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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.03013

Surfactant protein D deficiency aggravates cigarette smoke-induced lung inflammation

 Bartosz Pilecki1*, Helle Wulf-Johansson1, Christian Støttrup1, Patricia T. Jørgensen1, Pascal Djiadeu2, Anders B. Nexøe1,  Anders Schlosser1,  Soren W. Hansen1, Jens Madsen3, 4, 5, Howard W. Clark3, 4, 5, Claus H. Nielsen6,  Jørgen Vestbo7, 8,  Nades Palaniyar2, 9,  Uffe Holmskov1 and  Grith L. Sorensen1*
  • 1Institute of Molecular Medicine, University of Southern Denmark, Denmark
  • 2Program in Translational Medicine, Lung Innate Immunity Research Laboratory, Hospital for Sick Children, Canada
  • 3Department of Child Health, Sir Henry Wellcome Laboratories, Academic Unit for Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, United Kingdom
  • 4Institute for Life Sciences, University of Southampton, United Kingdom
  • 5National Institute for Health Research, Southampton Respiratory Biomedical Research Unit, Southampton, Centre for Biomedical Research, University Hospital Southampton NHS Foundation Trust, United Kingdom
  • 6Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Denmark
  • 7Department of Respiratory Medicine, Odense University Hospital, Denmark
  • 8Division of Infection, Immunity and Respiratory Medicine, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust (MFT), United Kingdom
  • 9Department of Laboratory Medicine and Pathobiology, and Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Canada

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defence in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation.
Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated.
Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro.
Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation.

Keywords: surfactant protein D (SP-D), Cigarette smoke (CS), mouse models, ceramide, Ceramide synthase

Received: 05 Sep 2018; Accepted: 05 Dec 2018.

Edited by:

Christoph Thiemermann, Queen Mary University of London, United Kingdom

Reviewed by:

Marco A. Martins, Fundação Oswaldo Cruz (Fiocruz), Brazil
Clair Hartmann, Klinik für Anästhesiologie, Universitätsklinikum Ulm, Germany  

Copyright: © 2018 Pilecki, Wulf-Johansson, Støttrup, Jørgensen, Djiadeu, Nexøe, Schlosser, Hansen, Madsen, Clark, Nielsen, Vestbo, Palaniyar, Holmskov and Sorensen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Bartosz Pilecki, University of Southern Denmark, Institute of Molecular Medicine, Odense, Denmark,
Prof. Grith L. Sorensen, University of Southern Denmark, Institute of Molecular Medicine, Odense, Denmark,