{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:19:36Z","timestamp":1785417576687,"version":"3.56.0"},"reference-count":80,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ES602105"],"award-info":[{"award-number":["ES602105"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"award":["ES602105"],"award-info":[{"award-number":["ES602105"]}],"id":[{"id":"https:\/\/ror.org\/00j4k1h63","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Airway pollutants, like the reactive oxygen species ozone, cause significant lung injury, which can lead to the development or exacerbation of lung diseases like asthma and chronic obstructive pulmonary disease (COPD), and drives worldwide morbidity and mortality. Altered epithelial function is a hallmark and trigger of ozone-induced lung injury, but its precise mechanisms are incompletely known. The extracellular matrix, and specifically its major component, hyaluronan (HA), plays a crucial role in cellular injury responses. We hypothesized that HA signaling mediates epithelial responses to ozone-induced injury. We exposed human and murine differentiated primary epithelia to ozone in vitro and evaluated epithelial integrity and transcriptomic responses. We used genetically deficient cells for cognate HA receptors cluster of differentiation 44 (CD44) and receptor for HA-mediated motility (RHAMM), and innate immune receptors toll-like receptor 4 (TLR4) and TLR5 to study signaling pathways, and evaluated high molecular weight HA (HMWHA) as a potential treatment for ozone-induced epithelial injury. In vitro ozone exposure caused significant reduction in epithelial integrity and very similar inflammatory changes in human and murine cells. CD44 deficiency led to decreased inflammation, while RHAMM deficiency exacerbated cell injury. HMWHA protected against ozone-induced epithelial injury, mediated by TLR4 and TLR5 but not CD44 or RHAMM. Our results identify novel contributions of HA signaling to ozone-induced epithelial injury and suggest that HMWHA protects epithelia via innate immune activation of TLR4 and TLR5.<\/jats:p>","DOI":"10.3390\/biom16060795","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T09:57:43Z","timestamp":1779962263000},"page":"795","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hyaluronan Signaling Ameliorates the Epithelial Injury Response and Barrier Disruption After Ozone Exposure"],"prefix":"10.3390","volume":"16","author":[{"given":"Jonas","family":"Ritter","sequence":"first","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"},{"name":"Institute of General Physiology, Ulm University, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandy P.","family":"Stober","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol S.","family":"Trempus","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9798-6704","authenticated-orcid":false,"given":"Yosuke","family":"Sakamachi","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6487-081X","authenticated-orcid":false,"given":"Jian-Liang","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9100-0027","authenticated-orcid":false,"given":"Erica L.","family":"Scappini","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiya","family":"Birukova","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Elaguech","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine, Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam R.","family":"Hall","sequence":"additional","affiliation":[{"name":"Wake Forest School of Medicine, Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3465-9861","authenticated-orcid":false,"given":"Robert M.","family":"Tighe","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1890-6471","authenticated-orcid":false,"given":"Oliver H.","family":"Wittekindt","sequence":"additional","affiliation":[{"name":"Institute of General Physiology, Ulm University, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4007-375X","authenticated-orcid":false,"given":"Stavros","family":"Garantziotis","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"042002","DOI":"10.1088\/1752-7163\/ac2589","article-title":"The physics of human breathing: Flow, timing, volume, and pressure parameters for normal, on-demand, and ventilator respiration","volume":"15","author":"Pleil","year":"2021","journal-title":"J. Breath Res."},{"key":"ref_2","unstructured":"(2026, January 13). Billions of People Still Breathe Unhealthy Air: New WHO Data. Available online: https:\/\/www.who.int\/news\/item\/04-04-2022-billions-of-people-still-breathe-unhealthy-air-new-who-data."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e535","DOI":"10.1016\/S2542-5196(22)00090-0","article-title":"Pollution and health: A progress update","volume":"6","author":"Fuller","year":"2022","journal-title":"Lancet Planet. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s43630-020-00001-x","article-title":"Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2020","volume":"20","author":"Neale","year":"2021","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_5","unstructured":"Health Effects Institute (2024). HEI State of Global Air 2024: A Special Report on Global Exposure to Air Pollution and Its Health Impacts, with a Focus on Children\u2019s Health, Health Effects Institute."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2866","DOI":"10.3390\/ijerph7072866","article-title":"Impact of climate change on ambient ozone level and mortality in southeastern United States","volume":"7","author":"Chang","year":"2010","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Gao, H., Wang, K., Au, W.W., Zhao, W., and Xia, Z.L. (2020). A Systematic Review and Meta-Analysis of Short-Term Ambient Ozone Exposure and COPD Hospitalizations. