Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers - PubMed (original) (raw)

Idiopathic pulmonary fibrosis: immunohistochemical analysis provides fresh insights into lung tissue remodelling with implications for novel prognostic markers

Nicola J Lomas et al. Int J Clin Exp Pathol. 2012.

Abstract

Aim: This study explored the cellular and biological interrelationships involved in Idiopathic Pulmonary Fibrosis (IPF) lung tissue remodelling using immunohistochemical analysis.

Methods and results: IPF and control lung tissues were examined for localisation of Epithelial Mesenchymal Transition (EMT), proliferation and growth factor markers assessing their relationship to key histological aberrations. E-cadherin was expressed in IPF and control (Alveolar type II) ATII cells (>75%). In IPF, mean expression of N-cadherin was scanty (<10%): however 4 cases demonstrated augmented expression in ATII cells correlating to histological disease status (Pearson correlation score 0.557). Twist was expressed within fibroblastic foci but not in ATII cells. Transforming Growth Factor- β (TGF-β) protein expression was significantly increased in IPF ATII cells with variable expression within fibroblastic foci. Antigen Ki-67 was observed within hyperplastic ATII cells but not in cells overlying foci. Collagen I and α-smooth muscle actin (α-SMA) were strongly expressed within fibroblastic foci (>75%); cytoplasmic collagen I in ATII cells was present in 3 IPF cases. IPF ATII cells demonstrated variable Surfactant Protein-C (SP-C).

Conclusions: The pathogenesis of IPF is complex and involves multiple factors, possibly including EMT. Histological analysis suggests TGF-β-stimulated myofib rob lasts initiate a contractile response within established fibroblastic foci while proliferating ATII cells attempt to instigate alveolar epithelium repair. Marker expression (N-cadherin and Ki-67) correlation with histological disease activity (as reflected by fibroblastic foci extent) may emerge as future prognostic indicators for IPF.

Keywords: Idiopathic Pulmonary Fibrosis; epithelial-mesenchymal transition; immunohistochemistry; prognostic markers; tissue repair and remodelling.

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Figures

Figure 1

Figure 1

Representative histological images of IPF patient lung tissue stained with H&E. A. IPF lung tissue showing a high number of fibroblastic foci (score 6). B. IPF lung tissue very few fibroblastic foci (score 1). Fibroblastic foci are indicated with black arrows, magnification x100.

Figure 2

Figure 2

Immunohistochemical analysis of IPF and control lungs for SP-C expression. A. Patchy expression of SP-C is observed in an area of ATII hyperpla-sia in IPF lung tissue. Black arrow SP-C expression, red arrow no SP-C expression. B. Representative histological image of SP-C expression in the cytoplasm of ATII cells in control lung tissue (arrow). C. Histological image of cytoplasmic SP-C expression in hyperplastic ATII cells in IPF lung tissue. Magnification x400.

Figure 3

Figure 3

Representative immunohistochemical images of E-cadherin expression in IPF and control lungs. A. Histological image of E-cadherin expressed around ATII cells in control lung tissue. B. Membrane expression of E-cadherin is seen in ATII cells overlying areas of fibroblastic foci in IPF lung tissue. Counterstained Alcian Blue with nuclear fast red. Magnification x200.

Figure 10

Figure 10

Semi-quantitative analysis of target molecule expression within ATII cells of IPF and control lung samples. Data are presented as mean expression score ±SD. * = significant difference in expression between the control and IPF group p≤0.05.

Figure 11

Figure 11

Semi-quantitative analysis of target molecule expression within the fibroblasticfoci of IPF lung tissue samples. Data are presented as mean expression score ±SD.

Figure 4

Figure 4

Dual-labelled immunohistochemistry of IPF and control lung samples for N-cadherin and Twist expression. A. Representative histological image of control lung tissue shows no N-cadherin and Twist. B. IPF lung tissue demonstrates Twist reactivity within the fibroblastic foci (arrow). Magnification A x100, B x400.

Figure 5

Figure 5

Immunohistochemical analysis of IPF and control lungs for the mesenchymal marker α-SMA expression. A. Representative histological image of α-SMA expression around a blood vessel in control lung. B. α-SMA expression within fibroblastic foci in IPF lung tissue demonstrates the population of cells being composed of myofibroblasts. Magnification panel A x200, panel B x400.

Figure 6

Figure 6

Immunohistochemical analysis of IPF and control lungs for collagen I expression. A. Representative histological image of collagen I immunoreactivity surrounding a vessel in control lung tissue. B. Collagen I immunoreactivity within a fibroblasticfoci is seen in IPF lung tissue. Magnification x200.

Figure 7

Figure 7

Immunohistochemical analysis of IPF and control lung samples labelled for either TGF- β protein or TGF- β receptor. A. Representative histological image showing no cytoplasmic TGF-β protein immunoreactivity in control lung tissue. B. Cytoplasmic TGF-β protein is seen in ATII cells overlyingfibroblastic foci in a representative histological image of IPF lung tissue. C. TGF-β receptor immunoreactivity is not observed in control lung tissue. D. TGF-β receptor immunoreactivity can be seen in lymphocytes in IPF lung tissue. Magnification A-C x200, D x400.

Figure 8

Figure 8

Immunohistochemical analysis of IPF and control lungs for the cell proliferation marker antigen Ki-67. A. Representative histological image shows antigen Ki-67 is not observed in control lung tissue. B. A representative histological image of IPF lung tissue shows antigen Ki-67 immunoreactivity is observed in the nucleus of ATII cells at the edges of fibroblastic foci (arrow) but not in the ATII cells directly overlying the area. Magnification x200.

Figure 9

Figure 9

Immunohistochemical analysis of IPF and control lungs for p16INK4A . A. p16INK4A reactivity is not observed in control lung tissue in this representative histological image. B. Cytoplasmic p16INK4A reactivity is seen in the ATII cells overlying fibroblastic foci (arrow) in a representative histological image of IPF lung tissue. Magnification x400.

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