{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:14:05Z","timestamp":1782274445743,"version":"3.54.5"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T00:00:00Z","timestamp":1760400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K08150, 24K11310"],"award-info":[{"award-number":["21K08150, 24K11310"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder primarily caused by prolonged exposure to harmful substances, such as cigarette smoke. Hyaluronic acid synthase 2 (HAS2) synthesizes high-molecular-weight hyaluronic acid (HMW-HA), which has anti-inflammatory properties. Previous studies have revealed that HAS2 dysfunction may exacerbate COPD. However, the specific impact of HAS2 on pulmonary emphysema progression remains unclear. Therefore, this study examined whether HAS2 dysfunction worsens airway inflammation and emphysema in a mouse COPD model.\n                    <jats:italic>Has2<\/jats:italic>\n                    heterozygous-deficient (\n                    <jats:italic>Has2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    ) mice and their wild-type (WT) littermates were evaluated using a porcine pancreatic elastase (PPE)-induced COPD model. After the administration of PPE, the\n                    <jats:italic>Has2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice exhibited a significant increase in total cell and neutrophil counts in the bronchoalveolar lavage fluid samples compared with the WT mice. Further, the\n                    <jats:italic>Has2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice presented with enhanced emphysema development on histological analyses, with higher mean linear intercept values relative to the WT mice. The PPE-stimulated\n                    <jats:italic>Has2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice also had increased G-CSF levels and tumor growth factor-beta (TGF-\u03b2) attenuation in the lungs. RNA-sequencing analysis revealed that PPE stimulation promoted the synthesis of HMW-HA and TGF-\u03b2 signaling. Gene Ontology analysis using\n                    <jats:italic>Has2<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice-specific differentially expressed genes showed that the genes associated with the pathways that promote the negative regulation of the TGF-\u03b2 receptor signaling pathway were activated after the administration of PPE. Therefore,\n                    <jats:italic>Has2<\/jats:italic>\n                    dysfunction exacerbates neutrophilic airway inflammation and emphysema, thereby underscoring the protective role of HAS2 in a PPE-induced emphysema model. The exacerbated response may involve G-CSF- and TGF-\u03b2-related signaling pathways. These findings may contribute to the development of novel therapeutic strategies for COPD management.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2025.1683385","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T04:16:43Z","timestamp":1760415403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Hyaluronic acid synthase 2 dysfunction exacerbates elastase-induced neutrophilic airway inflammation and emphysema in mice"],"prefix":"10.3389","volume":"16","author":[{"given":"Kengo","family":"Nishino","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Kiwamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Matsuyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenting","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sosuke","family":"Matsumura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenya","family":"Kuramoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Yabuuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Yazaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazufumi","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Matsuno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Morishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuyuki","family":"Hizawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202204-0671PP","article-title":"Definition and nomenclature of chronic obstructive pulmonary disease: time for its revision","volume":"206","author":"Celli","year":"2022","journal-title":"Am J Respir Crit Care Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S2589-7500(23)00177-2","article-title":"Machine learning and deep learning predictive models for long-term prognosis in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis","volume":"5","author":"Smith","year":"2023","journal-title":"Lancet Digit Health"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01273-9","article-title":"Towards the elimination of chronic obstructive pulmonary disease: a Lancet Commission","volume":"400","author":"Stolz","year":"2022","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)00470-6","article-title":"Chronic obstructive pulmonary disease","volume":"399","author":"Christenson","year":"2022","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2020.09.255","article-title":"Projecting long-term health and economic burden of COPD in the United States","volume":"159","author":"Zafari","year":"2021","journal-title":"Chest"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01805-2016","article-title":"The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease","volume":"50","author":"Burgstaller","year":"2017","journal-title":"Eur Respir J"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0124-2019","article-title":"Extracellular matrix remodelling in COPD","volume":"29","author":"Karakioulaki","year":"2020","journal-title":"Eur Respir Rev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1046\/j.1525-1373.2000.22508.x","article-title":"The effect of hyaluronan on elastic fiber injury in vitro and elastase-induced airspace enlargement in vivo","volume":"225","author":"Cantor","year":"2000","journal-title":"Proc Soc Exp Biol Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1177\/153537020222700205","article-title":"The effect of lysozyme on elastase-mediated injury","volume":"227","author":"Cantor","year":"2002","journal-title":"Exp Biol Med (Maywood)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00070808","article-title":"Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD","volume":"34","author":"Klagas","year":"2009","journal-title":"Eur Respir J"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrev.8b00354","article-title":"Proteoglycan chemical diversity drives multifunctional cell regulation and therapeutics","volume":"118","author":"Karamanos","year":"2018","journal-title":"Chem Rev"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/cea.12415","article-title":"Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population","volume":"44","author":"Yatagai","year":"2014","journal-title":"Clin Exp Allergy"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/all.14715","article-title":"Has2 deficiency enhances OVA-induced airway inflammation and hyperresponsiveness in mice","volume":"76","author":"Tsunoda","year":"2021","journal-title":"Allergy"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.770305","article-title":"Has2 regulates the development of ovalbumin-induced airway remodeling and steroid insensitivity in mice","volume":"12","author":"Sherpa","year":"2021","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10272","article-title":"Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme","volume":"106","author":"Camenisch","year":"2000","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2018-0109OC","article-title":"Transcription factor T-bet attenuates the development of elastase-induced emphysema in mice","volume":"61","author":"Hayashi","year":"2019","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0114-2","article-title":"Determining cell type abundance and expression from bulk tissues with digital cytometry","volume":"37","author":"Newman","year":"2019","journal-title":"Nat Biotechnol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/srep40508","article-title":"Inference of immune cell composition on the expression profiles of mouse tissue","volume":"7","author":"Chen","year":"2017","journal-title":"Sci Rep"},{"key":"B19","doi-asserted-by":"publisher","first-page":"186","DOI":"10.1016\/j.addr.2015.10.017","article-title":"Hyaluronan as a therapeutic target in human diseases","volume":"97","author":"Liang","year":"2016","journal-title":"Adv Drug Delivery Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1080\/00365516309051324","article-title":"The electrophoretic \u03b1;1-globulin pattern of serum in \u03b1;1-antitrypsin deficiency","volume":"15","author":"Laurell","year":"1963","journal-title":"Scandinavian J Clin Lab Invest"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2017.12.016","article-title":"The therapeutic potential of hyaluronan in COPD","volume":"153","author":"Turino","year":"2018","journal-title":"Chest"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00168.2015","article-title":"The role of hyaluronan in the pathobiology and treatment of respiratory disease","volume":"310","author":"Garantziotis","year":"2016","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2015.03.006","article-title":"Lung hyaluronan levels are decreased in alpha-1 antiprotease deficiency COPD","volume":"109","author":"Cantor","year":"2015","journal-title":"Respir Med"},{"key":"B24","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1164\/arrd.1982.126.5.797","article-title":"A biochemical study on glycosaminoglycans (mucopolysaccharides) in emphysematous and in aged lungs","volume":"126","author":"Konno","year":"1982","journal-title":"Am Rev Respir Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1080\/01902140590918669","article-title":"Aerosolized hyaluronan limits airspace enlargement in a mouse model of cigarette smoke-induced pulmonary emphysema","volume":"31","author":"Cantor","year":"2005","journal-title":"Exp Lung Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00214.2015","article-title":"Experimental progressive emphysema in BALB\/cJ mice as a model for chronic alveolar destruction in humans","volume":"309","author":"Limjunyawong","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s00441-016-2567-7","article-title":"Immune-mediated inflammation in the pathogenesis of emphysema: insights from mouse models","volume":"367","author":"Craig","year":"2017","journal-title":"Cell Tissue Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3390\/cells12151981","article-title":"The role of cytokines in neutrophil development, tissue homing, function and plasticity in health and disease","volume":"12","author":"Tsioumpekou","year":"2023","journal-title":"Cells"},{"key":"B29","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1183\/09031936.00040307","article-title":"Association of genetic variations in the CSF2 and CSF3 genes with lung function in smoking-induced COPD","volume":"32","author":"He","year":"2008","journal-title":"Eur Respir J"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI98224","article-title":"Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease","volume":"128","author":"Tsantikos","year":"2018","journal-title":"J Clin Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00836-2020","article-title":"High serum granulocyte-colony stimulating factor characterises neutrophilic COPD exacerbations associated with dysbiosis","volume":"7","author":"Chakrabarti","year":"2021","journal-title":"ERJ Open Res"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1126\/science.1069659","article-title":"Resolution of lung inflammation by CD44","volume":"296","author":"Teder","year":"2002","journal-title":"Sci (New York NY)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5338.672","article-title":"Requirement for CD44 in activated T cell extravasation into an inflammatory site","volume":"278","author":"DeGrendele","year":"1997","journal-title":"Sci (New York NY)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00068","article-title":"Interactions between CD44 and hyaluronan in leukocyte trafficking","volume":"6","author":"McDonald","year":"2015","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.2.151","article-title":"Blockade of transforming growth factor beta\/Smad signaling in T cells by overexpression of Smad7 enhances antigen-induced airway inflammation and airway reactivity","volume":"192","author":"Nakao","year":"2000","journal-title":"J Exp Med"},{"key":"B36","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1172\/JCI7589","article-title":"CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation","volume":"105","author":"Hansen","year":"2000","journal-title":"J Clin Invest"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2021.107839","article-title":"Therapeutic targets in lung tissue remodelling and fibrosis","volume":"225","author":"Liu","year":"2021","journal-title":"Pharmacol Ther"},{"key":"B38","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.matbio.2016.03.004","article-title":"Hyaluronan synthase 2 regulates fibroblast senescence in pulmonary fibrosis","volume":"55","author":"Li","year":"2016","journal-title":"Matrix biology: J Int Soc Matrix Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl8146","article-title":"Steroid-induced fibroblast growth factors drive an epithelial-mesenchymal inflammatory axis in severe asthma","volume":"14","author":"Guidi","year":"2022","journal-title":"Sci Transl Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.matbio.2014.01.011","article-title":"A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease","volume":"34","author":"Chang","year":"2014","journal-title":"Matrix biology: J Int Soc Matrix Biol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/s12931-020-01610-x","article-title":"Inhaled high molecular weight hyaluronan ameliorates respiratory failure in acute COPD exacerbation: a pilot study","volume":"22","author":"Galdi","year":"2021","journal-title":"Respir Res"},{"key":"B42","doi-asserted-by":"publisher","first-page":"17732","DOI":"10.1038\/s41598-019-54053-w","article-title":"G-CSFR antagonism reduces neutrophilic inflammation during pneumococcal and influenza respiratory infections without compromising clearance","volume":"9","author":"Wang","year":"2019","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15415","article-title":"G-CSFR antagonism reduces mucosal injury and airways fibrosis in a virus-dependent model of severe asthma","volume":"178","author":"Wang","year":"2021","journal-title":"Br J Pharmacol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01183-2018","article-title":"Serum levels of hyaluronic acid are associated with COPD severity and predict survival","volume":"53","author":"Papakonstantinou","year":"2019","journal-title":"Eur Respir J"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1683385\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T15:41:37Z","timestamp":1761925297000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1683385\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,14]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2025.1683385"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1683385","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,14]]},"article-number":"1683385"}}