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17062130"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/ni.3045","article-title":"Respiratory epithelial cells orchestrate pulmonary innate immunity","volume":"16","author":"Whitsett","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1513\/pats.200805-041HR","article-title":"Airway epithelial cells: Current concepts and challenges","volume":"5","author":"Crystal","year":"2008","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2301619","DOI":"10.1183\/13993003.01619-2023","article-title":"Airway remodelling in asthma and the epithelium: On the edge of a new era","volume":"63","author":"Varricchi","year":"2024","journal-title":"Eur. Respir. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2771","DOI":"10.1016\/j.bbagen.2016.07.015","article-title":"Mechanisms of the acute effects of inhaled ozone in humans","volume":"1860","author":"Bromberg","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.matbio.2018.01.027","article-title":"Hyaluronan interactions with innate immunity in lung biology","volume":"78\u201379","author":"Tighe","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/nyas.14415","article-title":"Hyaluronan and halogen-induced airway hyperresponsiveness and lung injury","volume":"1479","author":"Lazrak","year":"2020","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"253","DOI":"10.4161\/derm.21923","article-title":"Hyaluronic acid: A key molecule in skin aging","volume":"4","author":"Papakonstantinou","year":"2012","journal-title":"Dermatoendocrinol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1074\/jbc.M115.704288","article-title":"Hyaluronan Rafts on Airway Epithelial Cells","volume":"291","author":"Abbadi","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Iaconisi, G.N., Lunetti, P., Gallo, N., Cappello, A.R., Fiermonte, G., Dolce, V., and Capobianco, L. (2023). Hyaluronic Acid: A Powerful Biomolecule with Wide-Ranging Applications-A Comprehensive Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241210296"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Liu, M., Tolg, C., and Turley, E. (2019). Dissecting the Dual Nature of Hyaluronan in the Tumor Microenvironment. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.00947"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"107993","DOI":"10.1016\/j.pharmthera.2021.107993","article-title":"Modulation of hyaluronan signaling as a therapeutic target in human disease","volume":"232","author":"Garantziotis","year":"2021","journal-title":"Pharmacol. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.matbio.2019.02.002","article-title":"Hyaluronan biology: A complex balancing act of structure, function, location and context","volume":"78\u201379","author":"Garantziotis","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Hoarau, A., Polette, M., and Coraux, C. (2022). Lung Hyaluronasome: Involvement of Low Molecular Weight Ha (Lmw-Ha) in Innate Immunity. Biomolecules, 12.","DOI":"10.3390\/biom12050658"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1165\/rcmb.2008-0073OC","article-title":"Hyaluronan fragments\/CD44 mediate oxidative stress-induced MUC5B up-regulation in airway epithelium","volume":"40","author":"Monzon","year":"2009","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1096\/fj.01-0036com","article-title":"Hyaluronan serves a novel role in airway mucosal host defense","volume":"15","author":"Forteza","year":"2001","journal-title":"FASEB J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"11309","DOI":"10.1074\/jbc.M802400200","article-title":"Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice","volume":"284","author":"Garantziotis","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1165\/rcmb.2024-0385OC","article-title":"Hyaluronan Directs Alveolar Type II Cell Response to Acute Ozone Exposure in Mice","volume":"73","author":"Vose","year":"2025","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41467-023-44263-2","article-title":"Mucosal TLR5 activation controls healthspan and longevity","volume":"15","author":"Lim","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1126\/science.1256999","article-title":"Viral infection. Prevention and cure of rotavirus infection via TLR5\/NLRC4-mediated production of IL-22 and IL-18","volume":"346","author":"Zhang","year":"2014","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/s41586-018-0395-5","article-title":"Neonatal selection by Toll-like receptor 5 influences long-term gut microbiota composition","volume":"560","author":"Fulde","year":"2018","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.matbio.2018.08.002","article-title":"The Receptor for Hyaluronan-Mediated Motility (CD168) promotes inflammation and fibrosis after acute lung injury","volume":"78\u201379","author":"Cui","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7349","DOI":"10.1038\/s41598-018-25799-6","article-title":"A novel method for expansion and differentiation of mouse tracheal epithelial cells in culture","volume":"8","author":"Eenjes","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.cbi.2014.06.026","article-title":"The Gillings Sampler--an electrostatic air sampler as an alternative method for aerosol in vitro exposure studies","volume":"220","author":"Zavala","year":"2014","journal-title":"Chem. Biol. Interact."