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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook 2016     Display Documents

ID: 723977.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook 2016
Streptococcus pneumoniae triggers progression of pulmonary fibrosis through pneumolysin
Authors:Knippenberg, S.; Ueberberg, B.; Maus, R.; Bohling, J.; Ding, N.; Tort Tarres, M.; Hoymann, H. G.; Jonigk, D.; Izykowski, N.; Paton, J. C.; Ogunniyi, A. D.; Lindig, S.; Bauer, M.; Welte, T.; Seeger, W.; Guenther, A.; Sisson, T. H.; Gauldie, J.; Kolb, M.; Maus, U. A.
Date of Publication (YYYY-MM-DD):2015-07
Title of Journal:Thorax
Issue / Number:7
Start Page:636
End Page:646
Audience:Not Specified
Abstract / Description:RATIONALE: Respiratory tract infections are common in patients suffering from pulmonary fibrosis. The interplay between bacterial infection and fibrosis is characterised poorly. OBJECTIVES: To assess the effect of Gram-positive bacterial infection on fibrosis exacerbation in mice. METHODS: Fibrosis progression in response to Streptococcus pneumoniae was examined in two different mouse models of pulmonary fibrosis. MEASUREMENTS AND MAIN RESULTS: We demonstrate that wild-type mice exposed to adenoviral vector delivery of active transforming growth factor-beta1 (TGFss1) or diphteria toxin (DT) treatment of transgenic mice expressing the DT receptor (DTR) under control of the surfactant protein C (SPC) promoter (SPC-DTR) to induce pulmonary fibrosis developed progressive fibrosis following infection with Spn, without exhibiting impaired lung protective immunity against Spn. Antibiotic treatment abolished infection-induced fibrosis progression. The cytotoxin pneumolysin (Ply) of Spn caused this phenomenon in a TLR4-independent manner, as Spn lacking Ply (SpnDeltaply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFbeta1-exposed Ply-challenged TLR4 KO mice. Increased apoptotic cell death of alveolar epithelial cells along with an attenuated intrapulmonary release of antifibrogenic prostaglandin E2 was found to underlie progressive fibrogenesis in Ply-challenged AdTGFbeta1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFbeta1-exposed mice. CONCLUSIONS: Our data unravel a novel mechanism by which infection with Spn through Ply release induces progression of established lung fibrosis, which can be attenuated by protein-based vaccination of mice.
Free Keywords:Animals; Anti-Bacterial Agents/therapeutic use; Apoptosis/drug effects; Bacterial Proteins/pharmacology/physiology; Bronchoalveolar Lavage Fluid/immunology; Diphtheria Toxin; Disease Models, Animal; Disease Progression; Epithelial Cells/drug effects; Female; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pneumococcal Vaccines; Pneumonia, Pneumococcal/*complications/drug therapy/immunology/metabolism; Pulmonary Alveoli/drug effects/pathology; Pulmonary Fibrosis/immunology/metabolism/*microbiology/prevention & control; Streptolysins/deficiency/pharmacology/*physiology; Transforming Growth Factor beta1/metabolism; Bacterial Infection; Idiopathic pulmonary fibrosis; Respiratory Infection
External Publication Status:published
Document Type:Article
Communicated by:n.n.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. Institute of Pathology, Hannover Medical School, Hannover, Germany. Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia. Center for Sepsis Control and Care, University Hospital Jena, Friedrich Schiller University, Jena, Germany. Clinic for Pneumology, Hannover Medical School, Hannover, Germany German Centre for Lung Research, partner site BREATH and UGMLC. German Centre for Lung Research, partner site BREATH and UGMLC Faculty of Medicine, Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Giessen, Germany. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Hospital, Michigan, USA. Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany German Centre for Lung Research, partner site BREATH and UGMLC.
Identifiers:ISSN:1468-3296 (Electronic) 0040-6376 (Linking) %R 10.1136/thoraxjnl-2014-206420
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