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

{"title":"Aging, brain-derived neurotrophic factor, and allergen-induced pulmonary responses in mice.","authors":"Li Y Drake, Benjamin B Roos, Sarah A Wicher, Latifa Khalfaoui, Lisa L Nesbitt, Yun Hua Fang, Christina M Pabelick, Y S Prakash","doi":"10.1152/ajplung.00145.2024","DOIUrl":"10.1152/ajplung.00145.2024","url":null,"abstract":"<p><p>Asthma in the elderly is being recognized as more severe, resistant to standard therapies, and having greater morbidity. Therefore, it becomes important to understand the impact of aging-associated airway structure and functional changes toward pathogenesis of asthma in the elderly. Here, airway smooth muscle plays important roles in airway hyperreactivity and structural remodeling. The role of smooth muscle in asthma can be modulated by growth factors [including neurotrophins such as brain-derived neurotrophic factor (BDNF)] and proinflammatory senescence factors. In this study, we investigated aging effects on airway hyperreactivity, structural remodeling, inflammation, and senescence in a mouse model of allergic asthma. C57BL/6J wild-type mice or smooth muscle-specific BDNF knockout mice at 4, 18, and 24 mo of age were intranasally exposed to mixed allergens (MAs, ovalbumin, <i>Aspergillus</i>, <i>Alternaria</i>, and house dust mite) over 4 wk. Assessing lung function by flexiVent, we found that compared with 4-mo-old mice, 18- and 24-mo-old C57BL/6J mice showed decreased airway resistance and increased airway compliance after PBS or MA treatment. Deletion of smooth muscle BDNF blunted airway hyperreactivity in aged mice. Lung histology analysis revealed that aging increased bronchial airway thickness and decreased lung inflammation. Multiplex assays showed that aging largely reduced allergen-induced lung expression of proinflammatory chemokines and cytokines. By immunohistochemistry staining, we found that aging increased bronchial airway expression of senescence markers, including p21, phospho-p53, and phospho-γH2A.X. Our data suggest that aging-associated increase of airway senescence in the context of allergen exposure may contribute to asthma pathology in the elderly.<b>NEW & NOTEWORTHY</b> The pathogenesis of asthma in elderly is not well understood. Using a mouse model of asthma, we show that aging results in decreased lung function and less responsiveness to allergen exposure, impacted by locally produced brain-derived neurotrophic factor. Aging also decreases allergen-induced inflammation but increases airway remodeling and senescence. Our results suggest that senescence pathways may contribute to asthma pathogenesis in elderly.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L290-L300"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492916","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":"Role of voltage-gated Ca²⁺ channels and Ano1 Ca²⁺-activated Cl^- channels in M2 muscarinic receptor-dependent contractions of murine airway smooth muscle.","authors":"Srijit Ghosh, Tuleen Alkawadri, Lorcan P McGarvey, Mark A Hollywood, Keith D Thornbury, Gerard P Sergeant","doi":"10.1152/ajplung.00188.2024","DOIUrl":"10.1152/ajplung.00188.2024","url":null,"abstract":"<p><p>Cholinergic tone is elevated in obstructive lung conditions such as chronic obstructive pulmonary disease (COPD) and asthma, but the cellular mechanisms underlying cholinergic contractions of airway smooth muscle (ASM) are still unclear. Some studies report an important role for L-type Ca²⁺ channels (LTCC) and Ano1 Ca²⁺-activated Cl^- channels (CACC) in these responses, but others dispute their importance. Cholinergic contractions of ASM involve activation of M3Rs, however, stimulation of M2Rs exerts a profound hypersensitization of these responses. Here, we show that M2R-dependent potentiation of cholinergic nerve-evoked contractions of ASM was reversed by the LTCC blocker nifedipine and the Ano1 CACC inhibitors Ani9 and CaCC_inh-A01. Carbachol induced sustained contractions of ASM that were converted into oscillatory contractions when M3Rs were blocked with 4-DAMP. The 4-DAMP-resistant contractions were absent in preparations taken from M2R knockout (KO) mice. The remaining M2R-dependent responses, observed in wild-type (WT) mice, were abolished by nifedipine and Ani9. Inhibition of sarcoplasmic endoplasmic reticulum Ca²⁺ ATPases (SERCA) with thapsigargin increased the amplitude of contractions induced by electrical field stimulation (EFS) and these effects were also reversed by nifedipine and Ani9. Thapsigargin also potentiated contractions of ASM induced by the LTCC activator FPL64176. Therefore, contractions of ASM that involved Ca²⁺ influx via LTCC were enhanced by inhibition of SERCA. Immunocytochemistry experiments revealed prominent SERCA staining around the periphery of ASM cells. These data indicate that M2R-dependent contractions of ASM involve Ano1 CACC and LTCC by a mechanism involving inhibition of buffering of Ca²⁺ influx by SERCA.