Published ahead of print on June 23, 2006, doi:10.1164/rccm.200602-205OC
Am. J. Respir. Crit. Care Med., Volume 174, Number 6, September 2006, 654-658
A more recent version of this article appeared on September 15, 2006
Submitted on February 10, 2006
Accepted on June 19, 2006
Fibroblast Foci are Not Discrete Sites of Lung Injury/Repair: the Fibroblast Reticulum
Carlyne D Cool1, Steve D Groshong2, Pradeep R Rai3, Peter M Henson1, J. Scott Stewart4, and Kevin K Brown5*
1 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA; Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA; Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, CO, USA,
2 Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA; Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, CO, USA,
3 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA,
4 Department of Pathology, University of Colorado Health Sciences Center, Denver, CO, USA,
5 Department of Medicine, University of Colorado Health Sciences Center, Denver, CO, USA; Interstitial Lung Disease Program, National Jewish Medical and Research Center, Denver, CO, USA
* To whom correspondence should be addressed. E-mail: brownk{at}njc.org.
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 histological sections of UIP was performed. Using point-counting technique on serial sections, fibroblast foci, arteries and macrophage clusters were identified and their individual "connectiveness" determined by the estimation of the Euler number. Two-dimensional micrographs were also collated into a three-dimensional array from which a visual three-dimensional reconstruction could be constructed. Clonality analysis was performed using HUMARA.
Results: Blood vessels show significant connectivity with an Euler number of 2, while macrophage clusters exhibited no connectivity. The fibroblast foci showed a high level of interconnection with Euler numbers ranging from 19-39. The computer generated three-dimensional models provide a visual confirmation of this connectiveness. HUMARA 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.
Key words: Usual interstitial pneumonis, fibroblast foci, fibroblast reticulum, idiopathic pulmonary fibrosis
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