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

{"title":"Nanoparticles to target asthma.","authors":"Samantha K Hamrick, Michael A Thompson, Vincent M Rotello, Y S Prakash, Christina M Pabelick","doi":"10.1152/ajplung.00248.2024","DOIUrl":"10.1152/ajplung.00248.2024","url":null,"abstract":"<p><p>Asthma is a heterogeneous chronic lung disease that affects nearly 340 million people globally. Airway hyperresponsiveness, remodeling (thickening and fibrosis), and mucus hypersecretion are some hallmarks of asthma. With several current treatments having serious side effects from long-term use and a proportion of patients with uncontrolled asthma, there is an urgent need for new therapies. With an increasing understanding of asthma pathophysiology, there is a recognized need to target therapies to specific cell types of the airway, which necessitates the identification of delivery systems that can overcome increased mucus and thickened airways. Nanoparticles (NPs) that are highly customizable (material, size, charge, and surface modification) are a potential solution for delivery systems of a wide variety of cargoes (nucleic acids, proteins, and/or small molecules), as well as sole therapeutics for asthma. However, there is a need to consider the safety of the NPs in terms of potential for inflammation, toxicity, nonspecific targets, and accumulation in organs. Ongoing clinical trials using NPs, some FDA-approved for therapeutics in other diseases, provide confidence regarding the potential safety and efficacy of NPs in asthma treatment. This review highlights the current state of the use of NPs in asthma, identifying opportunities for further improvements in NP design and utilization for targeting this chronic lung disease.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L964-L971"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520718","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":"Tumor suppressors RBL1 and PTEN are epigenetically silenced in IPF mesenchymal progenitor cells by a CD44/Brg1/PRMT5 regulatory complex.","authors":"Libang Yang, Hong Xia, Karen Smith, Adam J Gilbertsen, Aiham H Jbeli, Juan E Abrahante, Peter B Bitterman, Craig A Henke","doi":"10.1152/ajplung.00182.2024","DOIUrl":"10.1152/ajplung.00182.2024","url":null,"abstract":"<p><p>The idiopathic pulmonary fibrosis (IPF) lung contains mesenchymal progenitor cells (MPCs) that display durable activation of oncogenic signaling and cell-autonomous fibrogenicity in vivo. Prior work identified a CD44/Brg1/PRMT5 nuclear regulatory module in IPF MPCs that increased the expression of genes positively regulating pluripotency and self-renewal. Left unanswered is how IPF MPCs evade negative regulation of self-renewal. Here we sought to identify mechanisms disabling negative regulation of self-renewal in IPF MPCs. We demonstrate that expression of the tumor suppressor genes <i>rbl1</i> and <i>pten</i> is decreased in IPF MPCs. The mechanism involves the CD44-facilitated association of the chromatin remodeler Brg1 with the histone-modifying methyltransferase PRMT5. Brg1 enhances chromatin accessibility leading to PRMT5-mediated methylation of H3R8 and H4R3 on the <i>rbl1</i> and <i>pten</i> genes, repressing their expression. Genetic knockdown or pharmacological inhibition of either Brg1 or PRMT5 restored RBL1 and PTEN expression reduced IPF MPC self-renewal in vitro and inhibited IPF MPC-mediated pulmonary fibrosis in vivo. Our studies indicate that the CD44/Brg1/PRMT5 regulatory module not only functions to activate positive regulators of pluripotency and self-renewal but also functions to repress tumor suppressor genes <i>rbl1</i> and <i>pten</i>. This confers IPF MPCs with the cancer-like property of cell-autonomous self-renewal providing a molecular mechanism for relentless fibrosis progression in IPF.<b>NEW & NOTEWORTHY</b> Here we demonstrate that a CD44/Brg1/PRMT5 epigenetic regulatory module represses the tumor suppressor genes RBL1 and PTEN in IPF mesenchymal progenitor cells, thereby promoting their self-renewal and maintenance of a critical pool of fibrogenic mesenchymal progenitor cells.