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Expression of Fibroblast Growth Factor 9 in Normal Human Lung and Idiopathic Pulmonary Fibrosis

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Expression of Fibroblast Growth Factor 9 in Normal Human Lung and Idiopathic Pulmonary Fibrosis JHCXXX10.1369/0022155413497366Coffey et al.FGF9 in IPF 497366research-article2013 Article Journal of Histochemistry & Cytochemistry 61(9) 671 –679 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1369/0022155413497366 jhc.sagepub.com Expression of Fibroblast Growth Factor 9 in Normal Human Lung and Idiopathic Pulmonary Fibrosis Emily Coffey, Donna R. Newman, and Philip L. Sannes Department of Molecular Biomedical Sciences, Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina Summary The fibroblast growth factor (FGF) family of signaling ligands contributes significantly to lung development and maintenance in the adult. FGF9 is involved in control of epithelial branching and mesenchymal proliferation and expansion in developing lungs. However, its activity and expression in the normal adult lung and by epithelial and interstitial cells in fibroproliferative diseases like idiopathic pulmonary fibrosis (IPF) are unknown. Tissue samples from normal organ donor human lungs and those of a cohort of patients with mild to severe IPF were sectioned and stained for the immunolocalization of FGF9. In normal lungs, FGF9 was confined to smooth muscle surrounding airways, alveolar ducts and sacs, and blood vessels. In addition to these same sites, lungs of IPF patients expressed FGF9 in a population of myofibroblasts within fibroblastic foci, hypertrophic and hyperplastic epithelium of airways and alveoli, and smooth muscle cells surrounding vessels embedded in thickened interstitium. The results demonstrate that FGF9 protein increased in regions of active cellular hyperplasia, metaplasia, and fibrotic expansion of IPF lungs, and in isolated human lung fibroblasts treated with TGF- β1 and/or overexpressing Wnt7B. The cellular distribution and established biologic activity of FGF9 make it a potentially strong candidate for contributing to the progression of IPF. (J Histochem Cytochem 61:671–679, 2013) Keywords smooth muscle cells, myofibroblast, metaplastic epithelium Introduction normal pulmonary architecture (Katzenstein and Myers 1998; Katzenstein et al. 2002). Other characteristics include Idiopathic pulmonary fibrosis (IPF), or usual interstitial honeycomb change and traction bronchiectasis. Its progres- pneumonia (UIP), is a devastating disease characterized by sion leads to end-stage fibrosis with diminishing pulmonary the ineffective repair of damaged pulmonary epithelium structure and function (Kapanci et al. 1995; Katzenstein and due to its failed differentiation. The results are epithelial Myers 1998; Katzenstein et al. 2002). hyperplasia and metaplasia, rapid expansion of a heteroge- A number of growth factors are believed to play key neous population of myofibroblast-like cells, and a fibrous roles in the cellular and ECM changes characteristic to IPF. extracellular matrix (ECM) with progressive loss of normal respiratory architecture and function (Schwartz et al. 1994; Green 2002). The hallmark lesions of this failed restructur- Received for publication April 17, 2013; accepted June 17, 2013. ing are fibroblastic foci (FF), indicative of progressive disease, which are believed to represent a complex, inter- Corresponding Author: Philip L. Sannes, PhD, Department of Molecular Biomedical Sciences, connected reticulum extending from the pleural surface into College of Veterinary Medicine, North Carolina State University, 1051 the lung parenchyma (Cool et al. 2006). Early lesions often William Moore Drive, Raleigh, NC 27607, USA. appear highly cellular, with subepithelial FF adjacent to E-mail: [email protected] 672 Coffey et al. Among them, TGF-β is well recognized for its regulatory 80% [major final clinical diagnosis as interstitial lung dis- contribution to fibrogenic processes in IPF (Chilosi ease (ILD, n=8) and minor final clinical diagnosis as usual et al. 2003; Fernandez and Eickelberg 2012) by promoting interstitial pneumonia (UIP)/idiopathic pulmonary fibro- the development of myofibroblasts and influencing the sis (IPF)]; and (3) patients with FVCs <50% (major final expansion of fibrillar collagen and other ECM compo- clinical diagnosis of ILD and minor final clinical diagno- nents, in many cases modulated by cooperative Wnt signal- sis as UIP/IPF, n=8). No other patient identifiers were pro- ing (Broekelmann et al. 1991; Scotton and Chambers 2007; vided, and their anonymity and confidentiality were Salazar, Lankford, and Brody 2009). Previous studies have preserved. The study was approved by the North Carolina demonstrated that Wnt7B mRNA is upregulated in IPF State University Institutional Review Board. Blocks