American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Multicohort Analysis of Bronchial Epithelial Cell Expression in Healthy Subjects and Patients with Asthma Reveals Four Clinically Distinct Clusters.","authors":"Ian Lee, Ananthakrishnan Ganesan, Laurynas Kalesinskas, Hong Zheng, Haejun C Ahn, Stephanie Christenson, Serpil C Erzurum, Joe Zein, Eugene R Bleecker, Deborah A Meyers, Mario Castro, John V Fahy, Elliot Israel, Nizar N Jarjour, Wendy Moore, Sally E Wenzel, David T Mauger, Bruce D Levy, Prescott G Woodruff, Victor E Ortega, Purvesh Khatri","doi":"10.1165/rcmb.2024-0125OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0125OC","url":null,"abstract":"<p><p>Asthma is a heterogeneous disease with variable presentation and characteristics. There is a critical need to identify underlying molecular endotypes of asthma. We performed the largest transcriptomic analysis of 808 bronchial epithelial cell (BEC) samples across 11 independent cohorts, including 3 cohorts from the Severe Asthma Research Program (SARP). Using 7 datasets (218 asthma patients, 148 healthy controls) as discovery cohorts, we identified 505 differentially expressed genes (DEGs), which we validated in the remaining four datasets. Unsupervised clustering using the 505 DEGs identified four reproducible clusters of patients with asthma across all datasets corresponding to healthy controls, mild/moderate asthma, and severe asthma with significant differences in several clinical markers of severity, including pulmonary function, T2 inflammation, FeNO, and max bronchodilator reversibility. Importantly, we found the same clusters in pediatric patients using nasal lavage fluid cells, demonstrating the gene signature and clusters are not confounded by age and conserved in both lower and upper airways. The four asthma clusters may represent a unifying framework for understanding the molecular heterogeneity of asthma. Further study could potentially enable a precision medicine approach of matching therapies with asthma patients most likely to benefit.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863023","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":"LPS Increases Artery but Not Airway Contraction in Precision Cut Lung Slices from a Mouse Model of ARDS.","authors":"Emma Lamanna, Zoe F Kropf, Raymond Luong, Matthew Narayan, Elizabeth A Richards, Bailey Cardwell, Simon G Royce, Claudia A Nold-Petry, Jane E Bourke","doi":"10.1165/rcmb.2024-0249OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0249OC","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) results in decreased quality of life, including increased risk of pulmonary hypertension (PH). In animal models, ARDS can be induced by lipopolysaccharide (LPS), which can disrupt the pulmonary endothelium and epithelium and induce inflammation. We tested whether <i>in vivo</i> administration or <i>ex vivo</i> treatment with LPS alters the reactivity of intrapulmonary arteries and airways to constrictors relevant to both ARDS and PH, using the precision cut lung slice (PCLS) technique. Mice were administered LPS (10μg/50μl, intranasal) or saline daily for 4d before collection of bronchoalveolar lavage fluid (BALF) or preparation of PCLS. Alternatively, PCLS from naïve mice were left untreated or treated <i>ex vivo</i> with LPS (10μg/mL) or tumour necrosis factor (TNF, 10ng/mL) for 18h. Contraction to endothelin-1 (ET-1), U46619 (a stable mimetic of TXA₂) or serotonin (5HT) were quantified. <i>In vivo</i> LPS administration increased BAL total inflammatory cells 5-fold, neutrophils 125-fold and protein 2-fold, as well as the thickness of the pulmonary arterial smooth muscle layer. After <i>in vivo</i> LPS, contraction of intrapulmonary arteries in PCLS to ET-1 and U46619, but not 5HT, increased, while bronchoconstrictor responses were unchanged. In PCLS treated with LPS <i>ex vivo</i>, these differential effects on pulmonary artery and airway contraction were maintained. While LPS increased TNF secretion from PCLS, TNF treatment only increased U46619-induced vasoconstriction. This study demonstrates the potential contributions of LPS-induced inflammation and vascular remodelling to altered intrapulmonary artery reactivity to specific agonists with implications for ARDS-associated PH.