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

• Published in: PloS one Vol. 8; no. 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: Journal Article
• Language: English
• Published: United States Public Library of Science 21.10.2013; Public Library of Science (PLoS)
• 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; Indiana; United States > US; Indianapolis Indiana
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076451

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.