Type V collagen induced tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determi...

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Bibliographic Details
Published in:PloS one 2013-10, Vol.8 (10), p.e76451
Main Authors: Vittal, Ragini, Mickler, Elizabeth A, Fisher, Amanda J, Zhang, Chen, Rothhaar, Katia, Gu, Hongmei, Brown, Krista M, Emtiazjoo, Amir, Lott, Jeremy M, Frye, Sarah B, Smith, Gerald N, Sandusky, George E, Cummings, Oscar W, Wilkes, David S
Format: Article
Language:English
Subjects:
Animal models
Animal tissues
Animals
Antibodies
Autoantibodies - blood
Autoantibodies - immunology
Binding sites
Bleomycin
Bleomycin - adverse effects
Collagen
Collagen (type V)
Collagen Type I - immunology
Collagen Type V - administration & dosage
Collagen Type V - genetics
Collagen Type V - immunology
Collagen Type V - metabolism
Consent
Cytokines - biosynthesis
Cytokines - genetics
Deposition
Disease
Disease Models, Animal
Extracellular matrix
Female
Fibrosis
Gene Expression
Gene Expression Regulation - drug effects
Growth factors
Humans
Idiopathic Pulmonary Fibrosis - drug therapy
Idiopathic Pulmonary Fibrosis - genetics
Idiopathic Pulmonary Fibrosis - immunology
Idiopathic Pulmonary Fibrosis - metabolism
Idiopathic Pulmonary Fibrosis - pathology
Immune Tolerance
Immunity
Immunological tolerance
Inflammation Mediators - metabolism
Interferon
Interleukin 6
Liquid oxygen
Lung diseases
Lungs
Lymphocyte Activation - immunology
Lymphocytes
Medicine
Mice
Nebulizers and Vaporizers
NF-κB protein
Pathogenesis
Pathology
Patients
Pulmonary fibrosis
Pulmonary Fibrosis - drug therapy
Pulmonary Fibrosis - genetics
Pulmonary Fibrosis - immunology
Pulmonary Fibrosis - metabolism
Pulmonary Fibrosis - pathology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Rodents
Scars
Signaling
Smad2 protein
Sp1 protein
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
Transcription
Transcription, Genetic - drug effects
Transforming Growth Factor beta - biosynthesis
Transforming Growth Factor beta - genetics
Tumor necrosis factor-α
γ-Interferon
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Summary:Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models. Col(V) and col(I) expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. Compared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V) and col(I). Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients. Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V)-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V) decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-β, Il-1β, Pdgfb), matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3) and members of the TGF-β superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb). Anti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- β-related signaling pathways.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0076451