{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:56:59Z","timestamp":1791982619951,"version":"4.4.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M008770\/1"],"award-info":[{"award-number":["BB\/M008770\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Toxicol."],"abstract":"<jats:p>Chronic obstructive pulmonary disease (COPD) is driven primarily by cigarette smoke exposure, yet modelling its immunopathogenesis in mice is complicated by systemic stress and welfare concerns associated with conventional exposure models. Here, we employ a refined intranasal cigarette smoke extract (CSE) model to examine pulmonary pathology and peripheral immune responses in male and female C57BL\/6J mice. Repeated intranasal CSE exposure over 12 weeks was well tolerated and induced dose-dependent pulmonary neutrophilia, airway remodelling, and collagen deposition, with more pronounced pathology observed in female mice at higher exposure levels. In contrast, longitudinal multiparametric flow cytometric analysis revealed no consistent dose-dependent alterations in peripheral immune cell composition or activation, as confirmed by both conventional gating and unbiased clustering approaches. These findings demonstrate that COPD-like lung pathology can arise in the absence of overt systemic immune disruption and highlight the importance of lung inflammatory processes in disease development. This refined intranasal model provides a welfare-conscious platform for studying pulmonary immunopathology in COPD.<\/jats:p>","DOI":"10.3389\/ftox.2026.1884554","type":"journal-article","created":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T22:10:07Z","timestamp":1785708607000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Impact of intranasal cigarette smoke exposure on murine peripheral immune responses and lung pathology"],"prefix":"10.3389","volume":"8","author":[{"given":"Laura G.","family":"Bartlett","sequence":"first","affiliation":[{"name":"School of Life Sciences, The University of Nottingham","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin","family":"Azizbayli","sequence":"additional","affiliation":[{"name":"School of Life Sciences, The University of Nottingham","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda L.","family":"Tatler","sequence":"additional","affiliation":[{"name":"School of Medicine, The University of Nottingham","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Watkins","sequence":"additional","affiliation":[{"name":"Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield","place":["Sheffield, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy C.","family":"Fairclough","sequence":"additional","affiliation":[{"name":"School of Life Sciences, The University of Nottingham","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/S2213-2600(21)00511-7","article-title":"Global, regional, and national prevalence of, and risk factors for, chronic obstructive pulmonary disease (COPD) in 2019: a systematic review and modelling analysis","volume":"10","author":"Adeloye","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e139481","DOI":"10.1172\/JCI139481","article-title":"Neutrophilic inflammation during lung development disrupts elastin assembly and predisposes adult mice to COPD","volume":"131","author":"Benjamin","year":"2020","journal-title":"J. Clin. Investigation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"769214","DOI":"10.1155\/2013\/769214","article-title":"Macrophage heterogeneity in respiratory diseases","volume":"2013","author":"Boorsma","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"B4","volume-title":"Animal Models of Chronic Obstructive Pulmonary. COPD: An Update in Pathogenesis and Clinical Management","author":"Chow","year":"2018"},{"key":"B5","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.pulmoe.2019.10.006","article-title":"Chronic obstructive pulmonary disease and phenotypes: a state-of-the-art","volume":"26","author":"Corlateanu","year":"2020","journal-title":"Pulmonology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1186\/s12890-019-0915-6","article-title":"Quantitative lung morphology: semi-automated measurement of mean linear intercept","volume":"19","author":"Crowley","year":"2019","journal-title":"BMC Pulm. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1080\/15412555.2020.1783648","article-title":"Alveolar macrophage phenotype and compartmentalization drive different pulmonary changes in mouse strains exposed to cigarette smoke","volume":"17","author":"De Cunto","year":"2020","journal-title":"COPD"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2645","DOI":"10.1056\/NEJMoa032158","article-title":"The nature of small-airway obstruction in chronic obstructive pulmonary disease","volume":"350","author":"Hogg","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"507","DOI":"10.2144\/000112729","article-title":"Standardized quantification of pulmonary fibrosis in histological samples","volume":"44","author":"H\u00fcbner","year":"2008","journal-title":"BioTechniques"},{"key":"B10","doi-asserted-by":"publisher","first-page":"L304","DOI":"10.1152\/ajplung.00332.2023","article-title":"The lung extracellular matrix protein landscape in severe early-onset and moderate chronic obstructive pulmonary disease","volume":"327","author":"Joglekar","year":"2024","journal-title":"Am. J. Physiology-Lung Cell. Mol. Physiology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"30068","DOI":"10.18632\/oncotarget.4027","article-title":"Inflammaging increases susceptibility to cigarette smoke-induced COPD","volume":"7","author":"John-Schuster","year":"2016","journal-title":"Oncotarget"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1152\/physrev.00036.2021","article-title":"Contribution of adaptive immunity to human COPD and experimental models of emphysema","volume":"103","author":"Kheradmand","year":"2023","journal-title":"Physiol. Rev."