title: A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis.
abstract: BACKGROUND
  Idiopathic pulmonary fibrosis exhibits differential progression from the time of diagnosis but the molecular basis for varying progression rates is poorly understood. The aim of the present study was to ascertain whether differential miRNA expression might provide one explanation for rapidly versus slowly progressing forms of IPF.
  
  
  RESULTS
  miRNA and mRNA were isolated from surgical lung biopsies from IPF patients with a clinically documented rapid or slow course of disease over the first year after diagnosis. A quantitative PCR miRNA array containing 88 of the most abundant miRNA in the human genome was used to profile lung biopsies from 9 patients with rapidly progressing IPF, 6 patients with slowly progressing IPF, and 10 normal lung biopsies. Using this approach, 11 miRNA were significantly increased and 36 were significantly decreased in rapid biopsies compared with normal biopsies. Slowly progressive biopsies exhibited 4 significantly increased miRNA and 36 significantly decreased miRNA compared with normal lung. Among the miRNA present in IPF with validated mRNA targets were those with regulatory effects on epithelial-mesenchymal transition (EMT). Five miRNA (miR-302c, miR-423-5p, miR-210, miR-376c, and miR-185) were significantly increased in rapid compared with slow IPF lung biopsies. Additional analyses of rapid biopsies and fibroblasts grown from the same biopsies revealed that the expression of AGO1 and AGO2 (essential components of the miRNA processing RISC complex) were lower compared with either slow or normal lung biopsies and fibroblasts.
  
  
  CONCLUSIONS
  These findings suggest that the development and/or clinical progression of IPF might be the consequence of aberrant miRNA processing.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
authors.forename: Sameer R
authors.initials: SR
authors.lastname: Oak
authors.forename: Lynne
authors.initials: L
authors.lastname: Murray
authors.forename: Athula
authors.initials: A
authors.lastname: Herath
authors.forename: Matthew
authors.initials: M
authors.lastname: Sleeman
authors.forename: Ian
authors.initials: I
authors.lastname: Anderson
authors.forename: Amrita D
authors.initials: AD
authors.lastname: Joshi
authors.forename: Ana Lucia
authors.initials: AL
authors.lastname: Coelho
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Flaherty
authors.forename: Galen B
authors.initials: GB
authors.lastname: Toews
authors.forename: Darryl
authors.initials: D
authors.lastname: Knight
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Martinez
authors.forename: Cory M
authors.initials: CM
authors.lastname: Hogaboam
mesh_terms: D000368:Aged; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000166:cytology / Q000473:pathology / Q000502:physiology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012189:Retrospective Studies; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C115848:AGO1 protein, human; C466422:AGO2 protein, human; D060565:Argonaute Proteins; D039642:Eukaryotic Initiation Factors; D035683:MicroRNAs; D012333:RNA, Messenger; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases