Migratory marker expression in fibroblast foci of idiopathic pulmonary fibrosis.
BACKGROUND
Fibroblast foci (FF) are considered a relevant morphologic marker of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), and are recognised as sites where fibrotic responses are initiated and/or perpetuated in this severe disease. Despite their relevance, the cellular and molecular mechanisms responsible for the formation of FF and their role in tissue remodelling are poorly defined. In previous studies we have provided evidence of abnormal activation of the wnt-signaling-pathway in IPF/UIP that is centred on FF and the overlying epithelium. This important morphogenetic pathway is able to trigger epithelial-mesenchymal-transition (EMT), a mechanism involved in developmental and metastatic processes, which is also potentially involved in pulmonary fibrosis.


METHODS
Since EMT is characterised by enhancement of migratory potential of cells, we investigated the molecular profile of FF in 30 biopsies of IPF/UIP and a variety of control samples, focussing on the immunohistochemical expression of three molecules involved in cell motility and invasiveness, namely laminin-5-gamma2-chain, fascin, and heat-shock-protein-27.


RESULTS
We provide evidence that in UIP these three molecules are abnormally expressed in discrete clusters of bronchiolar basal cells precisely localised in FF. These cellular clusters expressed laminin-5-gamma2-chain and heat-shock-protein-27 at very high levels, forming characteristic three-layered lesions defined as "sandwich-foci" (SW-FF). Upon quantitative analysis SW-FF were present in 28/30 UIP samples, representing more than 50% of recognisable FF in 21/30, but were exceedingly rare in a wide variety of lung pathologies examined as controls. In UIP, SW-FF were often observed in areas of microscopic honeycombing, and were also found at the interface between normal lung tissue and areas of dense scarring.


CONCLUSIONS
These molecular abnormalities strongly suggest that SW-FF represent the leading edge of pulmonary remodelling, where abnormal migration and re-epithelialisation take place, and that abnormal proliferation and migration of bronchiolar basal cells have a major role in the remodelling process characterising IPF/UIP. Further investigations will assess their possible use as reliable markers for better defining the UIP-pattern in difficult cases.
Chilosi
Marco
M
Department of Pathology, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy. marco.chilosi@univr.it
Zamò
Alberto
A
Doglioni
Claudio
C
Reghellin
Daniela
D
Lestani
Maurizio
M
Montagna
Licia
L
Pedron
Serena
S
Ennas
Maria Grazia
MG
Cancellieri
Alessandra
A
Murer
Bruno
B
Poletti
Venerino
V
D015415:Biomarkers / Q000032:analysis; D002352:Carrier Proteins / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D020869:Gene Expression Profiling; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000473:pathology / Q000503:physiopathology; D008840:Microfilament Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000473:pathology* / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D051153:Wnt Proteins / Q000502:physiology
D015415:Biomarkers; D002352:Carrier Proteins; D006360:Heat-Shock Proteins; C400567:LAMC2 protein, human; D007797:Laminin; D008840:Microfilament Proteins; D051153:Wnt Proteins; C020324:fascin