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sakamachi, Y., Wiley, E., Solis, A., Johnson, C.G., Meng, X., Hussain, S., Lipinski, J.H., O\u2019Dwyer, D.N., Randall, T., and Malphurs, J. (2024). Toll-Like-Receptor 5 protects against pulmonary fibrosis by reducing lung dysbiosis. bioRxiv.","DOI":"10.1101\/2024.04.30.591719"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4288","DOI":"10.1093\/nar\/gks042","article-title":"Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation","volume":"40","author":"McCarthy","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Arzt, M., Deschamps, J., Schmied, C., Pietzsch, T., Schmidt, D., Tomancak, P., Haase, R., and Jug, F. (2022). LABKIT: Labeling and Segmentation Toolkit for Big Image Data. Front. Comput. Sci., 4.","DOI":"10.3389\/fcomp.2022.777728"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e70008","DOI":"10.1002\/pgr2.70008","article-title":"High-fidelity and iterative affinity extraction of hyaluronan","volume":"2","author":"Erxleben","year":"2024","journal-title":"Proteoglycan Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/s41467-018-03439-x","article-title":"Label-free analysis of physiological hyaluronan size distribution with a solid-state nanopore sensor","volume":"9","author":"Rivas","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4469","DOI":"10.1038\/s41598-022-08533-1","article-title":"Optimizing the sensitivity and resolution of hyaluronan analysis with solid-state nanopores","volume":"12","author":"Rivas","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1038\/nnano.2010.202","article-title":"Rapid electronic detection of probe-specific microRNAs using thin nanopore sensors","volume":"5","author":"Wanunu","year":"2010","journal-title":"Nat. Nanotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"42345","DOI":"10.1074\/jbc.M402744200","article-title":"Synchronized chemoenzymatic synthesis of monodisperse hyaluronan polymers","volume":"279","author":"Jing","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1177\/2211068214561025","article-title":"TEER measurement techniques for in vitro barrier model systems","volume":"20","author":"Srinivasan","year":"2015","journal-title":"J. Lab. Autom."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e50458","DOI":"10.7554\/eLife.50458","article-title":"TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury","volume":"9","author":"Hussain","year":"2020","journal-title":"eLife"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1038\/nm.4192","article-title":"Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice","volume":"22","author":"Liang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17079","DOI":"10.1074\/jbc.M310859200","article-title":"Hyaluronan fragments stimulate endothelial recognition of injury through TLR4","volume":"279","author":"Taylor","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1007\/s11869-020-00900-z","article-title":"The impact of emissions and climate change on future ozone concentrations in the USA","volume":"13","author":"Moghani","year":"2020","journal-title":"Air Qual. Atmos. Health"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1080\/08958378.2021.1956021","article-title":"Effects of ozone and particulate matter on airway epithelial barrier structure and function: A review of in vitro and in vivo studies","volume":"33","author":"Smyth","year":"2021","journal-title":"Inhal. Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1093\/toxsci\/69.2.400","article-title":"Amelioration of ozone-induced lung injury by anti-tumor necrosis factor-alpha","volume":"69","author":"Bhalla","year":"2002","journal-title":"Toxicol. Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1164\/rccm.200509-1527OC","article-title":"Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice","volume":"175","author":"Cho","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1164\/rccm.200903-0381OC","article-title":"TLR4 Is Necessary for Hyaluronan-mediated Airway Hyperresponsiveness after Ozone Inhalation","volume":"181","author":"Garantziotis","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e00985-20","DOI":"10.1128\/JVI.00985-20","article-title":"Type I and Type III Interferons Restrict SARS-CoV-2 Infection of Human Airway Epithelial Cultures","volume":"94","author":"Vanderheiden","year":"2020","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.2147\/COPD.S105948","article-title":"Reduced sputum expression of interferon-stimulated genes in severe COPD","volume":"11","author":"Hilzendeger","year":"2016","journal-title":"Int. J. Chronic Obstr. Pulm. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1165\/rcmb.2025-0173OC","article-title":"Hyaluronan Ameliorates Viral Pneumonia in Mice and Humans by Inhibiting E2F1 Transcription Factor","volume":"74","author":"Stober","year":"2025","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"486","DOI":"10.3109\/08958378.2011.584919","article-title":"Increased transforming growth factor beta 1 expression mediates ozone-induced airway fibrosis in mice","volume":"23","author":"Katre","year":"2011","journal-title":"Inhal. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kraik, K., Tota, M., Laska, J., Lacwik, J., Pazdzierz, L., Sedek, L., and Gomulka, K. (2024). The Role of Transforming Growth Factor-beta (TGF-beta) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells, 13.","DOI":"10.3390\/cells13151271"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1165\/ajrcmb.21.1.3379","article-title":"Reactive oxygen and nitrogen intermediates increase transforming growth factor-beta1 release from human epithelial alveolar cells through two different mechanisms","volume":"21","author":"Bellocq","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6530","DOI":"10.1074\/jbc.M704819200","article-title":"Hyaluronan facilitates transforming growth factor-beta1-mediated fibroblast proliferation","volume":"283","author":"Meran","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"17618","DOI":"10.1074\/jbc.M111.226563","article-title":"Hyaluronan