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L949-L963"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455993","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":"Effects of spontaneous curvature on interfacial adsorption and collapse of phospholipid monolayers.","authors":"Bret A Brandner, Shankar B Rananavare, Stephen B Hall","doi":"10.1152/ajplung.00193.2024","DOIUrl":"10.1152/ajplung.00193.2024","url":null,"abstract":"<p><p>To function effectively, pulmonary surfactant must adsorb rapidly to the alveolar air/water interface but avoid collapse from the surface when compressed to high interfacial densities. Prior studies show that phospholipids in the cylindrical monolayers of the inverse hexagonal (H_II) phase adsorb quickly. The monolayers have negative curvature, defined by the concave shape of the hydrophilic face. Formation of the H_II structures, however, involves significant disruption of chain-packing. Samples with significant spontaneous curvature, formed in the absence of applied force, may nonetheless have lamellar structures that optimize chain-packing. The experiments here tested whether planar lamellar bilayers formed by phospholipids with negative spontaneous curvature might adsorb rapidly but collapse slowly. Prior studies have shown that binary mixtures of dioleoyl phosphatidylcholine-dioleoyl phosphatidylethanolamine (DOPC-DOPE) with higher mol fractions of DOPE (<i>X</i>_PE) have more negative spontaneous curvature. Samples of DOPC-DOPE with higher <i>X</i>_PE studied here adsorbed more rapidly but also collapsed more quickly. Over that range of <i>X</i>_PE, small-angle X-ray scattering showed only lamellar structures. The H_II phase was undetectable. The results suggest that the innate tendency of the phospholipids to form curvature has primary importance for adsorption rather than the presence of the H_II phase. Planar structures are insufficient to minimize the tendency of spontaneous curvature to promote collapse. These findings are consistent with adsorption and collapse that occur via rate-limiting transient structures with significant negative curvature.<b>NEW & NOTEWORTHY</b> Pulmonary surfactant must adsorb rapidly to the surface of the alveolar liquid but collapse slowly when compressed. Prior studies show that cylindrical monolayers of the inverse hexagonal phase adsorb rapidly. These structures have negative curvature; the hydrophilic face of the phospholipid leaflet is concave. Our studies tested whether planar lamellar structures with a greater tendency to form negative curvature would adsorb rapidly but collapse slowly. Compositional change accelerated adsorption but also yielded faster collapse.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L876-L882"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492918","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":"Gene expression responses of CF airway epithelial cells exposed to elexacaftor/tezacaftor/ivacaftor suggest benefits beyond improved CFTR channel function.","authors":"Thomas H Hampton, Roxanna Barnaby, Carolyn Roche, Amanda Nymon, Kiyoshi Ferreira Fukutani, Todd A MacKenzie, Lily A Charpentier, Bruce A Stanton","doi":"10.1152/ajplung.00272.2024","DOIUrl":"10.1152/ajplung.00272.2024","url":null,"abstract":"<p><p>The combination of elexacaftor/tezacaftor/ivacaftor (ETI, Trikafta) reverses the primary defect in cystic fibrosis (CF) by improving CFTR-mediated Cl^- and HCO₃^- secretion by airway epithelial cells (AECs), leading to improved lung function and less frequent exacerbations and hospitalizations. However, studies have shown that CFTR modulators like ivacaftor, a component of ETI, have numerous effects on CF cells beyond improved CFTR channel function. Because little is known about the effect of ETI on CF AEC gene expression, we exposed primary human AEC to ETI for 48 h and interrogated the transcriptome by RNA-seq and qPCR. ETI increased CFTR Cl^- secretion, and defensin gene expression (<i>DEFB1</i>), an observation consistent with reports of decreased bacterial burden in the lungs of people with CF (pwCF). ETI decreased <i>MMP10</i> and <i>MMP12</i> gene expression, suggesting that ETI may reduce proteolytic-induced lung destruction in CF. ETI also reduced the expression of the stress response gene heme oxygenase (<i>HMOX1</i>). qPCR analysis confirmed <i>DEFB1</i>, <i>HMOX1</i>, <i>MMP10</i>, and <i>MMP12</i> gene expression results observed by RNA-seq. Gene pathway analysis revealed that ETI decreased inflammatory signaling, cellular proliferation, and MHC class II antigen presentation. Collectively, these findings suggest that the clinical observation that ETI reduces lung infections in pwCF is related in part to drug-induced increases in <i>DEFB1</i> and that ETI may reduce lung damage by reducing <i>MMP10</i> and <i>MMP12</i> gene expression. Moreover, pathway analysis also identified several other genes responsible for the ETI-induced reduction in inflammation observed in pwCF.