Sarah Knippenberg1, Bianca Ueberberg1, Regina Maus1, Jennifer Bohling1, Nadine Ding1, Meritxell Tort Tarres1, Heinz-Gerd Hoymann2, Danny Jonigk3, Nicole Izykowski3, James C Paton4, Abiodun D Ogunniyi4, Sandro Lindig5, Michael Bauer5, Tobias Welte6, Werner Seeger7, Andreas Guenther7, Thomas H Sisson8, Jack Gauldie9, Martin Kolb9, Ulrich A Maus10. 1. Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany. 2. Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany. 3. Institute of Pathology, Hannover Medical School, Hannover, Germany. 4. Research Centre for Infectious Diseases, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia. 5. Center for Sepsis Control and Care, University Hospital Jena, Friedrich Schiller University, Jena, Germany. 6. Clinic for Pneumology, Hannover Medical School, Hannover, Germany German Centre for Lung Research, partner site BREATH and UGMLC. 7. 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. 8. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Hospital, Michigan, USA. 9. Department of Medicine, Pathology, and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. 10. Department of Experimental Pneumology, Hannover Medical School, Hannover, Germany German Centre for Lung Research, partner site BREATH and UGMLC.
Abstract
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-β1 (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 (SpnΔply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFβ1-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 AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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-β1 (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 (SpnΔply) failed to trigger progressive fibrogenesis, whereas purified recombinant Ply did. Progressive fibrogenesis was also observed in AdTGFβ1-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 AdTGFβ1-exposed mice. Importantly, vaccination of mice with the non-cytotoxic Ply derivative B (PdB) substantially attenuated Ply-induced progression of lung fibrosis in AdTGFβ1-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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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