Korean J Med.  2010 Jul;79(1):32-40.

Clonality analysis of fibroblast proliferation in patients with idiopathic pulmonary fibrosis

Affiliations
  • 1Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. sdlee@amc.seoul.kr
  • 2Asan Life Science Institute, Seoul, Korea.

Abstract

BACKGROUND/AIMS
Idiopathic pulmonary fibrosis (IPF) is defined pathologically by usual interstitial pneumonia (UIP), and contains characteristic discrete areas of fibroblasts, myofibroblasts, and newly formed collagen, termed "fibroblast foci". A new hypothesis postulates that IPF results from epithelial injury and abnormal wound repair without preceding chronic inflammation. We explored the hypothesis that fibroblasts in the fibroblast foci of IPF undergo neoplastic monoclonal proliferation rather than reactive polyclonal proliferation.
METHODS
We obtained fibroblasts from 24 fibroblast foci in seven female patients with IPF, endothelial cells from ten plexiform lesions of two female patients with idiopathic pulmonary arterial hypertension (IPAH) as a positive control for monoclonality, and lung parenchymal cells by microdissection of each formalin-fixed paraffin-embedded block of lung. To analyze clonality, we performed the human androgen-receptor gene methylation assay (HUMARA). DNA released by protein K digestion was subjected to polymerase chain reaction (PCR) amplification with prior digestion with and without the methylation-sensitive restriction enzyme HhaI. Then, we calculated the clonality ratio after electrophoretic analysis of the PCR amplification product. A clonality ratio <0.25 was considered evidence of monoclonal proliferation.
RESULTS
All of the patients included, i.e., the seven females with IPF and the two females with IPAH, showed polymorphism in the human androgen-receptor gene. The mean clonality ratio of the 24 fibroblast foci was 0.70 (SD: 0.18). All of the fibroblast foci had clonality ratios >0.25, suggesting polyclonality, whereas 7 of 10 plexiform lesions had clonality ratios <0.25 suggesting monoclonality.
CONCLUSIONS
The polyclonality of the fibroblast foci in IPF suggests that the fibroblast proliferation in IPF is not neoplastic, but is reactive in nature

Keyword

Idiopathic pulmonary fibrosis; Fibroblasts; Clone cells; X chromosome

MeSH Terms

Bacterial Outer Membrane Proteins
Clone Cells
Collagen
Digestion
DNA
Endothelial Cells
Female
Fibroblasts
Humans
Hypertension
Hypertension, Pulmonary
Idiopathic Pulmonary Fibrosis
Inflammation
Lung
Methylation
Microdissection
Myofibroblasts
Polymerase Chain Reaction
X Chromosome
Bacterial Outer Membrane Proteins
Collagen
DNA
Hypertension, Pulmonary
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