TY - JOUR
T1 - Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis
AU - Pilecki, Bartosz
AU - Wulf-Johansson, Helle
AU - Støttrup, Christian
AU - Jørgensen, Patricia Troest
AU - Djiadeu, Pascal
AU - Nexøe, Anders Bathum
AU - Schlosser, Anders
AU - Hansen, Søren Werner Karlskov
AU - Madsen, Jens
AU - Clark, Howard William
AU - Nielsen, Claus Henrik
AU - Vestbo, Jørgen
AU - Palaniyar, Nades
AU - Holmskov, Uffe
AU - Sorensen, Grith Lykke
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - A549 Cells
KW - Aged
KW - Animals
KW - Bronchoalveolar Lavage Fluid/cytology
KW - Ceramides/immunology
KW - Female
KW - Humans
KW - Lung/immunology
KW - Macrophages/immunology
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Middle Aged
KW - Pulmonary Disease, Chronic Obstructive/etiology
KW - Pulmonary Surfactant-Associated Protein D/deficiency
KW - Smoke/adverse effects
KW - Smoking/adverse effects
KW - Tobacco/adverse effects
KW - Up-Regulation
U2 - 10.3389/fimmu.2018.03013
DO - 10.3389/fimmu.2018.03013
M3 - Article
C2 - 30619359
SN - 1664-3224
VL - 9
SP - 3013
JO - Frontiers in Immunology
JF - Frontiers in Immunology
ER -