{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T20:56:09Z","timestamp":1765486569386,"version":"3.37.3"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T00:00:00Z","timestamp":1613952000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL-125602"],"award-info":[{"award-number":["HL-125602"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ES006694"],"award-info":[{"award-number":["ES006694"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI-135935"],"award-info":[{"award-number":["AI-135935"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\"><jats:title>Background<\/jats:title><jats:p>Increased exposure to Ozone (O<jats:sub>3<\/jats:sub>) is associated with adverse health effects in individuals afflicted with respiratory diseases. Surfactant protein-A (SP-A), encoded by<jats:italic>SP-A1<\/jats:italic>and<jats:italic>SP-A2<\/jats:italic>, is the largest protein component in pulmonary surfactant and is functionally impaired by O<jats:sub>3<\/jats:sub>-oxidation.<\/jats:p><\/jats:sec><jats:sec id=\"sec002\"><jats:title>Objective<\/jats:title><jats:p>We used humanized SP-A2 transgenic mice with allelic variation corresponding to a glutamine (Q) to lysine (K) amino acid substitution at position 223 in the lectin domain to determine the impact of this genetic variation in regards to O<jats:sub>3<\/jats:sub>exposure.<\/jats:p><\/jats:sec><jats:sec id=\"sec003\"><jats:title>Methods<\/jats:title><jats:p>Mice were exposed to 2ppm O<jats:sub>3<\/jats:sub>or Filtered Air (FA) for 3 hours and 24 hrs post-challenge pulmonary function tests and other parameters associated with inflammation were assessed in the bronchoalveolar lavage (BAL) fluid and lung tissue. Additionally, mouse tracheal epithelial cells were cultured and TEER measurements recorded for each genotype to determine baseline epithelial integrity.<\/jats:p><\/jats:sec><jats:sec id=\"sec004\"><jats:title>Results<\/jats:title><jats:p>Compared to FA, O<jats:sub>3<\/jats:sub>exposure led to significantly increased sensitivity to methacholine challenge in all groups of mice. SP-A2 223Q variant mice were significantly protected from O<jats:sub>3<\/jats:sub>-induced AHR compared to SP-A<jats:sup>-\/-<\/jats:sup>and SP-A2 223K mice. Neutrophilia was observed in all genotypes of mice post O<jats:sub>3<\/jats:sub>-exposure, however, SP-A2 223Q mice had a significantly lower percentage of neutrophils compared to SP-A<jats:sup>-\/-<\/jats:sup>mice. Albumin levels in BAL were unchanged in O<jats:sub>3<\/jats:sub>-exposed SP-A2 223Q mice compared to their FA controls, while levels were significantly increased in all other genotypes of O<jats:sub>3<\/jats:sub>-exposed mice. SP-A 223Q MTECS has significant higher TEER values than all other genotypes, and WT MTECS has significantly higher TEER than the SP-A KO and SP-A 223K MTECS.<\/jats:p><\/jats:sec><jats:sec id=\"sec005\"><jats:title>Significance<\/jats:title><jats:p>Taken together, our study suggests that expression of a glutamine (Q) as position 223 in SP-A2, as opposed to expression of lysine (K), is more protective in acute exposures to ozone and results in attenuated O<jats:sub>3<\/jats:sub>-induced AHR, neutrophilia, and vascular permeability.<\/jats:p><\/jats:sec>","DOI":"10.1371\/journal.pone.0247504","type":"journal-article","created":{"date-parts":[[2021,2,22]],"date-time":"2021-02-22T18:25:20Z","timestamp":1614018320000},"page":"e0247504","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic variation in surfactant protein-A2 alters responses to ozone"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9253-1279","authenticated-orcid":true,"given":"William P.","family":"Pederson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaime M.","family":"Cyphert-Daly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3465-9861","authenticated-orcid":true,"given":"Robert M.","family":"Tighe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loretta G.","family":"Que","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julie G.","family":"Ledford","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,2,22]]},"reference":[{"issue":"4","key":"pone.0247504.ref001","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1183\/09031936.00081910","article-title":"The