},{"key":"B13","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1016\/S2213-2600(18)30196-6","article-title":"Small airways disease in mild and moderate chronic obstructive pulmonary disease: a cross-sectional study","volume":"6","author":"Koo","year":"2018","journal-title":"Lancet Respir. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"2","DOI":"10.4172\/2161-105X.1000125","article-title":"Characterisation of a mouse model of cigarette smoke extract-induced lung inflammation","volume":"2","author":"Lamb","year":"2012","journal-title":"J. Pulmon Resp. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"897","DOI":"10.3390\/cells10040897","article-title":"The role of macrophages in the development of acute and chronic inflammatory lung diseases","volume":"10","author":"Lee","year":"2021","journal-title":"Cells"},{"key":"B16","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1164\/rccm.202006-2467OC","article-title":"Hypoxia increases the potential for neutrophil-mediated endothelial damage in chronic obstructive pulmonary disease","volume":"205","author":"Lodge","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1183\/09031936.06.00024605","article-title":"The natural history of chronic obstructive pulmonary disease","volume":"27","author":"Mannino","year":"2006","journal-title":"Eur. Respir. J."},{"key":"B18","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1080\/01902140290096728","article-title":"A murine model of cigarette smoke-induced pulmonary inflammation using intranasally administered smoke-conditioned medium","volume":"28","author":"Miller","year":"2002","journal-title":"Exp. Lung Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1258\/ebm.2012.012103","article-title":"Evaluation of the pulmonary effects of short-term nose-only cigarette smoke exposure in mice","volume":"237","author":"Nemmar","year":"2012","journal-title":"Exp. Biol. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1183\/09031936.00079611","article-title":"Systemic CD4+ and CD8+ T-cell cytokine profiles correlate with GOLD stage in stable COPD","volume":"40","author":"Paats","year":"2012","journal-title":"Eur. Respir. J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1111\/resp.12912","article-title":"Increased neutrophil expression of pattern recognition receptors during COPD exacerbations","volume":"22","author":"Pouwels","year":"2017","journal-title":"Respirology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"173","DOI":"10.3724\/abbs.2021009","article-title":"The functions of CD4 T-helper lymphocytes in chronic obstructive pulmonary disease","volume":"54","author":"Qin","year":"2022","journal-title":"Acta Biochim. Biophys. Sin. (Shanghai)"},{"key":"B23","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.clim.2017.11.003","article-title":"Enhanced activation of circulating plasmacytoid dendritic cells in patients with chronic obstructive pulmonary disease and experimental smoking-induced emphysema","volume":"195","author":"Qiu","year":"2018","journal-title":"Clin. Immunol."},{"key":"B24","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-4939-9086-3_1","article-title":"The applicability of mouse models to the study of human disease","volume-title":"Mouse Cell Culture: Methods and Protocols","author":"Rydell-T\u00f6rm\u00e4nen","year":"2019"},{"key":"B25","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1186\/s12931-021-01680-5","article-title":"Enhanced lung inflammatory response in whole-body compared to nose-only cigarette smoke-exposed mice","volume":"22","author":"Serre","year":"2021","journal-title":"Respir. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3416","DOI":"10.1007\/s12602-024-10300-9","article-title":"A lactobacillus combination ameliorates lung inflammation in an Elastase\/LPS\u2014Induced mouse model of chronic obstructive pulmonary disease","volume":"17","author":"Shen","year":"2025","journal-title":"Probiotics Antimicrob. Proteins"},{"key":"B27","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/npr2.12093","article-title":"Differential effects of stress exposure via two types of restraint apparatuses on behavior and plasma corticosterone level in inbred Male BALB\/cAJcl mice","volume":"40","author":"Shoji","year":"2020","journal-title":"Neuropsychopharmacol. Rep."},{"key":"B28","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1159\/000334178","article-title":"Neutrophil-mediated lung damage: a new COPD phenotype?","volume":"83","author":"Sin","year":"2012","journal-title":"Respiration"},{"key":"B29","doi-asserted-by":"publisher","first-page":"109537","DOI":"10.1016\/j.intimp.2022.109537","article-title":"Inhibition of neutrophil elastase prevents cigarette smoke exposure-induced formation of neutrophil extracellular traps and improves lung function in a mouse model of chronic obstructive pulmonary disease","volume":"114","author":"Wang","year":"2023","journal-title":"Int. Immunopharmacol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1080\/01616412.2019.1615670","article-title":"Neuroinflammation caused by mental stress: the effect of chronic restraint stress and acute repeated social defeat stress in mice","volume":"41","author":"Zhu","year":"2019","journal-title":"Neurological Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"4472","DOI":"10.3390\/ijms20184472","article-title":"Inflammaging and oxidative stress in human diseases: from molecular mechanisms to novel treatments","volume":"20","author":"Zuo","year":"2019","journal-title":"Int. J. Mol. Sci."}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1884554\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T22:10:09Z","timestamp":1785708609000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1884554\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,3]]},"references-count":31,"alternative-id":["10.3389\/ftox.2026.1884554"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2026.1884554","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,3]]},"article-number":"1884554"}}