facilitates transforming growth factor-beta1-dependent proliferation via CD44 and epidermal growth factor receptor interaction","volume":"286","author":"Meran","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ajpath.2011.09.036","article-title":"Antisense knockdown of Kras inhibits fibrosis in a rat model of unilateral ureteric obstruction","volume":"180","author":"Wang","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"402","DOI":"10.31083\/j.fbl2912402","article-title":"The Warburg Effect: Is it Always an Enemy?","volume":"29","author":"Papaneophytou","year":"2024","journal-title":"Front. Biosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.matbio.2018.04.012","article-title":"Activated hyaluronan metabolism in the tumor matrix\u2014Causes and consequences","volume":"78\u201379","author":"Tammi","year":"2019","journal-title":"Matrix Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.carbpol.2012.03.081","article-title":"Preparation of low-molecular-weight hyaluronic acid by ozone treatment","volume":"89","author":"Wu","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"L891","DOI":"10.1152\/ajplung.00377.2014","article-title":"Hyaluronan mediates airway hyperresponsiveness in oxidative lung injury","volume":"308","author":"Lazrak","year":"2015","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"L808","DOI":"10.1152\/ajplung.00510.2017","article-title":"Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier","volume":"314","author":"Zhou","year":"2018","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1126\/science.1069659","article-title":"Resolution of lung inflammation by CD44","volume":"296","author":"Teder","year":"2002","journal-title":"Science"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"42288","DOI":"10.1074\/jbc.M112.387795","article-title":"Hyaluronan and layilin mediate loss of airway epithelial barrier function induced by cigarette smoke by decreasing E-cadherin","volume":"287","author":"Forteza","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.4049\/jimmunol.177.2.1272","article-title":"Hyaluronan fragments act as an endogenous danger signal by engaging TLR2","volume":"177","author":"Scheibner","year":"2006","journal-title":"J. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6217","DOI":"10.4049\/jimmunol.170.12.6217","article-title":"Induction of macrophage nitric oxide production by Gram-negative flagellin involves signaling via heteromeric Toll-like receptor 5\/Toll-like receptor 4 complexes","volume":"170","author":"Mizel","year":"2003","journal-title":"J. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Enweasor, C., Flayer, C.H., and Haczku, A. (2021). Ozone-Induced Oxidative Stress, Neutrophilic Airway Inflammation, and Glucocorticoid Resistance in Asthma. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.631092"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1165\/rcmb.2004-0333OC","article-title":"Expression and role of the hyaluronan receptor RHAMM in inflammation after bleomycin injury","volume":"33","author":"Zaman","year":"2005","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1204.11","DOI":"10.1096\/fasebj.30.1_supplement.1204.11","article-title":"The Hyaluronan Receptor RHAMM is Necessary for the Activation of Src Kinase and the Signaling Pathway for Endothelial Nitric Oxide Production","volume":"30","author":"Savani","year":"2016","journal-title":"FASEB J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1042\/bj3350557","article-title":"Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression","volume":"335","author":"Schaper","year":"1998","journal-title":"Biochem. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1074\/jbc.M210552200","article-title":"SHP2 and SOCS3 contribute to Tyr-759-dependent attenuation of interleukin-6 signaling through gp130","volume":"278","author":"Lehmann","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1165\/rcmb.2006-0363OC","article-title":"CD44 regulates macrophage recruitment to the lung in lipopolysaccharide-induced airway disease","volume":"37","author":"Hollingsworth","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"L785","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":"ref_76","doi-asserted-by":"crossref","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":"ref_77","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1038\/35074106","article-title":"The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5","volume":"410","author":"Hayashi","year":"2001","journal-title":"Nature"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41586-023-06463-0","article-title":"Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice","volume":"621","author":"Zhang","year":"2023","journal-title":"Nature"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s12931-016-0442-4","article-title":"Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease","volume":"17","author":"Lamas","year":"2016","journal-title":"Respir. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"L787","DOI":"10.1152\/ajplung.00009.2018","article-title":"High molecular weight hyaluronan ameliorates allergic inflammation and airway hyperresponsiveness in the mouse","volume":"315","author":"Johnson","year":"2018","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/795\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:44:44Z","timestamp":1780537484000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/16\/6\/795"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":80,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["biom16060795"],"URL":"https:\/\/doi.org\/10.3390\/biom16060795","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]}}}