{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:30:19Z","timestamp":1787661019140,"version":"build-2736575974"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2012,2,1]],"date-time":"2012-02-01T00:00:00Z","timestamp":1328054400000},"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":[[2012,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Although empyema affects more than 65,000 people each year in the United States and in the United Kingdom, there are limited data on the pathogenesis of pleural infection. We investigated the pathogenesis of empyema using animal and cell culture models of Streptococcus pneumoniae infection. The pathological processes during the development of empyema associated with murine pneumonia due to S. pneumoniae (strain D39) were investigated. Lungs were examined using histology, and pleural fluid and blood bacterial colony-forming units, cytokine levels, and cellular infiltrate were determined over time. Bacterial migration across mesothelial monolayers was investigated using cell culture techniques, flow cytometry, and confocal microscopy. After intranasal inoculation with 107 \u00a0S. pneumoniae D39 strain, mice developed pneumonia associated with rapid bacterial invasion of the pleural space; raised intrapleural IL-8, VEGF, MCP-1, and TNF-\u03b1 levels; and caused significant intrapleural neutrophilia followed by the development of fibrinous pleural adhesions. Bacterial clearance from the pleural space was poor, and in vitro assays demonstrated that S. pneumoniae crossed mesothelial layers by translocation through cells rather than by a paracellular route. This study describes key events during the development of S. pneumoniae empyema using a novel murine model of pneumonia-associated empyema that closely mimics human disease. The model allows for future assessment of molecular mechanisms involved in the development of empyema and evaluation of potential new therapies. The data suggest that transmigration of bacteria through mesothelial cells could be important in empyema development. Furthermore, upon entry the pleural cavity offers a protected compartment for the bacteria.<\/jats:p>","DOI":"10.1165\/rcmb.2011-0182oc","type":"journal-article","created":{"date-parts":[[2011,9,1]],"date-time":"2011-09-01T21:01:45Z","timestamp":1314910905000},"page":"180-187","source":"Crossref","is-referenced-by-count":38,"title":["Characterization of a New Mouse Model of Empyema and the Mechanisms of Pleural Invasion by\n                    <i>Streptococcus pneumoniae<\/i>"],"prefix":"10.1093","volume":"46","author":[{"given":"Sylwia","family":"Wilkosz","sequence":"first","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey A.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Bielsa","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"},{"name":"Institut de Re\u00e7erca Biom\u00e8dica de Lleida, Pleural Diseases Unit, Department of Internal Medicine, Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Hyams","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail","family":"Taylor","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J. O.","family":"Davies","sequence":"additional","affiliation":[{"name":"UK NIHR Oxford Biomedical Research Centre and UKCRC Oxford Respiratory Trials Unit, Oxford, United Kingdom; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey J.","family":"Laurent","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel C.","family":"Chambers","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy S.","family":"Brown","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y. C. Gary","family":"Lee","sequence":"additional","affiliation":[{"name":"Centre for Respiratory Research, University College London, London, United Kingdom"},{"name":"Institut de Re\u00e7erca Biom\u00e8dica de Lleida, Pleural Diseases Unit, Department of Internal Medicine, Lleida, Spain"},{"name":"CAARR, School of Medicine & Pharmacology, University of Western Australia, Perth, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,2,1]]},"reference":[{"issue":"Suppl 2","key":"2026021904133626400_bib1","doi-asserted-by":"crossref","first-page":"ii18","DOI":"10.1136\/thx.58.suppl_2.ii18","article-title":"BTS guidelines for the management of pleural infection","volume":"58","author":"Davies","year":"2003","journal-title":"Thorax"},{"key":"2026021904133626400_bib2","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.jtcvs.2006.09.038","article-title":"Management of pleural space infections: a population-based analysis","volume":"133","author":"Farjah","year":"2007","journal-title":"J Thorac Cardiovasc Surg"},{"key":"2026021904133626400_bib3","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1136\/adc.2007.126540","article-title":"Trends in pneumonia and empyema in Scottish children in the past 25 years","volume":"93","author":"Roxburgh","year":"2008","journal-title":"Arch Dis Child"},{"key":"2026021904133626400_bib4","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1097\/INF.0b013e31817e5188","article-title":"Five-fold increase in pediatric parapneumonic empyema since introduction of pneumococcal conjugate vaccine","volume":"27","author":"Hendrickson","year":"2008","journal-title":"Pediatr Infect Dis J"},{"key":"2026021904133626400_bib5","first-page":"85","article-title":"Empyema: an increasing concern in Canada","volume":"15","author":"Finley","year":"2008","journal-title":"Can Respir J"},{"key":"2026021904133626400_bib6","first-page":"169","article-title":"Animal model in pleural diseases","author":"Stathopoulos"},{"key":"2026021904133626400_bib7","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1378\/chest.129.6.1577","article-title":"Tissue plasminogen activator combined with human recombinant deoxyribonuclease is effective therapy for empyema in a rabbit model","volume":"129","author":"Zhu","year":"2006","journal-title":"Chest"},{"key":"2026021904133626400_bib8","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1164\/rccm.2202043","article-title":"Pleural fluid transforming growth factor-beta1 correlates with pleural fibrosis in experimental empyema","volume":"168","author":"Sasse","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904133626400_bib9","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1378\/chest.111.6.1679","article-title":"The effects of early chest tube placement on empyema resolution","volume":"111","author":"Sasse","year":"1997","journal-title":"Chest"},{"key":"2026021904133626400_bib10","doi-asserted-by":"crossref","first-page":"L119","DOI":"10.1152\/ajplung.2001.281.1.L119","article-title":"Bacterial induction of pleural mesothelial monolayer barrier dysfunction","volume":"281","author":"Mohammed","year":"2001","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026021904133626400_bib11","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1086\/320700","article-title":"Polar production of interleukin-8 by mesothelial cells promotes the transmesothelial migration of neutrophils: role of intercellular adhesion molecule-1","volume":"183","author":"Nasreen","year":"2001","journal-title":"J Infect Dis"},{"key":"2026021904133626400_bib12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1021958529763","article-title":"Pleural mesothelial cells modulate polymorphonuclear leukocyte apoptosis in empyema","volume":"23","author":"Nasreen","year":"2003","journal-title":"J Clin Immunol"},{"key":"2026021904133626400_bib13","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1164\/rccm.200601-074OC","article-title":"The bacteriology of pleural infection by genetic and standard methods and its mortality significance","volume":"174","author":"Maskell","year":"2006","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904133626400_bib14","doi-asserted-by":"crossref","first-page":"16969","DOI":"10.1073\/pnas.012669199","article-title":"The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice","volume":"99","author":"Brown","year":"2002","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021904133626400_bib15","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1371\/journal.ppat.0030120","article-title":"Serum amyloid P aids complement-mediated immunity to Streptococcus pneumoniae","volume":"3","author":"Yuste","year":"2007","journal-title":"PLoS Pathog"},{"key":"2026021904133626400_bib16","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.4049\/jimmunol.175.3.1813","article-title":"Additive inhibition of complement deposition by pneumolysin and PspA facilitates Streptococcus pneumoniae septicemia","volume":"175","author":"Yuste","year":"2005","journal-title":"J Immunol"},{"key":"2026021904133626400_bib17","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1128\/IAI.66.3.912-922.1998","article-title":"Cytokine kinetics and other host factors in response to pneumococcal pulmonary infection in mice","volume":"66","author":"Bergeron","year":"1998","journal-title":"Infect Immun"},{"key":"2026021904133626400_bib18","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1111\/j.1365-2958.2007.06065.x","article-title":"Maturation of Streptococcus pneumoniae lipoproteins by a type II signal peptidase is required for ABC transporter function and full virulence","volume":"67","author":"Khandavilli","year":"2008","journal-title":"Mol Microbiol"},{"key":"2026021904133626400_bib19","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1056\/NEJMoa042473","article-title":"UK controlled trial of intrapleural streptokinase for pleural