<b>NEW & NOTEWORTHY</b> Gene expression responses by CF AECs exposed to ETI suggest that in addition to improving CFTR channel function, ETI is likely to enhance resistance to bacterial infection by increasing levels of beta-defensin 1 (hBD-1). ETI may also reduce lung damage by suppressing MMP10 and MMP12 and reduce airway inflammation by repressing proinflammatory cytokine secretion by CF AECs.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L905-L916"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492920","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 misuse of respiratory resistive loading during aerobic exercises: revisiting mechanisms of \"standalone\" inspiratory muscle training.","authors":"Gabriel Dias Rodrigues, Alison K McConnell","doi":"10.1152/ajplung.00396.2023","DOIUrl":"10.1152/ajplung.00396.2023","url":null,"abstract":"<p><p>Systematic reviews and meta-analyses support the benefits of inspiratory muscle training (IMT) for sports and clinical populations. A typical application of \"standalone\" IMT intervention consists of breathing against an inspiratory load (IRL), twice daily, for 5-7 days/wk, for 4-12 wk. However, the application of IRL during aerobic exercise is often seen in a training routine of sports and rehabilitation centers with no evidence-based guide. In this Perspective, we will revisit putative mechanisms underlying the established benefits of \"standalone\" IMT to support our contention that IMT need not and should not be used during aerobic exercise.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L815-L817"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339340","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":"Longitudinal microcomputed tomography detects onset and progression of pulmonary fibrosis in conditional <i>Nedd4-2</i> deficient mice.","authors":"Dominik H W Leitz, Philip Konietzke, Willi L Wagner, Mara Mertiny, Claudia Benke, Thomas Schneider, Rory E Morty, Christian Dullin, Wolfram Stiller, Hans-Ulrich Kauczor, Marcus A Mall, Julia Duerr, Mark O Wielpütz","doi":"10.1152/ajplung.00280.2023","DOIUrl":"10.1152/ajplung.00280.2023","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional <i>Nedd4-2</i> deficiency (<i>Nedd4-2^-/-</i>) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional <i>Nedd4-2^-/-</i> mice by longitudinal micro-computed tomography (CT). In vivo micro-CT was performed longitudinally in control and conditional <i>Nedd4-2^-/-</i> mice at 1, 2, 3, 4, and 5 mo after doxycycline induction. Furthermore, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. Histological assessment of lung collagen content was conducted as well. Micro-CT is sensitive to detect the onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional <i>Nedd4-2^-/-</i> mice. Nonspecific interstitial alterations were detected from 3 mo, whereas key features such as honeycombing-like lesions were detected from 4 mo onward. Pulmonary function correlated well with in vivo (<i>r</i> = -0.738) and post mortem (<i>r</i> = -0.633) micro-CT fibrosis scores and collagen content. Longitudinal micro-CT enables in vivo monitoring of the onset and progression and detects radiological key features of IPF-like lung disease in conditional <i>Nedd4-2^-/-</i> mice. Our data support micro-CT as a sensitive quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.<b>NEW & NOTEWORTHY</b> IPF diagnosis, particularly in early stages, remains challenging. In this study, micro-CT is used in conditional <i>Nedd4-2^-/-</i> mice to closely monitor the onset and progression of progressive pulmonary fibrosis in vivo. Together with high-resolution post mortem micro-CT, this allowed us to track how nonspecific lung lesions develop into key IPF-like features. This approach offers a noninvasive method to monitor pulmonary fibrosis, providing a quantitative endpoint for the preclinical evaluation of novel antifibrotic strategies.