{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T22:52:26Z","timestamp":1773355946770,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T00:00:00Z","timestamp":1623024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010225","name":"National Outstanding Youth Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Gasdermin D (GSDMD), controlling pyroptosis in cells, has multiple physiological functions. The diagnostic role of GSDMD in pleural effusion (PE) remains unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Sandwich ELISA kits that we developed were applied to measure the level of GSDMD for 335 patients with a definite cause of PE, including transudative PE, tuberculous pleural effusion (TPE), parapneumonic pleural effusion (PPE), and malignant pleural effusion (MPE). The diagnostic accuracy of Light\u2019s criteria vs. the new marker GSDMD was performed. Clinical follow-up of 40 cases of PPE was conducted and divided into efficacy and non-efficacy groups according to the therapeutic outcome. Nucleated cells (NCs) in PE were isolated and further infected with bacteria to verify the cell source of GSDMD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The diagnostic accuracy of GSDMD for the diagnosis of PE were 96% (sensitivity) and 94% (specificity). The receiver operating characteristic (ROC) curve indicated that GSDMD can be an efficient biomarker for the differential diagnosis of transudative PE and other groups (all AUC &amp;gt; 0.973). Noteworthily, the highest AUC belonged to tuberculosis diagnosis of 0.990, and the cut-off value was 18.40 ng\/mL. Moreover, the same cut-off value of PPE and MPE was 9.35 ng\/mL. The combination of GSDMD, adenosine deaminase (ADA), and lactate dehydrogenase (LDH) will further improve the diagnostic efficiency especially between TPE and PPE (AUC = 0.968). The AUC of GSDMD change at day 4, which could predict the therapeutic effect at an early stage, was 0.945 (<jats:italic>P<\/jats:italic> &amp;lt; 0.0001). Interestingly, bacterial infection experiments further confirm that the pleural fluid GSDMD was expressed and secreted mainly by the NCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>GSDMD and its combination are candidates as a potentially novel biomarker not only to separate PEs early and effectively, but also monitor disease progression.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmicb.2021.620322","type":"journal-article","created":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T04:23:37Z","timestamp":1623039817000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Pleural Fluid GSDMD Is a Novel Biomarker for the Early Differential Diagnosis of Pleural Effusion"],"prefix":"10.3389","volume":"12","author":[{"given":"Pu","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijing","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li Jun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuan","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dandan","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuemei","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weixian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,7]]},"reference":[{"key":"B1","first-page":"780","article-title":"The application value of the procalcitonin clearance rate on therapeutic effect and prognosis of ventilator associated pneumonia.","volume":"26","author":"Abula","year":"2014","journal-title":"Zhonghua Wei Zhong Bing Ji Jiu Yi Xue"},{"key":"B2","first-page":"844","article-title":"Guidance for clinical trials of anti-bacterial drugs.","volume":"30","year":"2014","journal-title":"Chin. J. Clin. Phanrmacol."},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16143-6","article-title":"Plasma membrane damage causes NLRP3 activation and pyroptosis during Mycobacterium tuberculosis infection.","volume":"11","author":"Beckwith","year":"2020","journal-title":"Nat. Commun."},{"key":"B4","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1038\/nri.2016.58","article-title":"Inflammasomes: mechanism of assembly, regulation and signaling.","volume":"16","author":"Broz","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1604","DOI":"10.1378\/chest.107.6.1604","article-title":"Comparative analysis of the biochemical parameters used to distinguish between pleural transudates and exudates.","volume":"107","author":"Burgess","year":"1995","journal-title":"Chest"},{"key":"B6","doi-asserted-by":"publisher","first-page":"4124","DOI":"10.1172\/JCI94495","article-title":"Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury.","volume":"127","author":"Cheng","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B7","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.5588\/ijtld.17.0232","article-title":"CXCR3 ligands in pleural fluid as markers for the diagnosis of tuberculous pleural effusion.","volume":"21","author":"Chung","year":"2017","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1152\/physrev.00037.2014","article-title":"Membrane repair: mechanisms and pathophysiology.","volume":"95","author":"Cooper","year":"2015","journal-title":"Physiol. Rev."