{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T05:47:23Z","timestamp":1772689643121,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,4,30]],"date-time":"2024-04-30T00:00:00Z","timestamp":1714435200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R15HL152257"],"award-info":[{"award-number":["1R15HL152257"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-\u03baB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities.<\/jats:p>","DOI":"10.3390\/ijms25094940","type":"journal-article","created":{"date-parts":[[2024,5,1]],"date-time":"2024-05-01T03:30:49Z","timestamp":1714534249000},"page":"4940","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Availability of Receptors for Advanced Glycation End-Products (RAGE) Influences Differential Transcriptome Expression in Lungs from Mice Exposed to Chronic Secondhand Smoke (SHS)"],"prefix":"10.3390","volume":"25","author":[{"given":"Katrina L.","family":"Curtis","sequence":"first","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashley","family":"Chang","sequence":"additional","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Van Slooten","sequence":"additional","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Cooper","sequence":"additional","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madison N.","family":"Kirkham","sequence":"additional","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Armond","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zack","family":"deBernardi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7930-8160","authenticated-orcid":false,"given":"Brett E.","family":"Pickett","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8818-8786","authenticated-orcid":false,"given":"Juan A.","family":"Arroyo","sequence":"additional","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0931-3025","authenticated-orcid":false,"given":"Paul R.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Lung and Placenta Laboratory, Department of Cell Biology and Physiology, Brigham Young University, Provo, UT 84602, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1007\/s11606-020-06070-z","article-title":"Changes in mortality in top 10 causes of death from 2011 to 2018","volume":"36","author":"Rana","year":"2021","journal-title":"J. Gen. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"105938","DOI":"10.1016\/j.rmed.2020.105938","article-title":"Goals of COPD treatment: Focus on symptoms and exacerbations","volume":"166","author":"Vogelmeier","year":"2020","journal-title":"Respir. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1164\/rccm.200811-1757ST","article-title":"An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease","volume":"182","author":"Eisner","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1513\/pats.200504-045SR","article-title":"Pathogenesis of chronic obstructive pulmonary disease","volume":"2","author":"MacNee","year":"2005","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12931-017-0548-3","article-title":"Understanding the impact of symptoms on the burden of COPD","volume":"18","author":"Miravitlles","year":"2017","journal-title":"Respir. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1016\/j.amjmed.2005.06.041","article-title":"Airway obstruction in never smokers: Results from the Third National Health and Nutrition Examination Survey","volume":"118","author":"Celli","year":"2005","journal-title":"Am. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"445","DOI":"10.21037\/atm.2020.03.145","article-title":"Objective secondhand smoke exposure in chronic obstructive pulmonary disease patients without active smoking: The US National Health and Nutrition Examination Survey (NHANES) 2007\u20132012","volume":"8","author":"Fu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1378\/chest.10-1253","article-title":"COPD in never smokers: Results from the population-based burden of obstructive lung disease study","volume":"139","author":"Lamprecht","year":"2011","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1136\/thoraxjnl-2015-206938","article-title":"Characteristics of COPD in never-smokers and ever-smokers in the general population: Results from the CanCOLD study","volume":"70","author":"Tan","year":"2015","journal-title":"Thorax"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.annepidem.2004.12.014","article-title":"A case-control study on the effect of exposure to different substances on the development of COPD","volume":"16","author":"Sezer","year":"2006","journal-title":"Ann. Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S0140-6736(07)61378-6","article-title":"Passive smoking exposure and risk of COPD among adults in China: The Guangzhou Biobank Cohort Study","volume":"370","author":"Yin","year":"2007","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.15585\/mmwr.mm6748a3","article-title":"Exposure to secondhand smoke among nonsmokers\u2014United States, 1988\u20132014","volume":"67","author":"Tsai","year":"2018","journal-title":"Morb. Mortal. Wkly. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"E103","DOI":"10.5888\/pcd17.200107","article-title":"Peer reviewed: Exposure to secondhand smoke in homes and vehicles among US youths, United States, 2011\u20132019","volume":"17","author":"Walton","year":"2020","journal-title":"Prev. Chronic Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.amepre.2018.05.005","article-title":"Secondhand smoke exposure in childhood and adulthood in relation to adult mortality among never smokers","volume":"55","author":"Diver","year":"2018","journal-title":"Am. J. Prev. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.freeradbiomed.2022.12.089","article-title":"The receptor for advanced glycation end products (RAGE) is involved in mitochondrial function and cigarette smoke-induced oxidative stress","volume":"195","author":"Kwon","year":"2023","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","first-page":"257","article-title":"Role of the receptor for advanced glycation end products (RAGE) in inflammation","volume":"51","author":"Mosquera","year":"2010","journal-title":"Investig. Clin."},{"key":"ref_17","first-page":"1025","article-title":"Advanced glycation endproducts and cigarette smoking","volume":"44","author":"Nicholl","year":"1998","journal-title":"Cell. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"L881","DOI":"10.1152\/ajplung.00135.2016","article-title":"Susceptibility for cigarette smoke-induced DAMP release and DAMP-induced inflammation in COPD","volume":"311","author":"Pouwels","year":"2016","journal-title":"Am. J. Physiol.-Lung Cell. Mol. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/cr.2011.13","article-title":"NF-\u03baB in immunobiology","volume":"21","author":"Hayden","year":"2011","journal-title":"Cell Res."},{"key":"ref_20","first-page":"40","article-title":"All the \u201cRAGE\u201d in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses","volume":"23","author":"Oczypok","year":"2017","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1007\/s00109-005-0688-7","article-title":"Understanding RAGE, the receptor for advanced glycation end products","volume":"83","author":"Bierhaus","year":"2005","journal-title":"J. Mol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/s12931-019-1032-z","article-title":"RNA-sequencing across three matched tissues reveals shared and tissue-specific gene expression and pathway signatures of COPD","volume":"20","author":"Morrow","year":"2019","journal-title":"Respir. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Pillai, S.G., Ge, D., Zhu, G., Kong, X., Shianna, K.V., Need, A.C., Feng, S., Hersh, C.P., Bakke, P., and Gulsvik, A. (2009). A genome-wide association study in chronic obstructive pulmonary disease (COPD): Identification of two major susceptibility loci. PLoS Genet., 5.","DOI":"10.1371\/journal.pgen.1000421"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.trsl.2022.03.009","article-title":"Impact of E-cig aerosol vaping on fetal and neonatal respiratory development and function","volume":"246","author":"Orzabal","year":"2022","journal-title":"Transl. Res."},{"key":"ref_25","first-page":"e22190","article-title":"Transient response of serpinA3 during cellular stress","volume":"36","author":"Linares","year":"2022","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Kelly-Robinson, G.A., Reihill, J.A., Lundy, F.T., McGarvey, L.P., Lockhart, J.C., Litherland, G.J., Thornbury, K.D., and Martin, S.L. (2021). The serpin superfamily and their role in the regulation and dysfunction of serine protease activity in COPD and other chronic lung diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126351"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"148147","DOI":"10.1172\/jci.insight.148147","article-title":"Type II alveolar epithelial cell\u2013specific loss of RhoA exacerbates allergic airway inflammation through SLC26A4","volume":"6","author":"Do","year":"2021","journal-title":"JCI Insight"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6262","DOI":"10.4049\/jimmunol.180.9.6262","article-title":"Identification of pendrin as a common mediator for mucus production in bronchial asthma and chronic obstructive pulmonary disease","volume":"180","author":"Nakao","year":"2008","journal-title":"J. Immunol."},{"key":"ref_29","first-page":"1","article-title":"Novel roles for chloride channels, exchangers, and regulators in chronic inflammatory airway diseases","volume":"2015","author":"Yurtsever","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1002\/cbf.3855","article-title":"The potential protective effect of liraglutide on valproic acid induced liver injury in rats: Targeting HMGB1\/RAGE axis and RIPK3\/MLKL mediated necroptosis","volume":"41","author":"Atef","year":"2023","journal-title":"Cell Biochem. Funct."