<b>NEW & NOTEWORTHY</b> The role of L-type Ca²⁺ channels and Ano1 Ca²⁺-activated Cl^- channels in cholinergic contractions of airway smooth muscle is disputed. Here, we show that both channels are involved in M2 muscarinic receptor-dependent contractions of murine airway smooth muscle via inhibition of buffering of Ca²⁺ influx by sarcoplasmic endoplasmic reticulum Ca²⁺ ATPases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L301-L312"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942589","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":"Opioid-induced respiratory depression: clinical aspects and pathophysiology of the respiratory network effects.","authors":"Brian A Baldo","doi":"10.1152/ajplung.00314.2024","DOIUrl":"10.1152/ajplung.00314.2024","url":null,"abstract":"<p><p>Important insights and consensus remain lacking for risk prediction of opioid-induced respiratory depression (OIRD), reversal of respiratory depression (RD), the pathophysiology of OIRD, and which sites make the most significant contribution to its induction. The ventilatory response to inhaled carbon dioxide is the most sensitive biomarker of OIRD. To accurately predict respiratory depression (RD), a multivariant RD prospective trial using continuous capnography and oximetry examining five independent variables, age ≥60, sex, opioid naivety, sleep disorders, and chronic heart failure (PRODIGY trial), were undertaken. Intermittent oximetry alone substantially underestimates the incidence of RD. Naloxone, with an elimination half-life of ∼33 min (cf. morphine 2-3 h; fentanyl and congeners only 5-15 min), has limitations for the rescue of patients with severe OIRD. Buprenorphine is potentially valuable in patients being treated long term since its high µ-receptor (MOR) affinity makes it difficult for an opioid of lower affinity (e.g., fentanyl) to displace it from the receptor. In the last decade, synthetic opioids, for example, fentanyl, its potent analogs such as carfentanil, and the benzimidazole derivative nitazene \"superagonists\" have contributed to the exponential growth in opioid deaths due to RD. The MOR, encoded by gene <i>Oprm1</i>, is widely expressed in the central and peripheral nervous systems, including centers that modulate breathing. Opioids bind to the receptors, but consensus is lacking on which site(s) makes the most significant contribution to the induction of OIRD. Both the preBötzinger complex (preBötC), the inspiratory rhythm generator, and the Kölliker-Fuse nucleus (KFN), the respiratory modulator, contribute to RD, but receptor binding is not restricted to a single site. Breathing is composed of three phases, inspiration, postinspiration, and active expiration, each generated by distinct rhythm-generating networks: the preBötC, the postinspiratory complex (PiCo), and the lateral parafacial nucleus (pF_L), respectively. Somatostatin-expressing mouse cells involved in breathing regulation are not involved in opioid-induced RD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L267-L289"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891430","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 as a therapeutic target for severe lung infection.","authors":"Jaime L Hook, Wolfgang M Kuebler","doi":"10.1152/ajplung.00289.2024","DOIUrl":"10.1152/ajplung.00289.2024","url":null,"abstract":"<p><p>Lung infection is one of the leading causes of morbidity and mortality worldwide. Even with appropriate antibiotic and antiviral treatment, mortality in hospitalized patients often exceeds 10%, highlighting the need for the development of new therapeutic strategies. Of late, cystic fibrosis transmembrane conductance regulator (CFTR) is-in addition to its well-established roles in the lung airway and extrapulmonary organs-increasingly recognized as a key regulator of alveolar homeostasis and defense. In the alveolar epithelium, CFTR mediates alveolar fluid secretion and liquid homeostasis; in the microvascular endothelium, CFTR maintains vascular barrier function. CFTR also contributes to alveolar immunity. Yet, in lung infection, diverse molecular mechanisms reduce CFTR abundance and otherwise impair its function, promoting alveolar inflammation, edema, and cell death. Preservation or restoration of CFTR function by CFTR modulator drugs thus presents a promising avenue to combat lung infection in a pathogen-independent manner.