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

{"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}

{"title":"Deep phenotyping of pulmonary edema and pulmonary vascular permeability in COVID-19 ARDS.","authors":"Job R Schippers, Leila N Atmowihardjo, Erik Duijvelaar, Lars G Knaap, Mihai G Netea, Lilian J Meijboom, Lieuwe D J Bos, Harm Jan Bogaard, Jurjan Aman","doi":"10.1152/ajplung.00196.2024","DOIUrl":"10.1152/ajplung.00196.2024","url":null,"abstract":"<p><p>Clinical monitoring of pulmonary edema due to vascular hyperpermeability in acute respiratory distress syndrome (ARDS) poses significant clinical challenges. Presently, no biological or radiological markers are available for quantifying pulmonary edema. Our aim was to phenotype pulmonary edema and pulmonary vascular permeability in patients with coronavirus disease 2019 (COVID-19) ARDS. Transpulmonary thermodilution measurements were conducted in 65 patients with COVID-19 ARDS on the day of intubation to determine the extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPi). In parallel, ventilatory parameters, clinical outcomes, the volume of lung opacity measured by chest computed tomography (CT), radiographic assessment of lung edema (RALE) score by chest radiography, and plasma proteomics (358 unique proteins) were compared between tertiles based on the EVLWi and PVPi. Regression models were used to associate EVLWi and PVPi with plasma, radiological, and clinical parameters. Computational pathway analysis was performed on significant plasma proteins in the regression models. Patients with the highest EVLWi values at intubation exhibited poorer oxygenation parameters and more days on the ventilator. Extravascular lung water strongly correlated with the total volume of opacity observed on CT (<i>r</i> = 0.72, <i>P</i> < 0.001), whereas the PVPi had weaker associations with clinical and radiological parameters. Extravascular lung water did not correlate with the RALE score (<i>r</i> = 0.15, <i>P</i> = 0.33). Plasma protein concentrations demonstrated a stronger correlation with PVPi than with EVLWi. The highest tertile of PVPi was associated with proteins linked to the acute phase response (cytokine and chemokine signaling) and extracellular matrix turnover. In the clinical setting of COVID-19 ARDS, pulmonary edema (EVLWi) can be accurately quantified through chest CT and parallels deterioration in ventilatory parameters and clinical outcomes. Vascular permeability (PVPi) is strongly reflected by inflammatory plasma proteins.<b>NEW & NOTEWORTHY</b> This study is unique in that it phenotypes pulmonary edema in COVID-19 ARDS using various clinical parameters and biomarkers. First, there is a noteworthy tipping point in the amount of pulmonary edema at which ventilatory and clinical parameters deteriorate. Second, chest CT gives a good approximation of the amount of pulmonary edema. Finally, pulmonary vascular permeability is strongly reflected by inflammatory plasma proteins.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L30-L40"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492917","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":"PDGFRα-positive cell-derived TIMP-1 modulates adaptive immune responses to influenza A viral infection.","authors":"Saugata Dutta, Yin Zhu, Sultan Almuntashiri, Hong Yong Peh, Joaquin Zuñiga, Duo Zhang, Payaningal R Somanath, Gustavo Ramírez, Valeria Irineo-Moreno, Fabiola Jiménez-Juárez, Karen López-Salinas, Nora Regino, Paloma Campero, Stephen J Crocker, Caroline A Owen, Xiaoyun Wang","doi":"10.1152/ajplung.00104.2024","DOIUrl":"10.1152/ajplung.00104.2024","url":null,"abstract":"<p><p>Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a physiologic inhibitor of the matrix metalloproteinases (MMPs), but little is known about the role of TIMP-1 in regulating the pathogenesis of influenza A virus (IAV) infection. Here, we performed both in vivo and in vitro experiments to investigate the regulation and function of TIMP-1 during IAV infection. Specifically, plasma levels of TIMP-1 are significantly increased in human subjects and wild-type (WT) mice infected with 2009 H1N1 IAV compared with levels in uninfected controls. Also, TIMP-1 is strikingly upregulated in PDGFRα positive (PDGFRα⁺) cells in IAV-infected murine lungs as demonstrated using conditional KO (cKO) mice with a specific deletion of <i>Timp-1</i> in PDGFRα⁺ cells. Our in vitro data indicated that TIMP-1 is induced by transforming growth factor-β (TGF-β) during lipofibroblasts (lipoFBs)-to-myofibroblast (myoFB) transdifferentiation. <i>Timp-1</i> deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. IAV-infected <i>Timp-1-</i>deficient mice showed increased macrophages, and B and T cell counts in bronchoalveolar lavage (BAL) on <i>day 7</i> postinfection (p.i.), but reduced BAL neutrophil counts. Increased Cxcl12 levels were detected in both BAL cells and lungs from <i>Timp-1-</i>deficient mice on <i>day 3</i> p.i. Taken together, our data strongly link TIMP-1 to IAV pathogenesis. We identified that PDGFRα-lineage cells are the main cellular source of elevated TIMP-1 during IAV infection. Loss of <i>Timp-1</i> attenuates IAV-induced mortality and promotes T and B cell recruitment. Thus, TIMP-1 may be a novel therapeutic target for IAV infection.<b>NEW & NOTEWORTHY</b> Our data strongly link tissue inhibitor of metalloproteinases-1 (TIMP-1) to influenza A virus (IAV) pathogenesis. TIMP-1 is highly increased in PDGFRα-lineage cells during IAV infection. Transforming growth factor-β (TGF-β) induces TIMP-1 during lipofibroblast (lipoFB)-to- myofibroblast (myoFB) transdifferentiation. <i>Timp-1</i> deficiency protects mice from H1N1 IAV-induced weight loss, mortality, and lung injury. TIMP-1 may be a novel therapeutic target for IAV infection.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L60-L74"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708980","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 effect of adrenalectomy on bleomycin-induced pulmonary fibrosis in mice.","authors":"John McGovern, Carrighan Perry, Alexander Ghincea, Erica L Herzog, Shuai Shao, Huanxing Sun","doi":"10.1152/ajplung.00062.2024","DOIUrl":"10.1152/ajplung.00062.2024","url":null,"abstract":"<p><p>Progressive lung fibrosis is often fatal and has limited treatment options. Though the mechanisms are poorly understood, fibrosis is increasingly linked with catecholamines such as adrenaline (AD) and noradrenaline (NA) and hormones such as aldosterone (ALD). The essential functions of the adrenal glands include the production of catecholamines and numerous hormones, but the contribution of adrenal glands to lung fibrosis remains less well studied. Here, we characterized the impact of surgical adrenal ablation in the bleomycin model of lung fibrosis. Wild-type mice underwent surgical adrenalectomy or sham surgery followed by bleomycin administration. We found that although bleomycin-induced collagen overdeposition in the lung was not affected by adrenalectomy, histologic indices of lung remodeling were ameliorated. These findings were accompanied by a decrease of lymphocytes in bronchoalveolar lavage (BAL) and macrophages in lung tissues, along with concomitant reductions in alpha-smooth muscle actin (αSMA) and fibronectin. Surgical adrenalectomy completely abrogated AD, not NA, detection in all compartments. Systemic ALD levels were reduced after adrenalectomy, whereas ALD levels in lung tissues remained unaffected. Taken together, these results support the presence of a pulmonary-adrenal axis in lung fibrosis and suggest that adrenalectomy is protective in this disease. Further investigation will be needed to better understand this observation and aid in the development of novel therapeutic strategies.<b>NEW & NOTEWORTHY</b> The lung-adrenal axis plays a significant role in pulmonary fibrosis. Adrenalectomy provides protection against lung fibrotic ECM remodeling and lung inflammation by reducing the levels of lymphocytes in BAL and macrophages in lung of bleomycin-treated mice. Although compared with sham surgery, adrenalectomy raised collagen concentration in uninjured mice, there was no discernible difference in bleomycin-induced collagen accumulation. However, adrenalectomy significantly reversed the enhanced expression and colocalization of αSMA and fibronectin induced by bleomycin.