title: Usual interstitial pneumonia and smoking-related interstitial fibrosis display epithelial to mesenchymal transition in fibroblastic foci.
abstract: BACKGROUND
  Fibroblastic foci (FF) are a major histological feature of usual interstitial pneumonia (UIP) in idiopathic pulmonary fibrosis (IPF) and collagen vascular diseases (non-IPF). In addition, FF are occasionally associated with smoking-related interstitial fibrosis (SRIF). Recent studies have suggested a role for epithelial to mesenchymal transition (EMT) in pulmonary fibrogenesis.
  
  
  METHODS
  Here, we investigated whether EMT was present in patients with IPF (n = 19), non-IPF (n = 17), and SRIF (n = 16) using morphometric immunohistochemistry, electron microscopy, and confocal microscopy. All patients had received lung biopsies or lobectomies for lung cancer.
  
  
  RESULTS
  IPF and non-IPF patients displayed restrictive lung function patterns, whereas those with SRIF presented mixed patterns. Cells within FF presented high number of alpha-smooth muscle actin (αSMA)-staining cells; however, the foci of IPF patients showed comparatively lower number. Moreover, colocalization of thyroid transcription factor-1 (TTF1) and αSMA within FF showed low number of staining cells for IPF and SRIF in comparison to non-IPF (p < 0.01). Nevertheless, all groups displayed colocalization of high rate of TTF1(+)-cells and low rate of αSMA(+)-cells within hyperplastic epithelioid cells in FF. Also, we observed areas with low proportion of TTF1(+)cells and αSMA(+)cells, which were present in SRIF and non-IPF more often than IPF (p < 0.001). Electron microscopy revealed small breaks in the alveolar basal lamina, which allowed epithelioid cells to directly contact the collagenous matrix and fibroblasts. Three-dimensional reconstruction revealed intense αSMA staining within some epithelioid cells, suggesting that they had gained a mesenchymal phenotype.
  
  
  CONCLUSIONS
  These findings constitute the first report of EMT in SRIF and suggest that EMT occurs more prominently in SRIF and non-IPF than IPF.
authors: Department of Pathology, Botucatu Medical School, São Paulo State University, Botucatu, Brazil. Electronic address: alexandretodofabro@gmail.com.
authors: Alexandre Todorovic
authors: AT
authors: Fabro
authors: Department of Pathology, Botucatu Medical School, São Paulo State University, Botucatu, Brazil.
authors: Igor Otavio
authors: IO
authors: Minatel
authors: Department of Pathology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors: Maristela Peres
authors: MP
authors: Rangel
authors: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors: Iris
authors: I
authors: Halbwedl
authors: Department of Pathology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors: Edwin Roger
authors: ER
authors: Parra
authors: Department of Pathology, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
authors: Vera Luiza
authors: VL
authors: Capelozzi
authors: Institute of Pathology, Medical University of Graz, Graz, Austria.
authors: Helmut
authors: H
authors: Popper
mesh_terms: D000328:Adult; D000368:Aged; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods; D017563:Lung Diseases, Interstitial / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*
keywords: Double-staining immunohistochemistry; Epithelial-mesenchymal transition; Idiopathic pulmonary fibrosis; Smoking-related interstitial fibrosis; Usual interstitial pneumonia