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L229-L238"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942652","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":"Toward in vivo bronchoscopic functional CFTR assessment using a short circuit current measurement probe.","authors":"David O Otuya, Zhongyu Liu, Reny Joseph, Mohammed A Hanafy, Kadambari Vijaykumar, Denise Stanford, S Vamsee Raju, Elizabeth H Baker, Steven M Rowe, Guillermo J Tearney, George M Solomon","doi":"10.1152/ajplung.00137.2024","DOIUrl":"10.1152/ajplung.00137.2024","url":null,"abstract":"<p><p>The epithelial lining of luminal organs provides an immune barrier against external factors and regulates the transport of nutrients, ions, and water into the body. Several conditions are associated with the breakdown or dysfunction of the epithelial lining. Short circuit current (<i>I</i>_sc) measurement using a bulky, expensive, and hard-to-deploy system known as the Ussing chamber is the gold standard for evaluation of epithelial transport function but requires tissue excision. We demonstrated the ability of the <i>I</i>_sc probe to measure <i>I</i>_sc in normal wild type (WT) versus reduced cystic fibrosis transmembrane conductance regulator (CFTR) function knockout (KO) rats as a relevant animal model for testing ion channel function.<b>NEW & NOTEWORTHY</b> We have conducted short circuit current measurements in animal models in vivo for studying cystic fibrosis transmembrane conductance regulator (CFTR) and ion channel restoration.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L313-L320"},"PeriodicalIF":3.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724783","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":"Lung Endothelial Cell Heterogeneity in Health and Pulmonary Vascular Disease.","authors":"K Mora Massad, Z Dai, I Petrache, C E Ventetuolo, T Lahm","doi":"10.1152/ajplung.00296.2024","DOIUrl":"10.1152/ajplung.00296.2024","url":null,"abstract":"<p><p>Lung endothelial cells (ECs) are essential for maintaining organ function and homeostasis. Despite sharing some common features with ECs from organ systems, lung ECs exhibit significant heterogeneity in morphology, function, and gene expression. This heterogeneity is increasingly recognized as a key contributor to the development of pulmonary diseases like pulmonary hypertension (PH). In this mini-review, we explore the evolving understanding of lung EC heterogeneity, particularly through the lens of single-cell RNA sequencing (scRNA-seq) technologies. These advances have provided unprecedented insights into the diverse EC subpopulations, their specific roles, and the disturbances in their homeostatic functions that contribute to PH pathogenesis. In particular, these studies identified novel and functionally distinct cell types such as aerocytes and general capillary ECs that are critical for maintaining lung function in health and disease. In addition, multiple novel pathways and mechanisms have been identified that contribute to aberrant pulmonary vascular remodeling in PH. Emerging techniques like single-nucleus RNA sequencing and spatial transcriptomics have further pushed the field forward by discovering novel disease mediators. As research continues to leverage these advanced techniques, the field is poised to uncover novel EC subtypes and disease mechanisms, paving the way for new therapeutic targets in PH and other lung diseases.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942655","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":"Post-transcriptional regulation of IFI16 promotes inflammatory endothelial pathophenotypes observed in pulmonary arterial hypertension.","authors":"Rashmi J Rao, Jimin Yang, Siyi Jiang, Wadih El-Khoury, Neha Hafeez, Satoshi Okawa, Yi Yin Tai, Ying Tang, Yassmin Al Aaraj, John C Sembrat, Stephen Y Chan","doi":"10.1152/ajplung.00048.2024","DOIUrl":"10.1152/ajplung.00048.2024","url":null,"abstract":"<p><p>Pulmonary arterial hypertension (PAH) is a progressive disease driven by endothelial cell inflammation and dysfunction, resulting in the pathological remodeling of the pulmonary vasculature. Innate immune activation has been linked to PAH development; however, the regulation, propagation, and reversibility of the induction of inflammation in PAH are poorly understood. Here, we demonstrate the role of interferon-inducible protein 16 (IFI16), an innate immune sensor, as a modulator of endothelial inflammation in pulmonary hypertension, using human pulmonary artery endothelial cells (PAECs). Inflammatory stimulus of PAECs with IL-1β upregulates <i>IFI16</i> expression, inducing proinflammatory cytokine upregulation and cellular apoptosis. <i>IFI16</i> mRNA stability is regulated by post-transcriptional m6A modification, mediated by Wilms' tumor 1-associated protein (WTAP), a structural stabilizer of the methyltransferase complex, via regulation of m6A methylation of <i>IFI16</i>. In addition, m6A levels are increased in the peripheral blood mononuclear cells of patients with PAH compared with control, indicating that quantifying this epigenetic change in patients may hold potential as a biomarker for disease identification. In summary, our study demonstrates that IFI16 mediates inflammatory endothelial pathophenotypes seen in pulmonary arterial hypertension.