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L15-L29"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520719","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":"Effects of patient pleural effusion fluids on the BBSome components expression of human benign mesothelial cells.","authors":"Rajesh M Jagirdar, Erasmia Rouka, Eleanna Pitaraki, Ioannis Sarrigeorgiou, Ourania S Kotsiou, Sotiris I Sinis, Eleftherios D Papazoglou, Periklis Marnas, Zoi Malami, Peggy Lymberi, Anastasios D Giannou, Chrissi Hatzoglou, Konstantinos I Gourgoulianis, Sotirios G Zarogiannis","doi":"10.1152/ajplung.00373.2023","DOIUrl":"10.1152/ajplung.00373.2023","url":null,"abstract":"<p><p>Malignant pleural mesothelial cells are affected by the extracellular milieu although such data on benign cells are scarce. Benign cells sense the extracellular environment with the primary cilium (PC) and its molecular complex, the Bardet-Biedl syndrome family of proteins (BBSome), is critical for this process. Here we aimed to assess the changes in BBSome gene expression in ordinary two-dimensional (2-D) and spheroid three-dimensional (3-D) cell cultures after incubation with pleural effusion fluids (PFs) of several etiologies. The benign human mesothelial cells (MeT-5A) were incubated with PF from patients with mesothelioma (Meso-PF), breast cancer (BrCa-PF), hemothorax (Hemo-PF), and congestive heart failure (CHF-PF). Gene expression of <i>BBS1, 2, 4, 5, 7, 9,</i> and <i>18</i> was assessed by quantitative real-time PCR (qRT-PCR) to monitor PF-induced gene expression changes. MeT-5A cell migration using the PC-modulating drugs ammonium sulfate (AS) and lithium chloride (LC) during PF incubation was also determined. BBSome gene expression upon influence of BrCa-PF and Hemo-PF was more pronounced in 2-D compared with 3-D, inducing global changes in 2-D. CHF-PF and Meso-PF also induced changes in 2-D but not as many, while in all cases, MeT-5A grown in 3-D were more resistant to the effects of the PF. Meso-PF decreased 2-D cell migration, while the disturbance of PC in all PF cases resulted in decreased cell migration. These data suggest distinct BBSome molecular profile changes in benign mesothelial cells exposed to malignant and benign PF that is different in each case, in both 2-D and 3-D. Cell migration is sensitive to drug disturbance with PC modulators in PF-exposed cells.<b>NEW & NOTEWORTHY</b> Studying mesothelial PC in pleural physiology and pathophysiology is at an early stage. Previously, we have highlighted the role of the PC in mesothelial cell phenotypes as well as the role of BBSome components in the context of benign and malignant mesothelial cell physiology. Here we extended our contributions by providing evidence on the BBSome changes induced in benign mesothelial cells by their exposure to different etiology PFs.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L105-L112"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142520717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired antiviral immunity in frequent exacerbators of chronic obstructive pulmonary disease.","authors":"Lydia J Finney, Peter Fenwick, Samuel V Kemp, Aran Singanayagam, Michael R Edwards, Kylie B R Belchamber, Tatiana Kebadze, Eteri Regis, Gavin D Donaldson, Patrick Mallia, Louise E Donnelly, Sebastian L Johnston, Jadwiga A Wedzicha","doi":"10.1152/ajplung.00118.2024","DOIUrl":"10.1152/ajplung.00118.2024","url":null,"abstract":"<p><p>Respiratory viruses cause chronic obstructive pulmonary disease (COPD) exacerbations. Rhinoviruses (RVs) are the most frequently detected. Some patients with COPD experience frequent exacerbations (≥2 exacerbations/yr). The relationship between exacerbation frequency and antiviral immunity remains poorly understood. The objective of this study was to investigate the relationship between exacerbation frequency and antiviral immunity in COPD. Alveolar macrophages and bronchial epithelial cells (BECs) were obtained from patients with COPD and healthy participants. Alveolar macrophages were infected with RV-A16 multiplicity of infection (MOI) 5 and BECs infected with RV-A16 MOI 1 for 24. Interferons (IFNs) and proinflammatory cytokines IL-1β, IL-6, C-X-C motif chemokine ligand (CXCL)-8, and TNF were measured in cell supernatants using a mesoscale discovery platform. Viral load and interferon-stimulated genes were measured in cell lysates using quantitative PCR. Spontaneous and RV-induced IFN-β, IFN-γ, and CXCL-11 release were significantly reduced in alveolar macrophages from patients with COPD compared with healthy subjects. IFN-β was further impaired in uninfected alveolar macrophages from patients with COPD with frequent exacerbations 82.0 pg/mL versus infrequent exacerbators 234.7 pg/mL, <i>P</i> = 0.008 and RV-infected alveolar macrophages from frequent exacerbators 158.1 pg/mL versus infrequent exacerbators 279.5 pg/mL, <i>P</i> = 0.022. Release of proinflammatory cytokines CXCL-8, IL-6, TNF, and IL-1β was higher in uninfected BECs from patients with COPD compared with healthy subjects but there was no difference in proinflammatory response to RV between groups. IFN responses to RV were impaired in alveolar macrophages from patients with COPD and further reduced in patients with frequent exacerbations.