continuing challenge of air pollution","volume":"36","author":"B Brunekreef","year":"2010","journal-title":"Eur Respir J"},{"issue":"1","key":"pone.0247504.ref002","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nri1528","article-title":"Immunoregulatory functions of surfactant proteins","volume":"5","author":"JR Wright","year":"2005","journal-title":"Nat Rev Immunol"},{"issue":"4","key":"pone.0247504.ref003","article-title":"The Emerging Roles of Surfactant Protein-A in Asthma","volume":"9","author":"ABC Dy","year":"2018","journal-title":"J Clin Cell Immunol"},{"issue":"14","key":"pone.0247504.ref004","doi-asserted-by":"crossref","first-page":"4227","DOI":"10.1021\/bi036023i","article-title":"Differences in biochemical properties and in biological function between human SP-A1 and SP-A2 variants, and the impact of ozone-induced oxidation","volume":"43","author":"G Wang","year":"2004","journal-title":"Biochemistry"},{"issue":"Suppl 1","key":"pone.0247504.ref005","doi-asserted-by":"crossref","first-page":"S101","DOI":"10.1513\/AnnalsATS.201508-520MG","article-title":"Genetic Variation in Surfactant Protein-A2 Results in Altered Regulation of Eosinophil Activities and Enhanced Eosinophilia in Patients with Asthma","volume":"13","author":"JG Ledford","year":"2016","journal-title":"Ann Am Thorac Soc"},{"volume-title":"565 for Biotechnology Information NLoM","author":"Center N","key":"pone.0247504.ref006"},{"issue":"12","key":"pone.0247504.ref007","doi-asserted-by":"crossref","first-page":"6123","DOI":"10.4049\/jimmunol.1500104","article-title":"Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses","volume":"194","author":"JG Ledford","year":"2015","journal-title":"J Immunol"},{"issue":"2","key":"pone.0247504.ref008","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/toxsci\/kfz056","article-title":"Sex Modifies Acute Ozone-Mediated Airway Physiologic Responses","volume":"169","author":"A Birukova","year":"2019","journal-title":"Toxicol Sci"},{"issue":"9","key":"pone.0247504.ref009","doi-asserted-by":"crossref","first-page":"4800","DOI":"10.4049\/jimmunol.1101312","article-title":"Ozone inhalation promotes CX3CR1-dependent maturation of resident lung macrophages that limit oxidative stress and inflammation","volume":"187","author":"RM Tighe","year":"2011","journal-title":"J Immunol"},{"issue":"1","key":"pone.0247504.ref010","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/0041-008X(88)90256-6","article-title":"Comparative study of ozone (O3) uptake in three strains of rats and in the guinea pig","volume":"96","author":"MJ Wiester","year":"1988","journal-title":"Toxicol Appl Pharmacol"},{"key":"pone.0247504.ref011","unstructured":"Eight-Hour Average Ozone Concentrations2015. www3.epa.gov\/region1\/airquality\/avg8hr.html."},{"issue":"3","key":"pone.0247504.ref012","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1164\/ajrccm.150.3.8087337","article-title":"Ozone dose and effect in humans and rats. A comparison using oxygen-18 labeling and bronchoalveolar lavage","volume":"150","author":"GE Hatch","year":"1994","journal-title":"Am J Respir Crit Care Med"},{"issue":"1","key":"pone.0247504.ref013","article-title":"A Novel in vivo System to Test Bronchodilators","volume":"3","author":"KJ Addison","year":"2017","journal-title":"J Infect Pulm Dis"},{"key":"pone.0247504.ref014","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/1465-9921-11-82","article-title":"Combined forced oscillation and forced expiration measurements in mice for the assessment of airway hyperresponsiveness","volume":"11","author":"KH Shalaby","year":"2010","journal-title":"Respir Res"},{"issue":"1","key":"pone.0247504.ref015","doi-asserted-by":"crossref","first-page":"10611","DOI":"10.1038\/s41598-018-28261-9","article-title":"Functional and morphological differences of the lung upon acute and chronic ozone exposure in mice","volume":"8","author":"C Michaudel","year":"2018","journal-title":"Sci Rep"},{"key":"pone.0247504.ref016","doi-asserted-by":"crossref","first-page":"1998","DOI":"10.3389\/fimmu.2018.01998","article-title":"The Role of Collectins and