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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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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cited_by cdi_FETCH-LOGICAL-c526t-af6bc97374b2fa2155705ecd1174a988e0f4f83df8fb2b252f645030ff4dec03
cites cdi_FETCH-LOGICAL-c526t-af6bc97374b2fa2155705ecd1174a988e0f4f83df8fb2b252f645030ff4dec03
container_end_page
container_issue 10
container_start_page e76451
container_title PloS one
container_volume 8
creator 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
description 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.
doi_str_mv 10.1371/journal.pone.0076451
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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). 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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.</description><subject>Animal models</subject><subject>Animal tissues</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Autoantibodies - blood</subject><subject>Autoantibodies - immunology</subject><subject>Binding sites</subject><subject>Bleomycin</subject><subject>Bleomycin - adverse effects</subject><subject>Collagen</subject><subject>Collagen (type V)</subject><subject>Collagen Type I - immunology</subject><subject>Collagen Type V - administration &amp; dosage</subject><subject>Collagen Type V - genetics</subject><subject>Collagen Type V - immunology</subject><subject>Collagen Type V - metabolism</subject><subject>Consent</subject><subject>Cytokines - biosynthesis</subject><subject>Cytokines - genetics</subject><subject>Deposition</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Extracellular matrix</subject><subject>Female</subject><subject>Fibrosis</subject><subject>Gene Expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Idiopathic Pulmonary Fibrosis - drug therapy</subject><subject>Idiopathic Pulmonary Fibrosis - genetics</subject><subject>Idiopathic Pulmonary Fibrosis - immunology</subject><subject>Idiopathic Pulmonary Fibrosis - metabolism</subject><subject>Idiopathic Pulmonary Fibrosis - pathology</subject><subject>Immune Tolerance</subject><subject>Immunity</subject><subject>Immunological tolerance</subject><subject>Inflammation Mediators - metabolism</subject><subject>Interferon</subject><subject>Interleukin 6</subject><subject>Liquid oxygen</subject><subject>Lung diseases</subject><subject>Lungs</subject><subject>Lymphocyte Activation - immunology</subject><subject>Lymphocytes</subject><subject>Medicine</subject><subject>Mice</subject><subject>Nebulizers and Vaporizers</subject><subject>NF-κB protein</subject><subject>Pathogenesis</subject><subject>Pathology</subject><subject>Patients</subject><subject>Pulmonary fibrosis</subject><subject>Pulmonary Fibrosis - 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blood</topic><topic>Autoantibodies - immunology</topic><topic>Binding sites</topic><topic>Bleomycin</topic><topic>Bleomycin - adverse effects</topic><topic>Collagen</topic><topic>Collagen (type V)</topic><topic>Collagen Type I - immunology</topic><topic>Collagen Type V - administration &amp; dosage</topic><topic>Collagen Type V - genetics</topic><topic>Collagen Type V - immunology</topic><topic>Collagen Type V - metabolism</topic><topic>Consent</topic><topic>Cytokines - biosynthesis</topic><topic>Cytokines - genetics</topic><topic>Deposition</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Extracellular matrix</topic><topic>Female</topic><topic>Fibrosis</topic><topic>Gene Expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Idiopathic Pulmonary Fibrosis - drug therapy</topic><topic>Idiopathic Pulmonary Fibrosis - genetics</topic><topic>Idiopathic Pulmonary Fibrosis - immunology</topic><topic>Idiopathic Pulmonary Fibrosis - metabolism</topic><topic>Idiopathic Pulmonary Fibrosis - pathology</topic><topic>Immune Tolerance</topic><topic>Immunity</topic><topic>Immunological tolerance</topic><topic>Inflammation Mediators - metabolism</topic><topic>Interferon</topic><topic>Interleukin 6</topic><topic>Liquid oxygen</topic><topic>Lung diseases</topic><topic>Lungs</topic><topic>Lymphocyte Activation - immunology</topic><topic>Lymphocytes</topic><topic>Medicine</topic><topic>Mice</topic><topic>Nebulizers and Vaporizers</topic><topic>NF-κB protein</topic><topic>Pathogenesis</topic><topic>Pathology</topic><topic>Patients</topic><topic>Pulmonary fibrosis</topic><topic>Pulmonary Fibrosis - drug therapy</topic><topic>Pulmonary Fibrosis - genetics</topic><topic>Pulmonary Fibrosis - immunology</topic><topic>Pulmonary Fibrosis - metabolism</topic><topic>Pulmonary Fibrosis - pathology</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Rodents</topic><topic>Scars</topic><topic>Signaling</topic><topic>Smad2 protein</topic><topic>Sp1 protein</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - metabolism</topic><topic>Transcription</topic><topic>Transcription, Genetic - drug effects</topic><topic>Transforming Growth Factor beta - biosynthesis</topic><topic>Transforming Growth Factor beta - genetics</topic><topic>Tumor necrosis factor-α</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vittal, Ragini</creatorcontrib><creatorcontrib>Mickler, Elizabeth A</creatorcontrib><creatorcontrib>Fisher, Amanda J</creatorcontrib><creatorcontrib>Zhang, Chen</creatorcontrib><creatorcontrib>Rothhaar, Katia</creatorcontrib><creatorcontrib>Gu, Hongmei</creatorcontrib><creatorcontrib>Brown, Krista M</creatorcontrib><creatorcontrib>Emtiazjoo, Amir</creatorcontrib><creatorcontrib>Lott, Jeremy M</creatorcontrib><creatorcontrib>Frye, Sarah B</creatorcontrib><creatorcontrib>Smith, Gerald N</creatorcontrib><creatorcontrib>Sandusky, George E</creatorcontrib><creatorcontrib>Cummings, Oscar W</creatorcontrib><creatorcontrib>Wilkes, David S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing &amp; Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological &amp; Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science &amp; Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>Advanced Technologies &amp; Aerospace Collection</collection><collection>Agricultural &amp; Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>Advanced Technologies &amp; Aerospace Database</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vittal, Ragini</au><au>Mickler, Elizabeth A</au><au>Fisher, Amanda J</au><au>Zhang, Chen</au><au>Rothhaar, Katia</au><au>Gu, Hongmei</au><au>Brown, Krista M</au><au>Emtiazjoo, Amir</au><au>Lott, Jeremy M</au><au>Frye, Sarah B</au><au>Smith, Gerald N</au><au>Sandusky, George E</au><au>Cummings, Oscar W</au><au>Wilkes, David S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Type V collagen induced tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-10-21</date><risdate>2013</risdate><volume>8</volume><issue>10</issue><spage>e76451</spage><pages>e76451-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><notes>Competing Interests: David S. Wilkes is a co-founder of ImmuneWorks, Inc., a biotechnology company involved in developing therapeutics for various forms of lung diseases. Katia Rothhaar is the Director of Research Operations while Sarah Frye is a Research Technician working at ImmuneWorks, Inc. All other authors declare no competing interests. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.</notes><notes>Conceived and designed the experiments: RV DSW. Analyzed the data: RV KR DSW. Wrote the paper: RV DSW. Pepsin digestion of clinical tissues, hydroxyproline analyses: EAM. Bleomycin instillations: AF. Real-time PCR on patient and animal tissues: CZ HG. Col(V) antibody analyses on patient and murine plasma: KR KMB SF. Patient demographic analyses: AE. Cytokine bead assay: JML. Received IPF tissues from LTRC: RV. Provided consultation on col(V) pepsin digestion: GNS. Board-certified pathologists: OWC GES. Patient demographic analyses: AE. Cytokine bead assay: JML.</notes><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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24204629</pmid><doi>10.1371/journal.pone.0076451</doi><oa>free_for_read</oa></addata></record>
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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
title Type V collagen induced tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis
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