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Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis

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  • Bartosz Pilecki
  • Helle Wulf-Johansson
  • Christian Støttrup
  • Patricia Troest Jørgensen
  • Pascal Djiadeu
  • Anders Bathum Nexøe
  • Anders Schlosser
  • Søren Werner Karlskov Hansen
  • Jens Madsen
  • Howard William Clark
  • Claus Henrik Nielsen
  • Jørgen Vestbo
  • Nades Palaniyar
  • Uffe Holmskov
  • Grith Lykke Sorensen
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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 defense 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.

OriginalsprogEngelsk
Artikelnummer3013
TidsskriftFrontiers in Immunology
Vol/bind9
Sider (fra-til)1-12
ISSN1664-3224
DOI
StatusUdgivet - 2018

ID: 56379658