Galectins in Lung Innate Immune Defense","volume":"9","author":"C Casals","year":"2018","journal-title":"Front Immunol"},{"issue":"8","key":"pone.0247504.ref017","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1002\/pmic.200400855","article-title":"High resolution mass spectrometric alveolar proteomics: identification of surfactant protein SP-A and SP-D modifications in proteinosis and cystic fibrosis patients","volume":"4","author":"Y Bai","year":"2004","journal-title":"Proteomics"},{"issue":"6","key":"pone.0247504.ref018","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1165\/ajrcmb.25.6.f221","article-title":"Surfactant protein A (SP-A)-mediated bacterial clearance: SP-A and cystic fibrosis","volume":"25","author":"TR Korfhagen","year":"2001","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"4","key":"pone.0247504.ref019","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1177\/000348941312200405","article-title":"Protective effects of exogenous surfactant protein A in allergic rhinitis: a mouse model","volume":"122","author":"J Ren","year":"2013","journal-title":"Ann Otol Rhinol Laryngol"},{"issue":"1","key":"pone.0247504.ref020","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1097\/ACI.0000000000000500","article-title":"The role of surfactant protein-A in sinusitis","volume":"19","author":"EH Chang","year":"2019","journal-title":"Curr Opin Allergy Clin Immunol"},{"issue":"5","key":"pone.0247504.ref021","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/j.ajpath.2013.01.030","article-title":"Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages","volume":"182","author":"A Mitsuhashi","year":"2013","journal-title":"Am J Pathol"},{"issue":"12","key":"pone.0247504.ref022","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1164\/rccm.200907-1002OC","article-title":"The role of surfactant protein A in bleomycin-induced acute lung injury","volume":"181","author":"H Goto","year":"2010","journal-title":"Am J Respir Crit Care Med"},{"issue":"3","key":"pone.0247504.ref023","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.jaci.2017.05.028","article-title":"Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications","volume":"141","author":"N Lugogo","year":"2018","journal-title":"J Allergy Clin Immunol"},{"issue":"4","key":"pone.0247504.ref024","doi-asserted-by":"crossref","first-page":"L598","DOI":"10.1152\/ajplung.00381.2010","article-title":"Surfactant protein A is defective in abrogating inflammation in asthma","volume":"301","author":"Y Wang","year":"2011","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"issue":"12","key":"pone.0247504.ref025","doi-asserted-by":"crossref","first-page":"e0144463","DOI":"10.1371\/journal.pone.0144463","article-title":"Surfactant Protein A in Exhaled Endogenous Particles Is Decreased in Chronic Obstructive Pulmonary Disease (COPD) Patients: A Pilot Study","volume":"10","author":"M Larstad","year":"2015","journal-title":"PLoS One"},{"issue":"1","key":"pone.0247504.ref026","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1378\/chest.09-1029","article-title":"Altered surfactant protein-A expression in type II pneumocytes in COPD","volume":"137","author":"EM Vlachaki","year":"2010","journal-title":"Chest"},{"key":"pone.0247504.ref027","unstructured":"dbSNP Short genetic variations [https:\/\/www.ncbi.nlm.nih.gov\/projects\/SNP\/snp_ref.cgi?rs=rs1965708]."},{"key":"pone.0247504.ref028","unstructured":"Asthma and African Americans. U.S. Department of Health and Human Services Office of Minority Health [Website]. [http:\/\/minorityhealth.hhs.gov\/omh\/browse.aspx?lvl=4&lvlid=15]."