<b>NEW & NOTEWORTHY</b> COPD exacerbations are commonly triggered by viral infections. Some patients with COPD have frequent exacerbations leading to rapid lung function decline and increased mortality. In this study, antiviral responses (interferons) from bronchial epithelial cells and alveolar macrophages were reduced in patients with COPD compared with healthy participants and further reduced in patients with COPD with frequent exacerbations. Impaired antiviral immunity may lead to frequent COPD exacerbations. Targeted vaccinations and antiviral therapy may reduce exacerbations in COPD.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L120-L133"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Surfactant Protein-A and its immunomodulatory roles in infant respiratory syncytial virus infection: a potential for therapeutic intervention?","authors":"Muhammad Pradhika Mapindra, Tania Castillo-Hernandez, Howard Clark, Jens Madsen","doi":"10.1152/ajplung.00199.2024","DOIUrl":"10.1152/ajplung.00199.2024","url":null,"abstract":"<p><p>The vast majority of early-life hospital admissions globally highlight respiratory syncytial virus (RSV), the leading cause of neonatal lower respiratory tract infections, as the major culprit behind the poor neonatal outcomes following respiratory infections. Unlike those of older children and adults, the immune system of neonates looks rather unique, therefore mostly counting on the innate immune system and antibodies of maternal origins. The collaborations between cells and immune compartments during infancy inclines bias toward a T-helper 2 (Th2) immune profile and thereby away from a T-helper 1 (Th1) immune response. What makes it more problematic is that RSV infection also tends to elicit a stronger Th2-biased immune response and drive an aberrant allergy-like inflammation. It is thus evident how RSV infections potentially pave the way for wheezing recurrences and childhood asthma later in life. Surfactant, the essential lung substance for normal breathing processes in mammals, has immunomodulatory properties including lung collectins such as Surfactant Protein-A (SP-A), which is the most abundant protein component of surfactant, and also Surfactant Protein-D (SP-D). Deficiency of SP-A and SP-D has been found to be associated with impaired pathogen clearance and exacerbated immune responses during infections. We therefore conducted a review of the literature to describe pathomechanisms of RSV infections during blunted neonatal immunity potentially facilitating allergy-like inflammatory events within the developing lungs and highlight the potential protective role of the humoral collectin SP-A to mitigate these in the \"early in life\" pulmonary immune system.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L179-L196"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leukocyte kinetics and bacterial clearance during <i>Streptococcus pneumoniae</i> pneumonia and contributions of ICAM-1.","authors":"Matthew K McPeek, John C Gomez, Jessica R Martin, Marie Anne Iannone, Hong Dang, Claire M Doerschuk","doi":"10.1152/ajplung.00039.2024","DOIUrl":"10.1152/ajplung.00039.2024","url":null,"abstract":"<p><p><i>Streptococcus pneumoniae</i> is a leading cause of community-acquired pneumonia. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that is highly expressed on the pulmonary capillary endothelium, alveolar epithelium, and other cell types within the lung. ICAM-1 plays important roles in leukocyte adhesion, migration, and motility. To determine the contributions of ICAM-1 to bacterial clearance and leukocyte kinetics during pneumonia, mice were inoculated with <i>S. pneumoniae</i> and evaluated 1, 4, and 7 days later. Our results show that <i>Icam1</i>^-/- mice have a greater number of viable bacteria within the lung at each time point. The impaired clearance observed in <i>Icam1</i>^-/- mice was not due to an impediment in leukocyte recruitment. In fact, <i>Icam1</i>^-/- mice had a greater number of neutrophils and recruited inflammatory macrophages in the lung tissue and the alveoli/airways on <i>day 7</i>. In contrast, fewer alveolar macrophages were present in the bronchoalveolar lavage (BAL) of <i>Icam1^-/-</i> mice. The loss of body weight and the concentrations of inflammatory mediators in the BAL were also significantly greater in <i>Icam1</i>^-/- mice. Mechanistic studies to understand the defect in clearance show that neutrophils and macrophage subpopulations had no defect in phagocytosis or acidification of phagosomes. RNA sequencing reveals many differences in gene expression but no suggestion of a defect in phagocytosis or killing. Thus, ICAM-1 is necessary for the clearance of <i>S. pneumoniae</i> and for the resolution of pneumonia but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways during <i>S. pneumoniae-</i>induced pneumonia.