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. 2018 Apr;188(4):853-862.
doi: 10.1016/j.ajpath.2017.12.004. Epub 2018 Jan 31.

A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis

Jennifer M S Sucre  1 , Gail H Deutsch  2 , Christopher S Jetter  3 , Namasivayam Ambalavanan  4 , John T Benjamin  3 , Linda A Gleaves  5 , Bryan A Millis  6 , Lisa R Young  7 , Timothy S Blackwell  8 , Jonathan A Kropski  5 , Susan H Guttentag  3
Affiliations

A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis

Jennifer M S Sucre et al. Am J Pathol. 2018 Apr.

Abstract

Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal and diseased human lung samples, we identified a distinct signature of nuclear accumulation of β-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of β-catenin phosphorylated at tyrosine 654 in early normal lung development and fibrotic lung diseases BPD and IPF. Furthermore, this signature was recapitulated in murine models of BPD and IPF. Image analysis of immunofluorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated β-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal lung. Nuclear β-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed β-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of β-catenin during normal lung development and again in response to lung injury supports the widely held concept that repair of lung injury involves the recapitulation of developmental programs. Furthermore, these observations suggest that β-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.

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Figures

Figure 1
Figure 1
Phosphorylated Y489 β-catenin (p–β-cateninY489) and phosphorylated Y654 β-catenin (p–β-cateninY654) localization in epithelial cells across lung development. A–F: Immunofluorescence (IF) for p–β-cateninY489 (red) and at 14, 18, 21, 31, and 40 weeks, and in adult lung sections. Some p–β-cateninY489 samples are also positive for epithelial cell adhesion molecule (Ep-CAM; green), with frequency of distribution curves (connecting line between means is shown in black) for intensity of p–β-cateninY489 staining. G: Mean intensity of p–β-cateninY489 staining by gestational age. One-way analysis of variance significant for differences between each group. H: IF for p–β-cateninY654 (red) and at 14, 18, 21, 31, and 40 weeks, and in adult lung sections. p–β-cateninY654 is exclusively present in Ep-CAM–positive cells (green). I and J: IF for p–β-cateninY489 (red) and p–β-cateninY654 (red) in neonatal and adult mouse lung sections shows almost no expression. Tiled images compiled as described. Boxed areas in left panels are shown in higher magnification in right panels (A–F and H–J). Data are expressed as means ± SD (G). ∗∗∗∗P < 0.0001. Scale bar = 50 μm (A–F and H–J). Original magnification, ×60 (A–F and H–J).
Figure 2
Figure 2
Phosphorylated Y489 β-catenin (p–β-cateninY489) and phosphorylated Y654 β-catenin (p–β-cateninY654) localization in epithelial cells in human bronchopulmonary dysplasia (BPD) and in hyperoxia mouse model. A: Immunofluorescence (IF) for p–β-cateninY489 (red) and p–β-cateninY654 (red) in human infant lungs with BPD at term corrected gestational age, with epithelial cell adhesion molecule (Ep-CAM; green counterstain). Some Ep-CAM (green)–positive cells are also positive for p–β-cateninY489, and p–β-cateninY654 is exclusively present in Ep-CAM–positive cells. B: Frequency of distribution curves of histocytometry data demonstrates overlap between BPD and 18-week fetal lung, with these two populations of nuclei distinct from the nuclei in term infants when sorted for nuclear intensity of p–β-cateninY489 staining (P < 0.0001). C: IF for p–β-cateninY489 (red) and p–β-cateninY654 (red) in neonatal mouse lungs exposed to hyperoxia from postnatal day 1 (PN1) to PN14. D: Frequency of distribution curves for quantitative IF for nuclear staining for p–β-cateninY489. Boxed areas in left panels are shown in higher magnification in right panels (A and C). Two-tailed t-test significant for differences between normoxia and hyperoxia exposed neonatal mice (P < 0.0001). Scale bar = 20 μm (A and C). Original magnification, ×60 (A and C).
Figure 3
Figure 3
Phosphorylated Y489 β-catenin (p–β-cateninY489) and phosphorylated Y654 β-catenin (p–β-cateninY654) localization in epithelial and mesenchymal cells in human idiopathic pulmonary fibrosis (IPF), bleomycin mouse model, and human chronic obstructive pulmonary disease (COPD). A: Immunofluorescence (IF) for p–β-cateninY489 (red) and p–β-cateninY654 (red) in mouse lungs after treatment with bleomycin B: Frequency of distribution curves for quantitative IF for nuclear staining for p–β-cateninY489. Two-tailed t-test significant for differences between IPF and normal lung tissue (P < 0.0001). C: IF for p–β-cateninY489 (red) and p–β-cateninY654 (red) in IPF lung tissue, with some p–β-cateninY489. Some p–β-cateninY489 is also positive for vimentin, pro–surfactant protein B (pro-SPB), and epithelial cell adhesion molecule (Ep-CAM) (counterstains in green). p–β-CateninY654 expression is limited to epithelial cells expressing pro-SPB or Ep-CAM. D: Frequency of distribution curves for quantitative IF for nuclear staining for p–β-cateninY489. E: IF for p–β-cateninY489 (red) and p–β-cateninY654 (red) in COPD lung tissue. F: Frequency of distribution curves for quantitative IF for intensity of nuclear staining for p–β-cateninY489 in normal adult lung, IPF lung, and COPD lung. One-way analysis of variance significant for differences between normal adult lung, COPD lung, and IPF lung nuclei (P < 0.0001). G: Frequency of distribution curves for histocytometry for intensity of nuclear staining for p–β-cateninY489 in 18 weeks' fetal lung, bronchopulmonary dysplasia (BPD) lung, and IPF lung, showing significant overlap between the groups (P > 0.1). Boxed areas in left panels are shown in higher magnification in right panels (A, C, and E). Scale bar = 20 μm (A, C, and E). Original magnification, ×60 (A, C, and E).
Figure 4
Figure 4
RNA in situ hybridization for AXIN2 expression in fetal lung, bronchopulmonary dysplasia (BPD) lung, idiopathic pulmonary fibrosis (IPF) lung, and healthy infant and adult controls using RNAscope. A:AXIN2 expression in human fetal, infant, and adult lung sections (red). B:AXIN2 expression in BPD and IPF tissue (red). C: Quantification of AXIN2 expression, normalized per thousand cells counted. There are significant differences between BPD and term infants and IPF and healthy adults. Data are expressed as means ± SD (C). Boxed areas in left panels are shown in higher magnification in right panels (A and B). ∗∗P < 0.01. Scale bar = 20 μm (A and B). Original magnification, ×60 (A and B).
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