infection","volume":"352","author":"Maskell","year":"2005","journal-title":"N Engl J Med"},{"key":"2026021904133626400_bib20","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1164\/rccm.200811-1729OC","article-title":"Clinical impact and reliability of pleural fluid mesothelin in undiagnosed pleural effusions","volume":"180","author":"Davies","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"2026021904133626400_bib21","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1172\/JCI2406","article-title":"Pneumococcal trafficking across the blood-brain barrier: molecular analysis of a novel bidirectional pathway","volume":"102","author":"Ring","year":"1998","journal-title":"J Clin Invest"},{"key":"2026021904133626400_bib22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1073\/pnas.93.1.136","article-title":"Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers","volume":"93","author":"Chang","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026021904133626400_bib23","article-title":"Cytological differential diagnosis among adenocarcinoma, epithelial mesothelioma, and reactive mesothelial cells in serous effusions by immunocytochemistry","author":"Su","journal-title":"Diagn Cytopathol"},{"key":"2026021904133626400_bib24","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1128\/IAI.01379-10","article-title":"Natural antibodies against several pneumococcal virulence proteins in children during the pre-pneumococcal-vaccine era: the generation R study","volume":"79","author":"Lebon","year":"2011","journal-title":"Infect Immun"},{"key":"2026021904133626400_bib25","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1136\/thx.2007.094250","article-title":"Role of routine computed tomography in paediatric pleural empyema","volume":"63","author":"Jaffe","year":"2008","journal-title":"Thorax"},{"key":"2026021904133626400_bib26","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1574-6968.2001.tb09454.x","article-title":"Use of green fluorescent protein in visualisation of pneumococcal invasion of broncho-epithelial cells in vivo","volume":"194","author":"Kadioglu","year":"2001","journal-title":"FEMS Microbiol Lett"},{"key":"2026021904133626400_bib27","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/S0092-8674(00)00071-4","article-title":"The polymeric immunoglobulin receptor translocates pneumococci across human nasopharyngeal epithelial cells","volume":"102","author":"Zhang","year":"2000","journal-title":"Cell"},{"key":"2026021904133626400_bib28","doi-asserted-by":"crossref","first-page":"23486","DOI":"10.1074\/jbc.M110.142703","article-title":"Complement regulator Factor H mediates a two-step uptake of Streptococcus pneumoniae by human cells","volume":"285","author":"Agarwal","year":"2010","journal-title":"J Biol Chem"},{"key":"2026021904133626400_bib29","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/377435a0","article-title":"Streptococcus pneumoniae anchor to activated human cells by the receptor for platelet-activating factor","volume":"377","author":"Cundell","year":"1995","journal-title":"Nature"},{"key":"2026021904133626400_bib30","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.amjmed.2006.03.042","article-title":"Thoracic empyema in patients with community-acquired pneumonia","volume":"119","author":"Ahmed","year":"2006","journal-title":"Am J Med"},{"key":"2026021904133626400_bib31","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1111\/j.1469-0691.2008.02028.x","article-title":"Identification of pneumococcal serotypes from culture-negative clinical specimens by novel real-time PCR","volume":"14","author":"Tarrago","year":"2008","journal-title":"Clin Microbiol Infect"},{"key":"2026021904133626400_bib32","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/01.inf.0000219535.14201.1b","article-title":"Childhood empyema: limited potential impact of 7-valent pneumococcal conjugate vaccine","volume":"25","author":"Fletcher","year":"2006","journal-title":"Pediatr Infect Dis J"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/46\/2\/180\/66898646\/ajrcmb_46_2_180.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/46\/2\/180\/66898646\/ajrcmb_46_2_180.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T09:13:49Z","timestamp":1771492429000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/46\/2\/180\/8483612"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,1]]},"references-count":32,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2012,2,1]]},"published-print":{"date-parts":[[2012,2,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2011-0182oc","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.13369983.14740098","asserted-by":"object"}]},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2012,2]]},"published":{"date-parts":[[2012,2,1]]}}}