<b>NEW & NOTEWORTHY</b> Our work establishes a paradigm of the regulatory role of the Wilms' tumor 1-associated protein (WTAP)-interferon inducible protein 16 (IFI16) axis that uses m6A RNA methylation to drive endothelial inflammatory activation in pulmonary hypertension. Consequently, because m6A epigenetic modifications are both reversible and dynamic, this axis is an attractive diagnostic and therapeutic target in pulmonary hypertension and more broadly in endothelial immune activation.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L148-L158"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806071","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":"Mice with lymphatic dysfunction develop pathogenic lung tertiary lymphoid organs that model an autoimmune emphysema phenotype of COPD.","authors":"Barbara Summers, Kihwan Kim, Anjali Trivedi, Tyler M Lu, Sean Houghton, Jade Palmer-Johnson, Joselyn Rojas-Quintero, Juan Cala-Garcia, Tania Pannellini, Francesca Polverino, Raphaël Lis, Hasina Outtz Reed","doi":"10.1152/ajplung.00209.2024","DOIUrl":"10.1152/ajplung.00209.2024","url":null,"abstract":"<p><p>We have previously shown that mice with a loss of C-type lectin-like type II (CLEC2), which have lymphatic dysfunction due to the role of CLEC2 in platelets for maintaining separation between the venous and lymphatic system, develop lung tertiary lymphoid organ (TLO) formation and lung injury that resembles an emphysema phenotype of chronic obstructive pulmonary disease (COPD). We now sought to investigate whether and how TLOs in these mice may play a pathogenic role in lung injury that is relevant to human disease. We found that inhibiting TLO formation using an anti-CD20 antibody in CLEC2-deficient mice partially blocked the development of emphysema. TLOs in CLEC2-deficient mice were rich in plasma cells and were a source of a broad array of autoantibodies. Chronic cigarette smoke exposure increased the size and number of lung TLOs in CLEC2-deficient mice and was associated with increased markers of antigen presentation and maturation, leading to increased autoantibody deposition. Using lung tissue from patients with COPD, we found an increase in lymphatic markers in patients with an emphysema phenotype and autoreactive TLOs compared with patients with COPD without emphysema that lack prominent TLOs. Taken together, these results demonstrate that emphysema in mice with lymphatic dysfunction can be partially rescued by blocking TLO formation and that these TLOs are the source of autoantibodies that are exacerbated by cigarette smoke. Our work suggests that lymphatic dysfunction in mice may recapitulate some aspects of an autoimmune emphysema phenotype that is seen in a subset of patients with COPD.<b>NEW & NOTEWORTHY</b> The lymphatic vasculature has been implicated in the pathogenesis of lung disease but remains understudied. Here, the authors use a mouse model to show that lymphatic dysfunction leads to a phenotype of emphysema that is characterized by lung tertiary lymphoid organs that are autoreactive and pathogenic. Analysis of human tissue showed increased lymphatic markers in autoimmune emphysema with prominent TLOs, compared with other COPD phenotypes.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L1-L14"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11905800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492938","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":"Neutrophil elastase activates macrophage calpain as a mechanism for phagocytic failure.","authors":"Jonathan Ma, Apparao B Kummarapurugu, Shuo Zheng, Andrew J Ghio, Laxmikant S Deshpande, Judith A Voynow","doi":"10.1152/ajplung.00132.2024","DOIUrl":"10.1152/ajplung.00132.2024","url":null,"abstract":"<p><p>Neutrophil elastase (NE), elevated in the cystic fibrosis (CF) airway, causes macrophage phagocytic failure. We previously reported that NE increases the release of protease calcium ion-dependent papain-like cysteine protease-2 (Calpain-2) in macrophages. We