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L917-L929"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492922","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":"Expression of Semaphorin3E/PlexinD1 in human airway smooth muscle cells of patients with COPD.","authors":"Duaa Alsubait, Huda Fatima Rajani, Lianyu Shan, Latifa Koussih, Andrew J Halayko, Bouchaib Lamkhioued, Abdelilah S Gounni","doi":"10.1152/ajplung.00284.2023","DOIUrl":"10.1152/ajplung.00284.2023","url":null,"abstract":"<p><p>Semaphorin3E (Sema3E) is a member of axon guidance proteins that have emerged recently as essential regulators of cell migration and proliferation. It binds to PlexinD1 with high affinity and is expressed in different cell types, including immune, cancer, and epithelial cells. Recent work in our lab has revealed a critical immunoregulatory role of Sema3E in experimental allergic asthma; however, its role in chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the expression of Sema3E and its receptor, PlexinD1, in the airways of patients with COPD and whether Sema3E regulates airway smooth muscle (ASM) cell proliferation, a key feature of airway remodeling in COPD. We first demonstrate that human ASM cells obtained from COPD express Sema3E and PlexinD1 at both mRNA and protein levels. Also, bronchial sections from patients with COPD displayed immunoreactivity of Sema3E and its receptor PlexinD1, suggestive of functional contribution of Sema3E in airway remodeling. In contrast to ASM cells from healthy donors, Sema3E did not inhibit the platelet-derived growth factor (PDGF) induced cell proliferation in ASM cells of patients with COPD that were consistent with the binding of endogenous Sema3E to its receptors on the cell surface and the expression and release of p61KDa-Sema3E isoform. Our results support the Sema3E-PlexinD1 axis involvement in COPD airway smooth muscle remodeling.<b>NEW & NOTEWORTHY</b> Semaphorin3E (Sema3E), a protein guiding cell movement, is found in various cell types like neural, immune, cancer, and epithelial cells. This study examines Sema3E in chronic obstructive pulmonary disease (COPD) airways. In patients with COPD, airway smooth muscle cells express Sema3E and its receptor PlxD1. Unlike healthy cells, Sema3E does not hinder cell proliferation in COPD, indicating involvement in airway remodeling. These findings highlight the Sema3E-PlxD1 axis in COPD airway changes.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L831-L838"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339330","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":"Inference of alveolar capillary network connectivity from blood flow dynamics.","authors":"Kerstin Schmid, Andy L Olivares, Oscar Camara, Wolfgang M Kuebler, Matthias Ochs, Andreas C Hocke, Sabine C Fischer","doi":"10.1152/ajplung.00025.2024","DOIUrl":"10.1152/ajplung.00025.2024","url":null,"abstract":"<p><p>The intricate lung structure is crucial for gas exchange within the alveolar region. Despite extensive research, questions remain about the connection between capillaries and the vascular tree. We propose a computational approach combining three-dimensional (3-D) morphological modeling with computational fluid dynamics simulations to explore alveolar capillary network connectivity based on blood flow dynamics. We developed three-dimensional sheet-flow models to accurately represent alveolar capillary morphology and conducted simulations to predict flow velocities and pressure distributions. Our approach leverages functional features to identify plausible system architectures. Given capillary flow velocities and arteriole-to-venule pressure drops, we deduced arteriole connectivity details. Preliminary analyses for nonhuman species indicate a single alveolus connects to at least two 20-µm arterioles or one 30-µm arteriole. Hence, our approach narrows down potential connectivity scenarios, but a unique solution may not always be expected. Integrating our blood flow model results into our previously published gas exchange application, Alvin, we linked these scenarios to gas exchange efficiency. We found that increased blood flow velocity correlates with higher gas exchange efficiency. Our study provides insights into pulmonary microvasculature structure by evaluating blood flow dynamics, offering a new strategy to explore the morphology-physiology relationship that is applicable to other tissues and organs. Future availability of experimental data will be crucial in validating and refining our computational models and hypotheses.<b>NEW & NOTEWORTHY</b> The alveolus is pivotal for gas exchange. Its complex, dynamic nature makes structural experimental studies challenging. Computational modeling offers an alternative. We developed a data-based three-dimensional (3-D) model of the alveolar capillary network and performed blood flow simulations within it. Choosing a novel perspective, we inferred structure from function. We systematically varied the properties of vessels connected to our capillary network and analyzed simulation results for blood flow and gas exchange to obtain plausible vessel configurations.