{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:22:16Z","timestamp":1790266936980,"version":"4.1.0"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator\u2013activated receptor \u03b3 (PPAR\u03b3). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPAR\u03b3-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPAR\u03b3-KO mice receiving MWCNT\u2009+\u2009ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPAR\u03b3-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c+ infiltrating alveolar macrophages in the presence of MWCNT\u2009+\u2009ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-\u03b2 and the TGF-\u03b2 pathway mediator IL-13 in PPAR\u03b3-KO mice that received MWCNT\u2009+\u2009ESAT-6 compared with wild-type or PPAR\u03b3-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-\u03b2 production, was elevated in PPAR\u03b3-KO mice by MWCNT\u2009+\u2009ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPAR\u03b3-KO but not wild-type mice. These data indicate that PPAR\u03b3 deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT\u2009+\u2009ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis.<\/jats:p>","DOI":"10.1165\/rcmb.2018-0346oc","type":"journal-article","created":{"date-parts":[[2019,2,11]],"date-time":"2019-02-11T11:44:50Z","timestamp":1549885490000},"page":"198-208","source":"Crossref","is-referenced-by-count":24,"title":["Peroxisome Proliferator\u2013Activated Receptor-\u03b3 Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model"],"prefix":"10.1093","volume":"61","author":[{"given":"Anagha","family":"Malur","sequence":"first","affiliation":[{"name":"Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjun","family":"Mohan","sequence":"additional","affiliation":[{"name":"Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5713-5369","authenticated-orcid":false,"given":"Robert A.","family":"Barrington","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of South Alabama, Mobile, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Leffler","sequence":"additional","affiliation":[{"name":"Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrita","family":"Malur","sequence":"additional","affiliation":[{"name":"Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4817-5323","authenticated-orcid":false,"given":"Barbara","family":"Muller-Borer","sequence":"additional","affiliation":[{"name":"Department of Engineering"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gina","family":"Murray","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0400-0433","authenticated-orcid":false,"given":"Kim","family":"Kew","sequence":"additional","affiliation":[{"name":"Department of Chemistry, East Carolina University, Greenville, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9353-7231","authenticated-orcid":false,"given":"Chuanzhen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Analytical Instrumentation Facility and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josh","family":"Russell","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob L.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, North Carolina State University, Raleigh, North Carolina; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8251-5678","authenticated-orcid":false,"given":"Christopher J.","family":"Wingard","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy, School of Movement and Rehabilitation Sciences, College of Health Professions, Bellarmine University, Louisville, Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara P.","family":"Barna","sequence":"additional","affiliation":[{"name":"Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1229-7668","authenticated-orcid":false,"given":"Mary Jane","family":"Thomassen","sequence":"additional","affiliation":[{"name":"Program in Lung Cell Biology and Translational Research, Division of Pulmonary, Critical Care and Sleep Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,8,1]]},"reference":[{"key":"2026021100395941800_bib1","article-title":"Nanomaterial exposure, toxicity, and impact on human health","author":"Pietroiusti","journal-title":"Wiley Interdiscip Rev Nanomed Nanobiotechnol"},{"key":"2026021100395941800_bib2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1080\/10408440600570233","article-title":"A review of carbon nanotube toxicity and assessment of potential occupational and environmental health risks","volume":"36","author":"Lam","year":"2006","journal-title":"Crit Rev Toxicol"},{"key":"2026021100395941800_bib3","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1289\/ehp.0901159","article-title":"Case report: lung disease in World Trade Center responders exposed to dust and smoke. Carbon nanotubes found in the lungs of World Trade Center patients and dust samples","volume":"118","author":"Wu","year":"2010","journal-title":"Environ Health Perspect"},{"key":"2026021100395941800_bib4","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1016\/j.ebiom.2015.10.012","article-title":"Anthropogenic carbon nanotubes found in the airways of Parisian children","volume":"2","author":"Kolosnjaj-Tabi","year":"2015","journal-title":"EBioMedicine"},{"key":"2026021100395941800_bib5","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1743-8977-9-10","article-title":"Factoring-in agglomeration of carbon nanotubes and