hypothesized that NE mediates macrophage failure through activation of Calpains. We demonstrate that Calpain inhibition rescued NE-induced macrophage phagocytic failure in murine alveolar macrophages in both cftr-null and wild-type genotypes. We then sought to determine how NE regulates Calpain-2. Human monocyte-derived macrophages (hMDMs) from persons with CF (PwCF) and non-CF subjects were treated with NE or control vehicle, and cell lysates were prepared to evaluate Calpain-2 protein abundance by Western and Calpain activity by a specific activity kit. Calpain is activated by intracellular calcium and inactivated by an endogenous inhibitor, Calpastatin. hMDMs were thus treated with NE or control vehicle and cell lysates were analyzed for increased intracellular calcium by Fluo-4 assay and for Calpastatin protein abundance by Western. NE increased Calpain-2 protein and activity, degraded Calpastatin, and increased intracellular calcium in macrophages. At baseline, there are no differences in Calpain activity, Calpain-2 and Calpastatin expression, and intracellular calcium between CF and non-CF macrophages. NE increased macrophage Calpain-2 protein and Calpain activity by two potential mechanisms: degradation of Calpastatin and/or increased intracellular calcium. In summary, Calpain inhibition restored NE-induced macrophage phagocytic failure suggesting a potential CFTR-independent target for phagocytic failure in the CF airway.<b>NEW & NOTEWORTHY</b> Neutrophil elastase, a cystic fibrosis airway inflammation biomarker, increases macrophage Calpain activity, and Calpain inhibition partially restores the decreased phagocytosis in neutrophil elastase-challenged macrophages. Neutrophil elastase increases Calpain-2 protein, degrades the Calpain inhibitor, Calpastatin, and increases intracellular calcium as potential mechanisms of Calpain activation. This presents a novel mechanism for macrophage dysfunction relevant to cystic fibrosis.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L93-L104"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581448","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":"Ultrastructural analysis of lamellar bodies in type II alveolar epithelial cells in the human lung.","authors":"Dimitri Vanhecke, Jens Randel Nyengaard, Beat Haenni, Julia Schipke, Matthias Ochs","doi":"10.1152/ajplung.00284.2024","DOIUrl":"10.1152/ajplung.00284.2024","url":null,"abstract":"<p><p>Pulmonary surfactant is produced by type II alveolar epithelial cells (AEC2) and stored in lamellar bodies (LBs) before secretion. Here, we characterize AEC2 and their LBs in the human lung ultrastructurally and quantitatively. Five human lungs were analyzed by transmission electron microscopy, serial section electron tomography, and stereology. A human lung contained about 24 billion AEC2 with a mean size of about 650 µm³. The number of AEC2 as well as the total volume of LBs per lung, about 1.9 mL, strongly correlated with total lung volume. A single AEC2 contained an LB volume of about 74 µm³. This amount was packed in about 324 LBs with a mean size of 0.24 µm³. Three morphologically distinct subpopulations of LBs were identified: <i>1</i>) isolated LBs which make up the majority (average 300 per AEC2), <i>2</i>) LBs connected to each other via pores (average 23 per AEC2), and <i>3</i>) LBs connected to the plasma membrane via a fusion pore (average 1 per AEC2). Along this sequence of subpopulations, the mean size of LBs increased. LBs that were connected either with each other or to the plasma membrane contained about 14% of an AEC2's LB volume. This is in line with the concept of an intermediate surfactant pool, stored in LBs either directly or indirectly connected to the plasma membrane. In summary, this study provides quantitative reference data on surfactant-storing LBs in AEC2 as well as morphological evidence for an intermediate surfactant pool in the human lung.<b>NEW & NOTEWORTHY</b> Human lung type II alveolar epithelial cells (AEC2) and their surfactant-storing lamellar bodies (LBs) are characterized quantitatively and ultrastructurally by transmission electron microscopy, serial section electron tomography, and stereology. On average, the 24 billion AEC2 in a human lung contain 324 LBs each. An intermediate surfactant pool in the human lung, comprising LBs in AEC2 not only directly but also indirectly connected to the plasma membrane via inter-LB connections, is demonstrated morphologically and characterized quantitatively.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L113-L119"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492939","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}