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L852-L866"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339332","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":"Moving on from clinical animal-derived surfactants to peptide-based synthetic pulmonary surfactant.","authors":"Frans J Walther, Alan J Waring","doi":"10.1152/ajplung.00186.2024","DOIUrl":"10.1152/ajplung.00186.2024","url":null,"abstract":"<p><p>Research on lung surfactant has exerted a great impact on newborn respiratory care and significantly improved survival and outcome of preterm infants with respiratory distress syndrome (RDS) due to surfactant deficiency because of lung immaturity. Current clinical, animal-derived, surfactants are among the most widely tested compounds in neonatology. However, limited availability, high production costs, and ethical concerns about using animal-derived products constitute important limitations in their universal application. Synthetic lung surfactant offers a promising alternative to animal-derived surfactants by providing improved consistency, quality and purity, availability and scalability, ease of production and lower costs, acceptance, and safety for the treatment of neonatal RDS and other lung conditions. Third-generation synthetic surfactants built around surfactant protein B (SP-B) and C (SP-C) peptide mimics stand at the forefront of innovation in neonatal pulmonary medicine, while nasal continuous positive airway pressure (nCPAP) has become the standard noninvasive respiratory support for preterm infants. nCPAP can prevent the risk of chronic lung disease (bronchopulmonary dysplasia) and reduce lung injury by avoiding intubation and mechanical ventilation, is a relatively simple technique, and can be initiated safely and effectively in the delivery room. Combining nCPAP with noninvasive, preferably aerosol, delivery of synthetic lung surfactant promises to improve respiratory outcomes for preterm infants, especially in low- and middle-income countries.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L883-L889"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455992","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":"Mechanisms of lung endothelial cell injury and survival in pulmonary arterial hypertension.","authors":"Ygor Marinho, Elizabeth S Villarreal, Omar Loya, Suellen D Oliveira","doi":"10.1152/ajplung.00208.2024","DOIUrl":"10.1152/ajplung.00208.2024","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive, chronic, and incurable inflammatory pulmonary vascular disease characterized by significant sex bias and largely unexplored microbial-associated molecular mechanisms that may influence its development and sex prevalence across various subgroups. PAH can be subclassified as idiopathic, heritable, or associated with conditions such as connective tissue diseases, congenital heart defects, liver disease, infections, and chronic exposure to drugs or toxins. During PAH progression, lung vascular endothelial cells (ECs) undergo dramatic morphofunctional transformations in response to acute and chronic inflammation. These transformations include the appearance and expansion of abnormal vascular cell phenotypes such as those derived from apoptosis-resistant cell growth and endothelial-to-mesenchymal transition (EndoMT). Compelling evidence indicates that these endothelial phenotypes seem to be triggered by chronic lung vascular injury and dysfunction, often characterized by reduced secretion of vasoactive molecules like nitric oxide (NO) and exacerbated response to vasoconstrictors such as Endothelin-1 (ET-1), both long-term known contributors of PAH pathogenesis. This review sheds light on the mechanisms of EC dysfunction, apoptosis, and EndoMT in PAH, aiming to unravel the intricate interactions between ECs, pathogens, and other cell types that drive the onset and progression of this devastating disease. Ultimately, we hope to provide an overview of the complex functions of lung vascular ECs in PAH, inspiring novel therapeutic strategies that target these dysfunctional cells to improve the treatment landscape for PAH, particularly in the face of current and emerging global pathogenic threats.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L972-L983"},"PeriodicalIF":3.6,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455991","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}