{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T13:53:36Z","timestamp":1762869216460,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T00:00:00Z","timestamp":1699315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82273669","82241086","tsqn202211121","2022KJ295"],"award-info":[{"award-number":["82273669","82241086","tsqn202211121","2022KJ295"]}]},{"name":"Taishan Scholars Program of Shandong Province","award":["82273669","82241086","tsqn202211121","2022KJ295"],"award-info":[{"award-number":["82273669","82241086","tsqn202211121","2022KJ295"]}]},{"name":"the Youth Innovation Technology Project of Higher School in Shandong Province","award":["82273669","82241086","tsqn202211121","2022KJ295"],"award-info":[{"award-number":["82273669","82241086","tsqn202211121","2022KJ295"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Guanidine disinfectants are important chemical agents with a broad spectrum of activity that are effective against most microorganisms. Chlorhexidine, one of the most used guanidine disinfectants, is added to shampoo and mouthwash and applied in medical device sterilization. During the use of chlorhexidine, aerosols with micron particle size may be formed, which may cause inhalation toxicity. To assess the toxicity of inhaled chlorhexidine aerosol, mice underwent the intratracheal instillation of different concentrations of chlorhexidine (0, 0.125%, 0.25%, 0.5%, and 1%) using a MicroSprayer Aerosolizer. The mice were exposed for eight weeks and then sacrificed to obtain lung tissue for subsequent experiments. Histopathology staining revealed damaged lung tissues and increased collagen exudation. At the same time, pulmonary function tests showed that chlorhexidine exposure could cause restrictive ventilatory dysfunction, consistent with pulmonary fibrosis. The results of transcriptome analyses suggest that chlorhexidine may trigger an inflammatory response and promote the activation of pathways related to extracellular matrix deposition. Further, we identified that chlorhexidine exposure might enhance mucus secretion by up-regulating Muc5b and Muc5ac genes, thereby inducing fibrosis-like injury. These findings underscore the need for standardized use of disinfectants and the assessment of their inhalation toxicity.<\/jats:p>","DOI":"10.3390\/toxics11110910","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T11:25:31Z","timestamp":1699356331000},"page":"910","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pulmonary Toxicity Assessment after a Single Intratracheal Inhalation of Chlorhexidine Aerosol in Mice"],"prefix":"10.3390","volume":"11","author":[{"given":"Jianzhong","family":"Zhang","sequence":"first","affiliation":[{"name":"Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China"},{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinmin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China"},{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"He","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanjun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haonan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Affiliated Hospital of Medical College of Qingdao University, Qingdao 266021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Affiliated Hospital of Medical College of Qingdao University, Qingdao 266021, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China"},{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lin","family":"Lu","sequence":"additional","affiliation":[{"name":"Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China"},{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9981-7966","authenticated-orcid":false,"given":"Jinglong","family":"Tang","sequence":"additional","affiliation":[{"name":"Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan 250001, China"},{"name":"Department of Environmental and Occupational Health, School of Public Health, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1080\/08958378.2019.1624896","article-title":"Guanidine-based disinfectants, polyhexamethylene guanidine-phosphate (PHMG-P), polyhexamethylene biguanide (PHMB), and oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH) induced epithelial-mesenchymal transition in A549 alveolar epithelial cells","volume":"31","author":"Park","year":"2019","journal-title":"Inhal. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1099\/jmm.0.047514-0","article-title":"Akwaton, polyhexamethylene-guanidine hydrochloride-based sporicidal disinfectant: A novel tool to fight bacterial spores and nosocomial infections","volume":"61","author":"Quinn","year":"2012","journal-title":"J. Med. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e257","DOI":"10.3346\/jkms.2022.37.e257","article-title":"Health Effects Associated With Humidifier Disinfectant Use: A Systematic Review for Exploration","volume":"37","author":"Song","year":"2022","journal-title":"J. Korean Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.fct.2014.04.027","article-title":"Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy","volume":"69","author":"Song","year":"2014","journal-title":"Food Chem. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Jeong, M.H., Jeon, M.S., Kim, G.E., and Kim, H.R. (2021). Polyhexamethylene Guanidine Phosphate Induces Apoptosis through Endoplasmic Reticulum Stress in Lung Epithelial Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22031215"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1016\/j.cmi.2018.09.012","article-title":"Daily bathing with 4% chlorhexidine gluconate in intensive care settings: A randomized controlled trial","volume":"25","author":"Pallotto","year":"2019","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1007\/s00134-018-5156-2","article-title":"Oropharyngeal and nasopharyngeal decontamination with chlorhexidine gluconate in lung cancer surgery: A randomized clinical trial","volume":"44","author":"Falcoz","year":"2018","journal-title":"Intensive Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chamsai, B., Soodvilai, S., Opanasopit, P., and Samprasit, W. (2022). Topical Film-Forming Chlorhexidine Gluconate Sprays for Antiseptic Application. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14061124"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"114609","DOI":"10.1016\/j.taap.2019.114609","article-title":"Inhalation toxicity of benzalkonium chloride and triethylene glycol mixture in rats","volume":"378","author":"Kwon","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Takanabe, Y., Maruoka, Y., Kondo, J., Yagi, S., Chikazu, D., Okamoto, R., and Saitoh, M. (2021). Dispersion of Aerosols Generated during Dental Therapy. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph182111279"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1177\/089686088500500204","article-title":"Sclerosing Peritonitis -The Contribution of Chlorhexidine in Alcohol","volume":"5","author":"Junor","year":"1985","journal-title":"Perit. Dial. Int."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Brezovec, N., Kojc, N., Erman, A., Hladnik, M., Stergar, J., Milani\u010d, M., Tom\u0161i\u010d, M., \u010cu\u010dnik, S., Sodin-\u0160emrl, S., and Per\u0161e, M. (2022). Molecular and Cellular Markers in Chlorhexidine-Induced Peritoneal Fibrosis in Mice. Biomedicines, 10.","DOI":"10.3390\/biomedicines10112726"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/ki.2011.305","article-title":"Pleiotrophin triggers inflammation and increased peritoneal permeability leading to peritoneal fibrosis","volume":"81","author":"Yokoi","year":"2012","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1177\/0960327111400104","article-title":"Acute pulmonary toxic effects of chlorhexidine (CHX) following an intratracheal instillation in rats","volume":"30","author":"Xue","year":"2011","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/01480540500408416","article-title":"Effects of single intratracheal exposure to chlorhexidine gluconate on the rat lung","volume":"29","author":"Orito","year":"2006","journal-title":"Drug Chem. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1213\/01.ANE.0000086896.90343.13","article-title":"ONO-1714, a nitric oxide synthase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits","volume":"97","author":"Mikawa","year":"2003","journal-title":"Anesth. Analg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1165\/rcmb.2008-0487OC","article-title":"Noninvasive and invasive pulmonary function in mouse models of obstructive and restrictive respiratory diseases","volume":"42","author":"Vanoirbeek","year":"2010","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6363","DOI":"10.1167\/iovs.13-11990","article-title":"Antimicrobial action of biguanides on the viability of Acanthamoeba cysts and assessment of cell toxicity","volume":"54","author":"Mafra","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s00590-021-02907-3","article-title":"Cytotoxic effect of sodium hypochlorite (Lavanox 0.08%) and chlorhexidine gluconate (Irrisept 0.05%) on human osteoblasts","volume":"32","author":"Zippelius","year":"2022","journal-title":"Eur. J. Orthop. Surg. Traumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3912","DOI":"10.1007\/s00167-020-05887-9","article-title":"Sodium hypochlorite is more effective than chlorhexidine for eradication of bacterial biofilm of staphylococci and Pseudomonas aeruginosa","volume":"28","author":"Jacob","year":"2020","journal-title":"Knee Surg. Sports Traumatol. Arthrosc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.3109\/00016357.2012.757646","article-title":"Assessment of cytogenetic and cytotoxic effects of chlorhexidine digluconate on cultured human lymphocytes","volume":"71","author":"Arabaci","year":"2013","journal-title":"Acta Odontol. Scand."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1002\/tox.21771","article-title":"Cytotoxicity and genotoxicity of chlorhexidine on macrophages in vitro","volume":"29","author":"Li","year":"2014","journal-title":"Environ. