title: Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum.
abstract: BACKGROUND
  Usual interstitial pneumonia (UIP), the pathologic correlate of idiopathic pulmonary fibrosis, contains characteristic discrete areas of fibroblasts, myofibroblasts, and newly formed collagen, termed "fibroblast foci." These lesions are argued to represent isolated sites of recurrent acute lung injury and suggested to be the mechanism of disease progression. We hypothesized that, rather than isolated, these lesions are part of an organized neoplasm.
  
  
  METHODS
  Morphometric analysis of pentachrome-stained histologic sections of UIP was performed. Using point-counting technique on serial sections, fibroblast foci, arteries, and macrophage clusters were identified and we determined their individual "connectiveness" by estimating the Euler number. Two-dimensional micrographs were collated into a three-dimensional array from which a visual three-dimensional reconstruction could be constructed. Clonality analysis was performed using human androgen receptor gene methylation assay.
  
  
  RESULTS
  Blood vessels show significant connectivity with a Euler number of 2, whereas macrophage clusters exhibited no connectivity. The fibroblast foci showed a high level of interconnection with Euler numbers ranging from 19 to 39. The computer generated three-dimensional models provide a visual confirmation of this connectiveness. Human androgen receptor gene methylation assay analysis of the foci showed balanced methylation consistent with polyclonality.
  
  
  CONCLUSIONS
  The fibroblast foci of UIP are the leading edge of a complex reticulum that is highly interconnected and extends from the pleura into the underlying parenchyma. It is a reactive, rather than a malignant, process.
authors.affiliation: Departments of Medicine and Pathology, University of Colorado Health Sciences Center; and Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
authors.forename: Carlyne D
authors.initials: CD
authors.lastname: Cool
authors.forename: Steve D
authors.initials: SD
authors.lastname: Groshong
authors.forename: Pradeep R
authors.initials: PR
authors.lastname: Rai
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.forename: J Scott
authors.initials: JS
authors.lastname: Stewart
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Brown
mesh_terms: D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000648:ultrastructure*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D066298:In Vitro Techniques; D008168:Lung / Q000473:pathology*; D017563:Lung Diseases, Interstitial / Q000150:complications / Q000473:pathology; D010784:Photomicrography; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000473:pathology*