},{"key":"B9","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/S1473-3099(16)00053-0","article-title":"Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomized, controlled, open-label trial.","volume":"16","author":"de Jong","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1914","DOI":"10.1038\/cdd.2014.117","article-title":"Liver X receptor activation induces pyroptosis of human and murine colon cancer cells.","volume":"21","author":"Derang\u00e8re","year":"2014","journal-title":"Cell Death Differ."},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nature20106","article-title":"Erratum: Pore-forming activity and structural autoinhibition of the gasdermin family.","volume":"540","author":"Ding","year":"2016","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.immuni.2017.11.013","article-title":"The pore-forming protein gasdermin d regulates interleukin-1 secretion from living macrophages.","volume":"48","author":"Evavold","year":"2018","journal-title":"Immunity"},{"key":"B13","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1056\/NEJMc1803858","article-title":"Pleural disease.","volume":"378","author":"Feller-Kopman","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.tube.2015.05.017","article-title":"Tuberculosis: a disease without boundaries.","volume":"95","author":"Fogel","year":"2015","journal-title":"Tuberculosis (Edinb)"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.3892\/or.2018.6634","article-title":"Downregulation of GSDMD attenuates tumor proliferation via the intrinsic mitochondrial apoptotic pathway and inhibition of EGFR\/Akt signaling and predicts a good prognosis in non-small cell lung cancer.","volume":"40","author":"Gao","year":"2018","journal-title":"Oncol. Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.cellimm.2018.10.009","article-title":"Regulation of host cell pyroptosis and cytokines production by Mycobacterium tuberculosis effector PPE60 requires LUBAC mediated NF-\u03baB signaling.","volume":"335","author":"Gong","year":"2019","journal-title":"Cell. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.3727\/096504016X14813859905646","article-title":"miRNA-214 inhibits cellular proliferation and migration in glioma cells targeting Caspase-1 involved in pyroptosis.","volume":"25","author":"Jiang","year":"2017","journal-title":"Oncol. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1007\/s10875-010-9440-3","article-title":"Molecular mechanism of NLRP3 inflammasome activation.","volume":"30","author":"Jin","year":"2010","journal-title":"J. Clin. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1111\/imr.12287","article-title":"Pyroptotic cell death defends against intracellular pathogens.","volume":"265","author":"Jorgensen","year":"2015","journal-title":"Immunol. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e61","DOI":"10.1093\/cid\/ciw353","article-title":"Management of adults with hospital-acquired and Ventilator-associated Pneumonia: 2016 clinical practice guidelines by the infectious diseases Society of America and the American Thoracic Society.","volume":"63","author":"Kalil","year":"2016","journal-title":"Clin. Infect, Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1016\/j.tcb.2017.05.005","article-title":"Gasdermins: effectors of pyroptosis.","volume":"27","author":"Kovacs","year":"2017","journal-title":"Trends Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s15010-016-0928-5","article-title":"Pleural fluid adenosine deaminase\/serum C-reactive protein ratio for the differentiation of tuberculous and parapneumonic effusions with neutrophilic predominance and high adenosine deaminase levels.","volume":"45","author":"Lee","year":"2017","journal-title":"Infection"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1111\/cmi.12480","article-title":"The innate immune response in human tuberculosis.","volume":"17","author":"Lerner","year":"2015","journal-title":"Cell. Microbiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1016\/j.rmed.2007.12.007","article-title":"Diagnostic accuracy of adenosine deaminase in tuberculous pleurisy: a meta-analysis.","volume":"102","author":"Liang","year":"2008","journal-title":"Respir. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1111\/j.1440-1843.2010.01723.x","article-title":"Update on tuberculous pleural effusion.","volume":"15","author":"Light","year":"2010","journal-title":"Respirology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"507","DOI":"10.7326\/0003-4819-77-4-507","article-title":"Pleural effusions: the diagnostic separation of transudates and exudates.","volume":"77","author":"Light","year":"1972","journal-title":"Ann. Intern. Med."},{"key":"B27","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.pedneo.2017.12.008","article-title":"Serum lactate dehydrogenase isoenzymes 4 plus 5 is a better biomarker than total lactate dehydrogenase for refractory Mycoplasma pneumoniae pneumonia in children.","volume":"59","author":"Liu","year":"2018","journal-title":"Pediatr. Neonatol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1038\/nature18629","article-title":"Inflammasome activated gasdermin D causes pyroptosis by forming membrane pores.","volume":"535","author":"Liu","year":"2016","journal-title":"Nature"},{"key":"B29","first-page":"87","article-title":"Research progress on absent in melanoma 2 in defendant pathogenic microorganism invasion.","volume":"9","author":"Ma","year":"2016","journal-title":"Chin. J. Clin. Infect. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1111\/imr.12534","article-title":"Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases.","volume":"277","author":"Man","year":"2017","journal-title":"Immunol Rev"},{"key":"B31","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1038\/ni.1960","article-title":"Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria.","volume":"11","author":"Miao","year":"2010","journal-title":"Nat. Immunol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-66873\/v1","article-title":"Pleural fluid GSDMD is a novel biomarker for the early differential diagnosis of pleural effusion.","author":"Pu","year":"2020","journal-title":"Res. Square [Preprint]"},{"key":"B33","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/mi.2016.73","article-title":"Neutrophil pyroptosis mediates pathology of P. aeruginosa lung infection in the absence of the NADPH oxidase NOX2.","volume":"10","author":"Ryu","year":"2017","journal-title":"Mucosal. Immunol."},{"key":"B34","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.tibs.2016.10.004","article-title":"Pyroptosis: gasdermin-mediated programmed necrotic cell death.","volume":"42","author":"Shi","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"B35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2217\/bmm-2018-0200","article-title":"Potential biomarkers for antidiastole of tuberculous and malignant pleural effusion by proteome analysis.","volume":"13","author":"Shi","year":"2019","journal-title":"Biomark Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/nature15514","article-title":"Cleavage of GSDMD by inflammatory caspases determines pyrotposis cell death.","volume":"526","author":"Shi","year":"2015","journal-title":"Nature"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-018-3654-z","article-title":"Pleural IFN-\u03b3 release assay combined with biomarkers distinguished effectively tuberculosis from malignant pleural effusion.","volume":"19","author":"Tang","year":"2019","journal-title":"BMC Infect. Dis."},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.1126\/science.aaf2154","article-title":"Programmed necrosis in inflammation: toward identification of the effector molecules.","volume":"352","author":"Wallach","year":"2016","journal-title":"Science"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-017-0526-z","article-title":"The pleural fluid lactate dehydrogenase\/adenosine deaminase ratio differentiates between tuberculous and parapneumonic pleural effusions.","volume":"17","author":"Wang","year":"2017","journal-title":"BMC Pulm Med."},{"key":"B40","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1136\/thoraxjnl-2016-209718","article-title":"Diagnostic accuracy of interleukin 27 for tuberculous pleural effusion: two prospective studies and one meta-analysis.","volume":"73","author":"Wang","year":"2018","journal-title":"Thorax"},{"key":"B41","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nature22393","article-title":"Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin.","volume":"547","author":"Wang","year":"","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1038\/nature22393","article-title":"Chemotherapy drugs induce pyroptosis through Caspase-3 cleavage of a Gasdermin.","volume":"547","author":"Wang","year":"","journal-title":"Nature"},{"key":"B43","first-page":"2350","article-title":"Serum NOX2 as a new biomarker candidate for HBV-related disorders.","volume":"10","author":"Xiong","year":"2018","journal-title":"Am. J. Transl. Res."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0040450","article-title":"Cell origins and diagnostic accuracy of interleukin 27 in pleural effusions.","volume":"7","author":"Yang","year":"2012","journal-title":"PLoS One"},{"key":"B45","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.immuni.2019.11.005","article-title":"Bacterial endotoxin activates the coagulation cascade through gasdermin D-dependent Phosphatidylserine Exposure.","volume":"51","author":"Yang","year":"2019","journal-title":"Immunity"},{"key":"B46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-3-030-38315-2_1","article-title":"IL-1 signaling in tumor microenvironment.","volume":"1240","author":"Zhang","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"B47","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s12088-013-0436-6","article-title":"The Pseudomonas aeruginosa mannose sensitive hamemagglutination strain (PA-MSHA) induces a Th1-polarizing phenotype by promoting human dendritic cells maturation.","volume":"54","author":"Zhang","year":"2014","journal-title":"Indian J. Microbiol."}],"container-title":["Frontiers in Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.620322\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,7]],"date-time":"2021-06-07T04:23:52Z","timestamp":1623039832000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmicb.2021.620322\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,7]]},"references-count":47,"alternative-id":["10.3389\/fmicb.2021.620322"],"URL":"https:\/\/doi.org\/10.3389\/fmicb.2021.620322","relation":{},"ISSN":["1664-302X"],"issn-type":[{"value":"1664-302X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,7]]},"article-number":"620322"}}