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1002\/jat.1662","article-title":"Comparative study on toxic effects induced by oral or intravascular administration of commonly used disinfectants and surfactants in rats","volume":"32","author":"Xue","year":"2012","journal-title":"J. Appl. Toxicol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"126642","DOI":"10.1016\/j.jhazmat.2021.126642","article-title":"Polyhexamethylene guanidine aerosol triggers pulmonary fibrosis concomitant with elevated surface tension via inhibiting pulmonary surfactant","volume":"420","author":"Li","year":"2021","journal-title":"J. Hazard. Mater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1080\/08958378.2020.1836091","article-title":"TGF\u03b2\/Smad mediated the polyhexamethyleneguanide areosol-induced irreversible pulmonary fibrosis in subchronic inhalation exposure","volume":"32","author":"Zhu","year":"2020","journal-title":"Inhal. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1165\/ajrcmb.24.3.4293","article-title":"Role of osteopontin in the pathogenesis of bleomycin-induced pulmonary fibrosis","volume":"24","author":"Takahashi","year":"2001","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1177\/096032719401301005","article-title":"Poisoning due to Savlon (cetrimide) liquid","volume":"13","author":"Chan","year":"1994","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1081\/CLT-100102884","article-title":"Intravenous chlorhexidine gluconate causing acute respiratory distress syndrome","volume":"39","author":"Ishigami","year":"2001","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s12931-015-0202-x","article-title":"Enhanced endogenous bone morphogenetic protein signaling protects against bleomycin induced pulmonary fibrosis","volume":"16","author":"Cailotto","year":"2015","journal-title":"Respir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1378\/chest.11-2879","article-title":"Effects of lecithinized superoxide dismutase and\/or pirfenidone against bleomycin-induced pulmonary fibrosis","volume":"142","author":"Tanaka","year":"2012","journal-title":"Chest"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1152\/physiol.00033.2018","article-title":"Mechanisms for the Resolution of Organ Fibrosis","volume":"34","author":"Horowitz","year":"2019","journal-title":"Physiology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e20190103","DOI":"10.1084\/jem.20190103","article-title":"Transforming growth factor-\u03b2 in tissue fibrosis","volume":"217","author":"Frangogiannis","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mam.2018.06.003","article-title":"Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications","volume":"65","author":"Weiskirchen","year":"2019","journal-title":"Mol. Aspects Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1002\/path.4530","article-title":"A novel profibrotic mechanism mediated by TGF\u03b2-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells","volume":"236","author":"Luo","year":"2015","journal-title":"J. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1136\/thoraxjnl-2012-202943","article-title":"Expression of cilium-associated genes defines novel molecular subtypes of idiopathic pulmonary fibrosis","volume":"68","author":"Yang","year":"2013","journal-title":"Thorax"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"L675","DOI":"10.1152\/ajplung.00258.2020","article-title":"The evolving role of the lung microbiome in pulmonary fibrosis","volume":"319","author":"Lipinski","year":"2020","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Peng, Y., Wang, Z.N., Xu, A.R., Fang, Z.F., Chen, S.Y., Hou, X.T., Zhou, Z.Q., Lin, H.M., Xie, J.X., and Tang, X.X. (2021). Mucus Hypersecretion and Ciliary Impairment in Conducting Airway Contribute to Alveolar Mucus Plugging in Idiopathic Pulmonary Fibrosis. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.810842"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1136\/thoraxjnl-2013-204179","article-title":"What is top of the charts? BPIFB1\/LPLUNC1 localises to the bronchiolised epithelium in the honeycomb cysts in UIP","volume":"68","author":"Bingle","year":"2013","journal-title":"Thorax"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Boon, K., Bailey, N.W., Yang, J., Steel, M.P., Groshong, S., Kervitsky, D., Brown, K.K., Schwarz, M.I., and Schwartz, D.A. (2009). Molecular phenotypes distinguish patients with relatively stable from progressive idiopathic pulmonary fibrosis (IPF). PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0005134"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12931-023-02400-x","article-title":"Morphologically intact airways in lung fibrosis have an abnormal proteome","volume":"24","author":"Herrera","year":"2023","journal-title":"Respir. Res."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/11\/11\/910\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:18:36Z","timestamp":1760131116000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/11\/11\/910"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,7]]},"references-count":40,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["toxics11110910"],"URL":"https:\/\/doi.org\/10.3390\/toxics11110910","relation":{},"ISSN":["2305-6304"],"issn-type":[{"type":"electronic","value":"2305-6304"}],"subject":[],"published":{"date-parts":[[2023,11,7]]}}}