title: Type V collagen induced tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis.
abstract: 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.
authors.affiliation: Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Ragini
authors.initials: R
authors.lastname: Vittal
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mickler
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fisher
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.forename: Katia
authors.initials: K
authors.lastname: Rothhaar
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gu
authors.forename: Krista M
authors.initials: KM
authors.lastname: Brown
authors.forename: Amir
authors.initials: A
authors.lastname: Emtiazjoo
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Lott
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Frye
authors.forename: Gerald N
authors.initials: GN
authors.lastname: Smith
authors.forename: George E
authors.initials: GE
authors.lastname: Sandusky
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001761:Bleomycin / Q000009:adverse effects; D024042:Collagen Type I / Q000276:immunology; D024062:Collagen Type V / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009330:Nebulizers and Vaporizers; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D001323:Autoantibodies; D024042:Collagen Type I; D024062:Collagen Type V; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001761:Bleomycin