},{"issue":"5","key":"pone.0247504.ref029","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.4049\/jimmunol.1900546","article-title":"Genetic Variation in Surfactant Protein-A2 Delays Resolution of Eosinophilia in Asthma","volume":"203","author":"ABC Dy","year":"2019","journal-title":"J Immunol"},{"key":"pone.0247504.ref030","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1471-2350-8-15","article-title":"Respiratory symptoms among infants at risk for asthma: association with surfactant protein A haplotypes","volume":"8","author":"MM Pettigrew","year":"2007","journal-title":"BMC Med Genet"},{"issue":"18","key":"pone.0247504.ref031","doi-asserted-by":"crossref","first-page":"2751","DOI":"10.1093\/hmg\/9.18.2751","article-title":"Surfactant proteins A and B as interactive genetic determinants of neonatal respiratory distress syndrome","volume":"9","author":"R Haataja","year":"2000","journal-title":"Hum Mol Genet"},{"issue":"10","key":"pone.0247504.ref032","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1164\/rccm.200304-524OC","article-title":"Surfactant protein A and B genetic variants in respiratory distress syndrome in singletons and twins","volume":"168","author":"R Marttila","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"issue":"5","key":"pone.0247504.ref033","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1080\/07853890310006389","article-title":"Surfactant protein A gene locus and respiratory distress syndrome in Finnish premature twin pairs","volume":"35","author":"R Marttila","year":"2003","journal-title":"Ann Med"},{"issue":"3","key":"pone.0247504.ref034","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1086\/338473","article-title":"Association between surfactant protein A gene locus and severe respiratory syncytial virus infection in infants","volume":"185","author":"J Lofgren","year":"2002","journal-title":"J Infect Dis"},{"issue":"2","key":"pone.0247504.ref035","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1067\/mpd.2001.110133","article-title":"Surfactant protein-A gene locus associated with recurrent otitis media","volume":"138","author":"M Ramet","year":"2001","journal-title":"J Pediatr"},{"key":"pone.0247504.ref036","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1186\/1471-2350-7-68","article-title":"Association of surfactant protein A polymorphisms with otitis media in infants at risk for asthma","volume":"7","author":"MM Pettigrew","year":"2006","journal-title":"BMC Med Genet"},{"issue":"1","key":"pone.0247504.ref037","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.taap.2006.12.017","article-title":"Role of surfactant protein-A (SP-A) in lung injury in response to acute ozone exposure of SP-A deficient mice","volume":"220","author":"R Haque","year":"2007","journal-title":"Toxicol Appl Pharmacol"},{"issue":"2","key":"pone.0247504.ref038","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1093\/toxsci\/kfw226","article-title":"Editor\u2019s Highlight: CCR2 Regulates Inflammatory Cell Accumulation in the Lung and Tissue Injury following Ozone Exposure","volume":"155","author":"M Francis","year":"2017","journal-title":"Toxicol Sci"},{"issue":"2","key":"pone.0247504.ref039","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.yexmp.2012.01.004","article-title":"Ozone-induced lung injury and sterile inflammation. Role of toll-like receptor 4","volume":"92","author":"AJ Connor","year":"2012","journal-title":"Exp Mol Pathol"},{"issue":"3","key":"pone.0247504.ref040","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1152\/japplphysiol.00337.2011","article-title":"Pulmonary function, bronchial reactivity, and epithelial permeability are response phenotypes to ozone and develop differentially in healthy humans","volume":"111","author":"LG Que","year":"2011","journal-title":"J Appl Physiol (1985)"},{"key":"pone.0247504.ref041","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.3389\/fimmu.2019.02169","article-title":"Acute Respiratory Barrier Disruption by Ozone Exposure in Mice","volume":"10","author":"M Sokolowska","year":"2019","journal-title":"Front Immunol"},{"issue":"2","key":"pone.0247504.ref042","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":"B Srinivasan","year":"2015","journal-title":"J Lab Autom"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247504","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,18]],"date-time":"2022-12-18T14:58:12Z","timestamp":1671375492000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0247504"}},"subtitle":[],"editor":[{"given":"Shama","family":"Ahmad","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,2,22]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0247504","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2021,2,22]]}}}