<b>NEW & NOTEWORTHY</b> <i>Streptococcus pneumoniae</i> is the leading cause of community-acquired pneumonia. Our study examined ICAM-1, an adhesion molecule that is expressed on most cell types and plays important roles in leukocyte adhesion, migration, and motility. The data demonstrate that ICAM-1 is necessary for the clearance of <i>S. pneumoniae</i> and for the resolution of pneumonia but is not required for the recruitment of neutrophils or inflammatory macrophages into the pneumonic lung parenchyma or the alveoli/airways.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L41-L59"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pulmonary-delivered Anticalin Jagged-1 antagonists reduce experimental airway mucus hyperproduction and obstruction.","authors":"Katharina Heinzelmann, Athanasios Fysikopoulos, Thomas J Jaquin, Janet K Peper-Gabriel, Eva-Maria Hansbauer, Stefan Grüner, Josef Prassler, Claudia Wurzenberger, Joseph G C Kennedy, Jazmin Y Snead, Joe A Wrennall, Kristina Heinig, Cornelia Wurzenberger, Rachida-Siham Bel Aiba, Robert Tarran, Alessandra Livraghi-Butrico, Mary F Fitzgerald, Gary P Anderson, Christine Rothe, Gabriele Matschiner, Shane A Olwill, Matthias Hagner","doi":"10.1152/ajplung.00059.2024","DOIUrl":"10.1152/ajplung.00059.2024","url":null,"abstract":"<p><p>Mucus hypersecretion and mucus obstruction are pathogenic features in many chronic lung diseases directly linked to disease severity, exacerbation, progression, and mortality. The Jagged-1/Notch pathway is a promising therapeutic target that regulates secretory and ciliated cell trans-differentiation in the lung. However, the Notch pathway is also required in various other organs. Hence, pulmonary delivery of therapeutic agents is a promising approach to target this pathway while minimizing systemic exposure. Using Anticalin technology, Jagged-1 Anticalin binding proteins were generated and engineered to potent and selective inhalable Jagged-1 antagonists. Their therapeutic potential to reduce airway mucus hyperproduction and obstruction was investigated ex vivo and in vivo. In primary airway cell cultures grown at an air-liquid interface and stimulated with inflammatory cytokines, Jagged-1 Anticalin binding proteins reduced both mucin gene expression and mucous cell metaplasia. In vivo, prophylactic and therapeutic treatment with a pulmonary-delivered Jagged-1 Anticalin binding protein reduced mucous cell metaplasia, epithelial thickening, and airway mucus hyperproduction in IL-13 and house dust mite allergen-challenged mice, respectively. Furthermore, in a transgenic mouse model with pathophysiologic features of cystic fibrosis and chronic obstructive pulmonary disease (COPD), pulmonary-delivered Jagged-1 Anticalin binding protein reduced hallmarks of airway mucus obstruction. In all in vivo models, a reduction of mucous cells with a concomitant increase of ciliated cells was observed. Collectively, these findings support Jagged-1 antagonists' therapeutic potential for patients with muco-obstructive lung diseases and the feasibility of targeting the Jagged-1/Notch pathway by inhalation.<b>NEW & NOTEWORTHY</b> Airway mucus drives severity and mortality in diverse chronic lung diseases. The Jagged-1/Notch pathway controls the balance of ciliated versus mucous cells, but targeting the pathway systemically carries the risk of side effects. Here we developed novel, Anticalin-derived, pulmonary-delivered Jagged-1 antagonists, to inhibit airway mucus hyperproduction and obstruction in chronic lung diseases. Our preclinical data demonstrate the effectiveness of these antagonists in diminishing secretory cell and mucus levels and alleviating hallmarks of mucus obstruction.</p>","PeriodicalId":7593,"journal":{"name":"American journal of physiology. Lung cellular and molecular physiology","volume":" ","pages":"L75-L92"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142581450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}