nanofibers for better prediction of their toxicity versus asbestos","volume":"9","author":"Murray","year":"2012","journal-title":"Part Fibre Toxicol"},{"key":"2026021100395941800_bib6","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/1743-8977-10-57","article-title":"Effect of MWCNT size, carboxylation, and purification on in vitro and in vivo toxicity, inflammation and lung pathology","volume":"10","author":"Hamilton","year":"2013","journal-title":"Part Fibre Toxicol"},{"key":"2026021100395941800_bib7","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1164\/rccm.200402-249OC","article-title":"A case control etiologic study of sarcoidosis: environmental and occupational risk factors","volume":"170","author":"Newman","year":"2004","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021100395941800_bib8","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1378\/chest.116.5.1183","article-title":"The incidence, prevalence, and severity of sarcoidosis in New York City firefighters","volume":"116","author":"Prezant","year":"1999","journal-title":"Chest"},{"key":"2026021100395941800_bib9","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1002\/ajim.20924","article-title":"\u201cSarcoid like\u201d granulomatous pulmonary disease in World Trade Center disaster responders","volume":"54","author":"Crowley","year":"2011","journal-title":"Am J Ind Med"},{"key":"2026021100395941800_bib10","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1165\/rcmb.2010-0401OC","article-title":"Novel murine model of chronic granulomatous lung inflammation elicited by carbon nanotubes","volume":"45","author":"Huizar","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021100395941800_bib11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1165\/rcmb.2003-0304RC","article-title":"Peroxisome proliferator\u2013activated receptor gamma activity is deficient in alveolar macrophages in pulmonary sarcoidosis","volume":"30","author":"Culver","year":"2004","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021100395941800_bib12","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1165\/rcmb.2015-0332OC","article-title":"Elevated microRNA-33 in sarcoidosis and a carbon nanotube model of chronic granulomatous disease","volume":"54","author":"Barna","year":"2016","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021100395941800_bib13","doi-asserted-by":"crossref","first-page":"L617","DOI":"10.1152\/ajplung.00289.2017","article-title":"Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis","volume":"314","author":"Mohan","year":"2018","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021100395941800_bib14","doi-asserted-by":"crossref","first-page":"3740","DOI":"10.1128\/IAI.00142-09","article-title":"Cellular responses to mycobacterial antigens are present in bronchoalveolar lavage fluid used in the diagnosis of sarcoidosis","volume":"77","author":"Oswald-Richter","year":"2009","journal-title":"Infect Immun"},{"key":"2026021100395941800_bib15","doi-asserted-by":"crossref","first-page":"340","DOI":"10.4172\/2157-7439.1000340","article-title":"Exposure to a mycobacterial antigen, ESAT-6, exacerbates granulomatous and fibrotic changes in a multiwall carbon nanotube model of chronic pulmonary disease","volume":"6","author":"Malur","year":"2015","journal-title":"J Nanomed Nanotechnol"},{"key":"2026021100395941800_bib16","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1128\/IAI.00732-06","article-title":"Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis","volume":"75","author":"Drake","year":"2007","journal-title":"Infect Immun"},{"key":"2026021100395941800_bib17","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1465-9921-14-7","article-title":"The role of PPAR\u03b3 in carbon nanotube-elicited granulomatous lung inflammation","volume":"14","author":"Huizar","year":"2013","journal-title":"Respir Res"},{"key":"2026021100395941800_bib18","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.4049\/jimmunol.0803504","article-title":"Deletion of PPAR \u03b3 in alveolar macrophages is associated with a Th-1 pulmonary inflammatory response","volume":"182","author":"Malur","year":"2009","journal-title":"J Immunol"},{"key":"2026021100395941800_bib19","doi-asserted-by":"crossref","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":"2026021100395941800_bib20","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1165\/rcmb.2016-0121TR","article-title":"Immune mechanisms in pulmonary fibrosis","volume":"55","author":"Kolahian","year":"2016","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021100395941800_bib21","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1165\/rcmb.2013-0086MA","article-title":"Flow cytometric analysis of macrophages and dendritic cell subsets in the mouse lung","volume":"49","author":"Misharin","year":"2013","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021100395941800_bib22","first-page":"425","article-title":"Comparison between cardiopulmonary exercise testing parameters and computed tomography findings in patients with thoracic sarcoidosis","volume":"189","author":"Lopes","year":"2011","journal-title":"Hai"},{"key":"2026021100395941800_bib23","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1164\/ajrccm.160.2.ats4-99","article-title":"Statement on sarcoidosis: joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999","volume":"160","author":"American Thoracic Society","year":"1999","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021100395941800_bib24","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1016\/j.trsl.2012.03.005","article-title":"The clinical and immunologic features of pulmonary fibrosis in sarcoidosis","volume":"160","author":"Patterson","year":"2012","journal-title":"Transl Res"},{"key":"2026021100395941800_bib25","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1513\/pats.201203-023AW","article-title":"The impact of TGF-\u03b2 on lung fibrosis: from targeting to biomarkers","volume":"9","author":"Fernandez","year":"2012","journal-title":"Proc Am Thorac Soc"},{"key":"2026021100395941800_bib26","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.bbadis.2013.03.001","article-title":"Fibrosis of two: epithelial cell-fibroblast interactions in pulmonary fibrosis","volume":"1832","author":"Sakai","year":"2013","journal-title":"Biochim Biophys Acta"},{"key":"2026021100395941800_bib27","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1084\/jem.194.6.809","article-title":"Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor \u03b21","volume":"194","author":"Lee","year":"2001","journal-title":"J Exp Med"},{"key":"2026021100395941800_bib28","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1136\/thorax.58.6.519","article-title":"Increased interleukin-13 expression in patients with sarcoidosis","volume":"58","author":"Hauber","year":"2003","journal-title":"Thorax"},{"key":"2026021100395941800_bib29","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1165\/ajrcmb.18.1.2627","article-title":"Production of interleukin 13 by alveolar macrophages from normal and fibrotic lung","volume":"18","author":"Hancock","year":"1998","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026021100395941800_bib30","first-page":"18","article-title":"Osteopontin enhances multi-walled carbon nanotube-triggered lung fibrosis by promoting TGF-\u03b21 activation and myofibroblast differentiation","volume-title":"Part Fibre Toxicol","author":"Dong","year":"2017"},{"key":"2026021100395941800_bib31","doi-asserted-by":"crossref","first-page":"L341","DOI":"10.1152\/ajplung.00122.2010","article-title":"New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2\/CCR2 axis","volume":"300","author":"Sun","year":"2011","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021100395941800_bib32","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1159\/000430268","article-title":"Platelet-derived growth factor and transforming growth factor \u03b21 regulate ARDS-associated lung fibrosis through distinct signaling pathways","volume":"36","author":"Deng","year":"2015","journal-title":"Cell Physiol Biochem"},{"key":"2026021100395941800_bib33","doi-asserted-by":"crossref","first-page":"2614","DOI":"10.4049\/jimmunol.1200495","article-title":"Systemic analysis of PPAR\u03b3 in mouse macrophage populations reveals marked diversity in expression with critical roles in resolution of inflammation and airway immunity","volume":"189","author":"Gautier","year":"2012","journal-title":"J Immunol"},{"key":"2026021100395941800_bib34","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1631\/jzus.B1100218","article-title":"Expression and preliminary functional analysis of Siglec-F on mouse macrophages","volume":"13","author":"Feng","year":"2012","journal-title":"J Zhejiang Univ Sci B"},{"key":"2026021100395941800_bib35","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nri3737","article-title":"Siglec-mediated regulation of immune cell function in disease","volume":"14","author":"Macauley","year":"2014","journal-title":"Nat Rev Immunol"},{"key":"2026021100395941800_bib36","first-page":"549691","article-title":"PPAR\u03b3 and the innate immune system mediate the resolution of inflammation","volume-title":"PPAR Res","author":"Croasdell","year":"2015"},{"key":"2026021100395941800_bib37","doi-asserted-by":"crossref","first-page":"426","DOI":"10.4049\/jimmunol.0902564","article-title":"Diesel exhaust particles stimulate adaptive immunity by acting on pulmonary dendritic cells","volume":"184","author":"Provoost","year":"2010","journal-title":"J Immunol"},{"key":"2026021100395941800_bib38","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1165\/rcmb.2015-0084OC","article-title":"Urban particulate matter-activated human dendritic cells induce the expansion of potent inflammatory Th1, Th2, and Th17 effector cells","volume":"54","author":"Matthews","year":"2016","journal-title":"Am J Respir Cell Mol Biol"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/61\/2\/198\/66762642\/ajrcmb_61_2_198.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/61\/2\/198\/66762642\/ajrcmb_61_2_198.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T05:40:11Z","timestamp":1770788411000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/61\/2\/198\/8461440"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,1]]},"references-count":38,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,8,1]]},"published-print":{"date-parts":[[2019,8,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2018-0346oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,8]]},"published":{"date-parts":[[2019,8,1]]}}}