Document Detail


TLR9 differentiates rapidly from slowly progressing forms of idiopathic pulmonary fibrosis.
MedLine Citation:
PMID:  21068441     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Idiopathic pulmonary fibrosis is characterized by diffuse alveolar damage and severe fibrosis, resulting in a steady worsening of lung function and gas exchange. Because idiopathic pulmonary fibrosis is a generally progressive disorder with highly heterogeneous disease progression, we classified affected patients as either rapid or slow progressors over the first year of follow-up and then identified differences between the two groups to investigate the mechanism governing rapid progression. Previous work from our laboratory has demonstrated that Toll-like receptor 9 (TLR9), a pathogen recognition receptor that recognizes unmethylated CpG motifs in bacterial and viral DNA, promotes myofibroblast differentiation in lung fibroblasts cultured from biopsies of patients with idiopathic pulmonary fibrosis. Therefore, we hypothesized that TLR9 functions as both a sensor of pathogenic molecules and a profibrotic signal in rapidly progressive idiopathic pulmonary fibrosis. Indeed, TLR9 was present at higher concentrations in surgical lung biopsies from rapidly progressive patients than in tissue from slowly progressing patients. Moreover, fibroblasts from rapid progressors were more responsive to the TLR9 agonist, CpG DNA, than were fibroblasts from slowly progressing patients. Using a humanized severe combined immunodeficient mouse, we then demonstrated increased fibrosis in murine lungs receiving human lung fibroblasts from rapid progressors compared with mice receiving fibroblasts from slowly progressing patients. This fibrosis was exacerbated by intranasal CpG challenges. Furthermore, CpG induced the differentiation of blood monocytes into fibrocytes and the epithelial-to-mesenchymal transition of A549 lung epithelial cells. These data suggest that TLR9 may drive the pathogenesis of rapidly progressive idiopathic pulmonary fibrosis and may serve as a potential indicator for this subset of the disease.
Authors:
Glenda Trujillo; Alessia Meneghin; Kevin R Flaherty; Lynette M Sholl; Jeffrey L Myers; Ella A Kazerooni; Barry H Gross; Sameer R Oak; Ana Lucia Coelho; Holly Evanoff; Elizabeth Day; Galen B Toews; Amrita D Joshi; Matthew A Schaller; Beatrice Waters; Gabor Jarai; John Westwick; Steven L Kunkel; Fernando J Martinez; Cory M Hogaboam
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Science translational medicine     Volume:  2     ISSN:  1946-6242     ISO Abbreviation:  Sci Transl Med     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-11     Completed Date:  2011-03-01     Revised Date:  2014-09-13    
Medline Journal Info:
Nlm Unique ID:  101505086     Medline TA:  Sci Transl Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  57ra82     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Aged
Cell Differentiation
Cell Line
CpG Islands
DNA, Bacterial / metabolism
DNA, Viral / metabolism
Disease Progression
Epithelial-Mesenchymal Transition
Female
Humans
Idiopathic Pulmonary Fibrosis / pathology,  physiopathology*
Male
Middle Aged
Toll-Like Receptor 9 / metabolism,  physiology*
Grant Support
ID/Acronym/Agency:
HL073728/HL/NHLBI NIH HHS; P50HL56402/HL/NHLBI NIH HHS; R01 HL089216/HL/NHLBI NIH HHS; R01 HL089216-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Bacterial; 0/DNA, Viral; 0/TLR9 protein, human; 0/Toll-Like Receptor 9
Comments/Corrections

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