC2 from obese mice exhibited more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared to lean mice. Consistent with prior reports linking FAO perturbation to surfactant impairment, we also observed that high fat diet was associated with reduced surfactant related phospholipids in hyperoxic AEC2 and increased BALF surface tension, although obese Cpt1a^loxp/loxpSftpc^CreERT2+/- mice were not protected from increased lung injury. In a reanalysis of a human single-cell lung atlas of COVID19 ARDS, the downregulation of the FAO signature in AEC2 was significant only in obese, and not lean, ARDS patients compared to controls. These findings demonstrate a previously underappreciated effect of diet on AEC2 function in acute lung injury.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688646","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":"Functional modulation of retrotrapezoid neurons drives fentanyl-induced respiratory depression.","authors":"Thiago S Moreira, Nicholas J Burgraff, Ana C Takakura, Luiz M Oliveira, Emmanuel Veríssimo de Araujo, Steven Guan, Jan-Marino Ramirez","doi":"10.1152/ajplung.00025.2025","DOIUrl":"https://doi.org/10.1152/ajplung.00025.2025","url":null,"abstract":"<p><p>The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), characterized by severe suppression of respiratory rate, destabilized breathing patterns, hypercapnia, and heightened risk of apnea. The retrotrapezoid nucleus (RTN), a critical chemosensitive brainstem region in the rostral ventrolateral medullary reticular formation contains Phox2b⁺/Neuromedin-B (<i>Nmb</i>) propriobulbar neurons. These neurons, stimulated by CO₂/H⁺, regulate breathing to prevent respiratory acidosis. Since the RTN shows limited expression of opioid-receptors, we expected that opioid-induced hypoventilation should activate these neurons to restore ventilation and stabilize arterial blood gases. However, the ability of the RTN to stimulate ventilation during OIRD has never been tested. We used optogenetic and pharmacogenetic approaches, to activate and inhibit RTN Phox2b⁺/<i>Nmb</i>⁺ neurons before and after fentanyl administration. As expected, fentanyl (500 μg/kg, ip) suppressed respiratory rate and destabilized breathing. Before fentanyl, optogenetic stimulation of Phox2b⁺/<i>Nmb</i>⁺ or chemogenetic inhibition of <i>Nmb</i>⁺ cells increased and decreased breathing activity, respectively. Surprisingly, optogenetic stimulation after fentanyl administration caused a significantly greater increase in breathing activity compared to pre-fentanyl levels. By contrast chemogenetic inhibition of RTN <i>Nmb</i> neurons caused profound hypoventilation and breathing instability after fentanyl. The results suggest that fentanyl does not inhibit the ability of Phox2b⁺<i>/Nmb</i>⁺ cells within the RTN region to stimulate breathing. Thus, this study highlights the potential of stimulating RTN neurons as a possible therapeutic approach to restore respiratory function in cases of OIRD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688645","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":"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":"https://doi.org/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 <i>per se</i> and had 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 post-stretch 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 non-stretched cells but slightly increased proliferation in stretched cells. Piezo1 and Piezo2 inhibition did not alter IL-6 production. These results suggest that stretch induces sustained increase in cell proliferation and inflammatory responses, which may contribute to long-term remodeling in former preterm infants initially exposed to CPAP.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Pulmonary Surfactant on Lung Fluid Balance.","authors":"Gary F Nieman, Egidio Beretta, Joaquin Araos, Giuseppe A Miserocchi","doi":"10.1152/ajplung.00329.2024","DOIUrl":"https://doi.org/10.1152/ajplung.00329.2024","url":null,"abstract":"<p><p>Karl von Neegaard's classic publication, in 1929, first identified the physiologic function of pulmonary surfactant on alveolar mechanics. Dr. John Allen Clements brought this work to the clinic in the 1960s, culminating in the development of surfactant replacement therapy for infant respiratory distress syndrome (RDS). In this mini-review, we discuss pulmonary surfactants' role in maintaining lung fluid balance, which is essential in preventing pulmonary edema. Alveolar surface tension (γ) is transmitted into the perialveolar space surrounding pulmonary capillaries and corner vessels. Increasing surface tension at end-expiration would increase alveolar recoil pressure and decrease alveolar radius, thus causing more sub-atmospheric pressure in the perialveolar space, generating an increased gradient for microvascular filtration. Studies have demonstrated a positive correlation between increased pulmonary extravascular water volume (PEWV) and high γ (γ=8.3±1.7 dyn/cm; PEWV=3.4±0.2 ml/g vs. γ=23.2±0.4 dyn/cm; PEWV=6.1±1.0 ml/g dry lung). A subsequent study demonstrated that the high γ did not increase capillary permeability, supporting the mechanism of high γ-induced pulmonary edema as a decrease in interstitial hydrostatic pressure. Computational modeling, as presented in our previous publications based on the Starling Equation of fluid flux, identifies the impact of elevated alveolar surface tension on lung fluid balance. Loss of surfactant function favors fluid moving from the capillary across the endothelium into the perialveolar space and across the epithelium into the alveoli. We conclude that elevated alveolar surface tension plays a pivotal role in lung fluid balance and, if sufficiently elevated, can cause pulmonary edema even with normal capillary permeability.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625212","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":"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":3.6,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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}