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"907133","DOI":"10.3389\/fphar.2022.907133","article-title":"Receptor of advanced glycation end products deficiency attenuates cisplatin-induced acute nephrotoxicity by inhibiting apoptosis, inflammation and restoring fatty acid oxidation","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Lazzari, T.K., Cavalheiro, E., Coutinho, S.E., da Silva, L.F., and Silva, D.R. (2021). Leptin and advanced glycation end products receptor (RAGE) in tuberculosis patients. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0254198"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1007\/s11010-020-04022-z","article-title":"Contribution of RAGE axis activation to the association between metabolic syndrome and cancer","volume":"476","author":"Rojas","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_34","first-page":"254","article-title":"Effect of vitamin D on the HMGB1\/RAGE pathway and adipokines levels in obese asthmatic mice","volume":"22","author":"Fan","year":"2023","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/1475-2840-13-78","article-title":"Advanced glycation endproducts trigger autophagy in cadiomyocyte via RAGE\/PI3K\/AKT\/mTOR pathway","volume":"13","author":"Hou","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.2147\/OTT.S240378","article-title":"Downregulation of RAGE inhibits cell proliferation and induces apoptosis via regulation of PI3K\/AKT pathway in cervical squamous cell carcinoma","volume":"13","author":"Li","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"115757","DOI":"10.1016\/j.taap.2021.115757","article-title":"Arsenic-induced lung inflammation and fibrosis in a rat model: Contribution of the HMGB1\/RAGE, PI3K\/AKT, and TGF-\u03b21\/SMAD pathways","volume":"432","author":"Wang","year":"2021","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3892\/ijmm.2023.5270","article-title":"Inflammation and coagulation abnormalities via the activation of the HMGB1-RAGE\/NF-\u03baB and F2\/Rho pathways in lung injury induced by acute hypoxia","volume":"52","author":"Gao","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"107419","DOI":"10.1016\/j.intimp.2021.107419","article-title":"The receptor for advanced glycation end products mediates dysfunction of airway epithelial barrier in a lipopolysaccharides-induced murine acute lung injury model","volume":"93","author":"Li","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"121713","DOI":"10.1016\/j.lfs.2023.121713","article-title":"RAGE pathways play an important role in regulation of organ fibrosis","volume":"323","author":"Liu","year":"2023","journal-title":"Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Curtis, K.L., Homer, K.M., Wendt, R.A., Stapley, B.M., Clark, E.T., Harward, K., Chang, A., Clarke, D.M., Arroyo, J.A., and Reynolds, P.R. (2023). Inflammatory Cytokine Elaboration Following Secondhand Smoke (SHS) Exposure Is Mediated in Part by RAGE Signaling. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115645"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Hirschi-Budge, K.M., Tsai, K.Y., Curtis, K.L., Davis, G.S., Theurer, B.K., Kruyer, A.M., Homer, K.W., Chang, A., Van Ry, P.M., and Arroyo, J.A. (2022). RAGE signaling during tobacco smoke-induced lung inflammation and potential therapeutic utility of SAGEs. BMC Pulm. Med., 22.","DOI":"10.1186\/s12890-022-01935-x"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/nmeth.1226","article-title":"Mapping and quantifying mammalian transcriptomes by RNA-Seq","volume":"5","author":"Mortazavi","year":"2008","journal-title":"Nat. Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D988","DOI":"10.1093\/nar\/gkab1049","article-title":"Ensembl 2022","volume":"50","author":"Cunningham","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_45","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_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"D687","DOI":"10.1093\/nar\/gkab1028","article-title":"The reactome pathway knowledgebase 2022","volume":"50","author":"Gillespie","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_49","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_50","first-page":"100141","article-title":"clusterProfiler 4.0: A universal enrichment tool for interpreting omics data","volume":"2","author":"Wu","year":"2021","journal-title":"Innovation"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Young, M.D., Wakefield, M.J., Smyth, G.K., and Oshlack, A. (2010). Gene ontology analysis for RNA-seq: Accounting for selection bias. Genome Biol., 11.","DOI":"10.1186\/gb-2010-11-2-r14"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4940\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:37:51Z","timestamp":1760107071000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/9\/4940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,30]]},"references-count":51,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25094940"],"URL":"https:\/\/doi.org\/10.3390\/ijms25094940","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,30]]}}}