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863020","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":"Sectm1a Depletion Promotes Neutrophil Recruitment during Pneumococcal Pneumonia.","authors":"Hiromu Tanaka, Hirofumi Kamata, Makoto Ishii, Takanori Asakura, Ho Namkoong, Kensuke Nakagawara, Atsuho Morita, Tatsuya Kusumoto, Shuhei Azekawa, Masanori Kaji, Genta Nagao, Naoki Fukunaga, Tomoyasu Nishimura, Keisuke Asakura, Naoki Hasegawa, Koichi Fukunaga","doi":"10.1165/rcmb.2024-0276OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0276OC","url":null,"abstract":"<p><p>Airway epithelial cells (AECs) play an essential role in the immune response during bacterial pneumonia. Secreted and transmembrane 1a (Sectm1a) is specifically expressed in AECs during early <i>Streptococcus pneumoniae</i> (SP) infection. However, its function remains largely unexplored. Here, we aimed to clarify the function of Sectm1a during serotype 3 pneumococcal pneumonia primarily using an <i>in vivo</i> mouse model. Our findings showed that type Ⅰ interferons (IFNs) directly induced Sectm1a expression in AECs. Sectm1a depletion in an <i>in vivo</i> mouse model improved survival rate and enhanced the clearance of intrapulmonary bacterial burden at an early stage of SP infection. Correspondingly, Sectm1a depletion increased the count of intrapulmonary γδT cells, promoted IL-17A production by these cells, and enhanced intrapulmonary neutrophil responses against SP. Notably, IL-17A production in the isolated lung γδT cells was directly suppressed by Sectm1a <i>ex vivo</i>. Furthermore, Sectm1a depletion altered the migration and activation markers of γδT cells <i>in vivo</i>, indicating that the AEC-derived Sectm1a is associated with the phenotypes of γδT cells. These findings suggest that type Ⅰ IFNs may play an important role via AEC-derived Sectm1a in this model, and Sectm1a signaling modulates excessive neutrophil inflammation and influences bacterial clearance by directly altering γδT cell functions during pneumococcal pneumonia. In summary, this study demonstrates that the type Ⅰ IFN-Sectm1a pathway could be a potential target to modify the acute response to bacterial pneumonia.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863027","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":"Targeting S1PR2 in Sepsis, One Fragmented Mitochondrion at a Time.","authors":"Chao He, Jennifer L Larson-Casey","doi":"10.1165/rcmb.2024-0561ED","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0561ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811763","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":"Fetal Tracheal Occlusion Corelates with Normalized YAP Expression and Alveolar Epithelial Differentiation in CDH.","authors":"Ophelia Aubert, Yuichiro Miyake, Gaurang M Amonkar, Olivia M Dinwoodie, Brian M Varisco, Mario Marotta, Caiqi Zhao, Richard Wagner, Ya-Wen Chen, Alessandra Moscatello, Caterina Tiozzo, Xaralabos Varelas, Paul H Lerou, Jose L Peiro, Richard Keijzer, Xingbin Ai","doi":"10.1165/rcmb.2024-0323OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0323OC","url":null,"abstract":"<p><p>Congenital diaphragmatic hernia (CDH) is characterized by incomplete closure of the diaphragm. While the ensuing compression to the fetal lung causes lung hypoplasia, specific cellular phenotypes and developmental signaling defects in the alveolar epithelium in CDH are not fully understood. Employing lung samples from human CDH, a surgical lamb model and a nitrogen rat model, we investigate whether lung compression impairs alveolar epithelial differentiation and Yes-associated protein (YAP)-mediated mechanosensing. We showed that CDH in humans and lambs caused defective alveolar epithelial differentiation manifested by more abundant ATII cells, fewer ATI cells, and the emergence of cells expressing both ATI and ATII markers. Associated with the alveolar epithelial defects, we found a decrease in the level and nuclear localization of YAP. Reduced nuclear YAP and abnormal distal lung development were evident as early as 21 weeks in gestation in human CDH. In addition, rat fetuses with CDH also showed diminished nuclear YAP and mor abundant ATII cells. In contrast, the littermates without the hernia had no such alveolar phenotypes. Furthermore, fetal tracheal occlusion (TO) in the surgical lamb model of CDH fully normalized nuclear YAP and rescued alveolar epithelial defects in a gestational age-dependent manner. Taken together, our findings across species indicate that lung compression in CDH is sufficient to disrupt alveolar epithelial differentiation and impair YAP signaling. TO can restore nuclear YAP and rescue the alveolar defects in CDH, depending on the timing and the duration of this prenatal surgical intervention. