title: Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β.
abstract: BACKGROUND
  Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease.
  
  
  METHODS
  C57BL/6 wild-type (WT) and SP-D-/- mice (C57BL/6 background) were chronically challenged with house dust mite antigen (Dermatophagoides pteronyssinus, Dp). Studies with SP-D rescue and neutralization of TGF-β were conducted. Lung histopathology and the concentrations of collagen, growth factors, and cytokines present in the airspace and lung tissue were determined. Cultured eosinophils were stimulated by Dp in presence or absence of SP-D.
  
  
  RESULTS
  Dp-challenged SP-D-/- mice demonstrate increased sub-epithelial fibrosis, collagen production, eosinophil infiltration, TGF-β1, and IL-13 production, when compared to Dp-challenged WT mice. By immunohistology, we detected an increase in TGF-β1 and IL-13 positive eosinophils in SP-D-/- mice. Purified eosinophils stimulated with Dp produced TGF-β1 and IL-13, which was prevented by co-incubation with SP-D. Additionally, treatment of Dp challenged SP-D-/- mice with exogenous SP-D was able to rescue the phenotypes observed in SP-D-/- mice and neutralization of TGF-β1 reduced sub-epithelial fibrosis in Dp-challenged SP-D-/- mice.
  
  
  CONCLUSIONS
  These data support a protective role for SP-D in the pathogenesis of sub-epithelial fibrosis in a mouse model of allergic inflammation through regulation of eosinophil-derived TGF-β.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA. hogawa@basic.med.tokushima-u.ac.jp.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. hogawa@basic.med.tokushima-u.ac.jp.|Department of Molecular and Environmental Pathology, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan. hogawa@basic.med.tokushima-u.ac.jp.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA. julie.ledford@duke.edu.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. julie.ledford@duke.edu.
authors.forename: Julie G
authors.initials: JG
authors.lastname: Ledford
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA. sambuddho@gmail.com.|Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. sambuddho@gmail.com.
authors.forename: Sambuddho
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan. yoshi_aoao1014@hotmail.co.jp.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aono
authors.affiliation: Department of Respiratory Medicine and Rheumatology, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan. yasuhiko@tokushima-u.ac.jp.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Nishioka
authors.affiliation: Department of Biochemistry and Molecular Biology, Division of Pulmonary Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA. jjlee@mayo.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Molecular and Environmental Pathology, Institute of Health Bioscience, University of Tokushima Graduate School, Tokushima, Japan. izumi-k@tokushima-u.ac.jp.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA. john.hollingsworth@osumc.edu.|Department of Medicine, Wexner Medical Center at Ohio State University, Columbus, Ohio, USA. john.hollingsworth@osumc.edu.|Davis Heart & Lung Research Institute at Ohio State University, 473 West 12th Avenue, Columbus, OH, USA. john.hollingsworth@osumc.edu.
authors.forename: John W
authors.initials: JW
authors.lastname: Hollingsworth
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D001249:Asthma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005838:Genotype; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011657:Pulmonary Eosinophilia / Q000276:immunology / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D039741:Antigens, Dermatophagoides; D060829:Arthropod Proteins; D018793:Interleukin-13; D037663:Pulmonary Surfactant-Associated Protein D; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D003094:Collagen