were lungs (Konigshoff et al. 2008) and is histochemically local- sectioned and stained with hematoxylin and eosin (H&E) ized in discrete sites including the ECM and cells within and examined by a board-certified pathologist to inde- FF of IPF lungs (Meuten et al. 2012). Furthermore, one of pendently confirm/reclassify initial clinical diagnoses its downstream signaling targets, β-catenin, has also been (Meuten et al. 2012). localized histochemically in FF (Chilosi et al. 2003). Sections were treated with citrate buffer for antigen Wnt7B is an important signaling glycopeptide that coordi- retrieval and treated with a polyclonal goat anti-human nates proliferation of adjacent epithelium and mesenchy- FGF9 antibody (AF-273-NA, lot UZ03; R&D Systems, mal cells (Rajagopal et al. 2008) and regulates vascular Minneapolis, MN) at a concentration of 5 μg/ml for 2 hr at growth during early lung development (Shu et al. 2002). room temperature. The immunogen was a recombinant Accordingly, it has been proposed to have a potentially sig- human FGF9, whose specific IgG was purified by affinity nificant impact on the progression of IPF in the adult lung chromatography, according to the manufacturer. A poly- (Morrisey 2003; Meuten et al. 2012). clonal goat anti-Wnt7B antibody (sc-26363, lot I0205; Fibroblast growth factor 9 (FGF9) is expressed by pul- Santa Cruz Biotechnology, Santa Cruz, CA) at a concentra- monary epithelium and mesothelium during the pseudo- tion of 2 μg/ml and incubated overnight at 4C was raised glandular stage of lung development (Colvin et al. 1999). against a peptide mapping near the C-terminus of human Fgf9-/- mice have severely impaired lung development and Wnt7B and was affinity purified, according to the manufac- do not survive (Colvin et al. 2001; White et al. 2006). turer. A mouse monoclonal anti-smooth muscle actin anti- FGF9 and Wnt7B/β-catenin signaling pathways have been body (A5228, lot 110M4795; Sigma, St Louis, MO) was shown to coordinately control critical communication used at a concentration of 5 μg/ml for 2 hr at room tempera- between mesothelial-mesenchymal and epithelial- ture. The antibody to α-smooth muscle actin (mouse IgG2a mesenchymal compartments during lung development, isotype) was derived from a 1A4 hybridoma produced from resulting in epithelial growth and mesenchymal expansion mice immunized with the NH terminal synthetic decapep- 2 (Yin et al. 2008; Yin, Wang, and Ornitz 2011). This dem- tide. The isotype was determined by double diffusion onstrated relationship coupled with our recent observa- immunoassay. tions of epithelial, mesothelial, and fibroblast expression Primary antibody treatment was followed by multiple of Wnt7B in adult IPF lungs (Meuten et al. 2012) raised washes, incubation with peroxidase-labeled secondary the question of FGF9’s potential involvement in intersti- antibodies, according to the instructions of the manufac- tial expansion during fibrosis in the adult lung. Results turer (Dako LSAB+SystempHRP; Dako Laboratories, presented here show strong expression of FGF9 in airway Carpinteria, CA), and visualization with the NovaRED Kit and vascular smooth muscle, endothelium, mesothelium, a for Peroxidase, according to the directions of the manufac- population of fibroblasts within fibroblastic foci, hyper- turer (Vector Laboratories; Burlingame, CA). Control sam- plastic and metaplastic epithelium of airways and alveoli, ples substituted normal goat serum, mouse ascites, or and smooth muscle cells associated with vessels embed- heat-inactivated goat anti-Wnt2 antibody (AF3464, lot ded in thickened interstitium. XjH0312061; R&D Systems) for the primary antibody at an equivalent protein concentration. Sections were counter- stained with methylene blue or Celestine blue and routinely Materials & Methods mounted. When possible, adjacent or parallel sections were Immunostaining used to compare localization of different target molecules in the same site. Slides were evaluated and photographed on Tissue blocks of formalin-fixed lung tissue samples were an Olympus BX-40 microscope with a DP-25 digital cam- obtained from the Lung Tissue Research Consortium era attachment and computerized storage management. (LTRC). The samples had previously been placed into Photographs were taken using either a 10X plan achromat three groups: (1) patients with forced vital capacities objective with a 0.25 numerical aperture and 10.50-mm (FVCs) >80% (normal, or no specified major or minor working distance or 40X plan achromat objective with 0.65 diagnosis, n=3); (2) patients with FVCs between 50% and numerical aperture and 0.57-mm working distance. FGF9 in IPF 673 Cell Preparations 1996; Meuten et al. 2012) and could be expected to modu- late FGF9 expression. Human AT2 (hAT2) cells were isolated from organ donor lungs provided by the
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