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142811750","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":"Targeting the Epigenetic Regulator CBX5 Promotes Fibroblast Metabolic Reprogramming and Inhibits Lung Fibrosis.","authors":"Jeongmin Hong, Tho X Pham, Jisu Lee, Ahmed A Raslan, Kristina Nicolas, Andrei Sharov, Jeffrey A Meridew, Raul A Urrutia, Gwen Lomberk, Steven K Huang, Giovanni Ligresti","doi":"10.1165/rcmb.2024-0255OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0255OC","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is characterized by the sustained activation of interstitial fibroblasts leading to excessive collagen deposition and progressive organ failure. Epigenetic and metabolic abnormalities have been shown to contribute to the persistent activated state of scar-forming fibroblasts. However, how epigenetic changes regulate fibroblast metabolic responses to promote fibroblast activation and progressive fibrosis remains largely unknown. Here we show that the epigenetic regulator chromobox protein homolog 5 (CBX5) is critical to the transition of quiescent fibroblasts to activated collagen-producing fibroblasts in response to bleomycin induced lung injury. Loss of mesenchymal CBX5 attenuated fibrosis development, and this effect was accompanied by the downregulation of pathogenic fibroblast genes, including <i>Cthrc1</i>, <i>Col1a1</i>, and <i>Spp1</i>, and by the upregulation of metabolic genes with anti-fibrotic activity such as <i>Ppara</i> and <i>Pparg</i>. scRNA-seq and immunohistochemistry analyses revealed that CBX5 expression was enriched in pathogenic fibroblasts and fibroblastic foci of IPF lungs. Bulk RNA-seq analysis combined with metabolic assessments demonstrated that CBX5 silencing in IPF fibroblasts potently inhibited TGFβ-stimulated glycolysis while enhancing AMPK signaling and mitochondrial metabolism. Finally, interruption of the CBX5 pathway in IPF fibroblasts in vitro and in IPF lung explants ex vivo synergistically potentiated metformin-induced AMPK activation and inhibited collagen secretion. Collectively, our findings identify CBX5 as an epigenetic regulator linking metabolic maladaptation to the persistent activated state of lung fibroblasts during IPF progression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789484","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":"From Epithelium to Therapy: Transitional Cells in Lung Fibrosis.","authors":"Sarah Y Shin, Jichao Chen, Irit Milman Krentsis, Yair Reisner, Rodeo Abrencillo, Rahat Hussain, Danielle Wu, Harry Karmouty-Quintana","doi":"10.1165/rcmb.2024-0372TR","DOIUrl":"10.1165/rcmb.2024-0372TR","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) and lung fibrosis secondary to infections such as influenza A and COVID-19 have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that comprise the lung epithelium. We then focus on two subpopulations of KRT5+ or KRT8+ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells' potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both <i>in vivo</i> models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells pre-cultured as 3D organoids.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789483","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":"Parasympathetic Airway Hyperreactivity Is Enhanced in Acute but Not Chronic Eosinophilic Asthma Mouse Models.","authors":"Alexandra B Pincus, Aubrey B Pierce, Nicole Kappel, Katie M Lebold, Matthew G Drake, Allison D Fryer, David B Jacoby","doi":"10.1165/rcmb.2024-0360OC","DOIUrl":"10.1165/rcmb.2024-0360OC","url":null,"abstract":"<p><p>Airway hyperreactivity in asthma is mediated by airway nerves, including sensory nerves in airway epithelium and parasympathetic nerves innervating airway smooth muscle. Isolating the function of these two nerve populations in vivo, to distinguish how each is affected by inflammatory processes and contributes to hyperreactivity in asthma, has been challenging. In this study, we used optogenetic acti-vation of airway nerves in vivo to study parasympathetic contributions to airway hyperreactivity in two mouse models of asthma: 1) acute challenge with house dust mite antigen, and 2) chronic airway hy-pereosinophilia due to genetic IL-5 overexpression in airways. Overall airway hyperreactivity, as meas-ured by bronchoconstriction to an inhaled agonist, was increased in both models. In contrast, optoge-netic stimulation of isolated efferent parasympathetic nerves induced bronchoconstriction only in the acute house dust mite antigen challenge group. Using whole mount tissue immunofluorescence and modeling software, we then measured, in three dimensions, the interactions between eosinophils and parasympathetic nerves in both models and found that eosinophils were more numerous and more proximal to airway parasympathetic nerves in antigen challenged and IL-5 transgenic mice than in their respective controls, but were not significantly different between the two asthma models. Thus even though eosinophils were increased around nerves in both models, parasympathetic nerves only mediated airway hyperreactivity in the antigen challenged mice. This study demonstrates divergent effects of acute versus chronic eosinophilia on parasympathetic airway nerve activity and points to eo-sinophil-nerve interactions as a key regulator of airway hyperreactivity in antigen challenged mice.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765568","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":"Macrophage S1PR2 Drives Sepsis-induced Immunosuppression by Exacerbating Mitochondrial Fragmentation.","authors":"Xiangyang Yu, Xin Hu, Dongdong Wang, Ping Cui, Min Zeng, Min Li, Chenchen Gong, Dongqin Huang, Yan Wang, Kai Zhang, Xiangming Fang","doi":"10.1165/rcmb.2024-0161OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0161OC","url":null,"abstract":"<p><p>Macrophage mitochondrial dysfunction is associated with immunosuppression and poor prognosis of septic patients. Mitochondrial fragmentation drives mitochondrial dysfunction. Our previous study has found that S1PR2 regulates macrophage phagocytosis during sepsis, while the role of S1PR2 in immunosuppression and the mechanisms remain further studied. This study aimed to unveil the relationship between macrophage mitochondrial fragmentation and sepsis-induced immunosuppression, as well as the S1PR2-related mechanisms thereof. Peripheral blood monocytes were collected from healthy controls (n = 12), nonseptic critical controls (n = 13) and septic patients (n = 19). Peritoneal macrophages were harvested from wildtype and <i>S1pr2^-/-</i> mice (MMRRC strain iD, 12830) after cecal ligation and puncture (CLP). Mitochondrial ultrastructure was evaluated using transmission electron microscopy. The impact of mitochondrial ultrastructure alteration on immunosuppression of monocytes-macrophages was evaluated. Compared with nonseptic and healthy controls, peripheral blood monocytes from septic patients exhibited increased S1PR2 expression, mitochondrial fragmentation, and mitochondrial dysfunction. Mitochondrial fragmentation was negatively associated with HLA-DR expression. S1PR2 expression was positively correlated with mitochondrial fragmentation and negatively correlated with HLA-DR expression. In mice subjected to CLP, S1PR2 depletion ameliorated macrophage mitochondrial fragmentation and dysfunction, boosted immunity, and improved survival. Mechanistically, in response to sepsis, S1PR2 activates ROCK I to induce Drp1 phosphorylation, resulting in Drp1-dependent mitochondrial fragmentation of macrophages. Drp1 inhibition by Mdivi-1 mitigated S1PR2-induced macrophage immunosuppression and improved the prognosis of mice following CLP. In conclusion, S1PR2-induced mitochondrial fragmentation is a crucial factor mediating septic immunosuppression, highlighting its potential as a promising therapeutic target in sepsis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765567","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":"Enzymatic Modulation of the Pulmonary Glycocalyx Enhances Susceptibility to <i>Streptococcus pneumoniae</i>.","authors":"Cengiz Goekeri, Kerstin A K Linke, Karen Hoffmann, Elena Lopez-Rodriguez, Vladimir Gluhovic, Anne Voß, Sandra Kunder, Andreas Zappe, Sara Timm, Alina Nettesheim, Sebastian M K Schickinger, Christian M Zobel, Kevin Pagel, Achim D Gruber, Matthias Ochs, Martin Witzenrath, Geraldine Nouailles","doi":"10.1165/rcmb.2024-0003OC","DOIUrl":"10.1165/rcmb.2024-0003OC","url":null,"abstract":"<p><p>The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with <i>Streptococcus pneumoniae</i> in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combination with <i>S. pneumoniae</i> infection further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma concentrations of proinflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage, and pulmonary inflammation in mice infected with <i>S. pneumoniae</i>. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier during <i>S. pneumoniae</i> infection. Notably, enzymatic pretreatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococci-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, and epithelial barrier function and integrity.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"646-658"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622634/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747231","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}