Grainyhead-like 2 (GRHL2) distribution reveals novel pathophysiological differences between human idiopathic pulmonary fibrosis and mouse models of pulmonary fibrosis

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 306; no. 5; pp. L405 - L419
• Main Authors: Varma, Saaket, Mahavadi, Poornima, Sasikumar, Satish, Cushing, Leah, Hyland, Tessa, Rosser, Ann E, Riccardi, Daniela, Lu, Jining, Kalin, Tanya V, Kalinichenko, Vladimir V, Guenther, Andreas, Ramirez, Maria I, Pardo, Annie, Selman, Moisés, Warburton, David
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2014
• Series: Translational Research in Acute Lung Injury and Pulmonary Fibrosis
• Subjects: Animals; Call for Papers; Cells; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Fetus - metabolism; Gene expression; Gene Expression Regulation, Developmental - physiology; Humans; Idiopathic Pulmonary Fibrosis - genetics; Idiopathic Pulmonary Fibrosis - metabolism; Idiopathic Pulmonary Fibrosis - physiopathology; Lungs; Male; Mesoderm - metabolism; Mesoderm - physiology; Mice; Mice, Mutant Strains; Middle Aged; Pathogenesis; Pregnancy; Pulmonary Alveoli - cytology; Pulmonary Alveoli - metabolism; Pulmonary Alveoli - physiology; Pulmonary fibrosis; Respiratory Mucosa - cytology; Respiratory Mucosa - metabolism; Respiratory Mucosa - physiology; Rodents; Species Specificity; Transcription Factors - genetics; Transcription Factors - metabolism; cell flattening; idiopathic pulmonary fibrosis; epithelial plasticity; epithelial integrity; GRHL2
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00143.2013

Chronic injury of alveolar lung epithelium leads to epithelial disintegrity in idiopathic pulmonary fibrosis (IPF). We had reported earlier that Grhl2, a transcriptional factor, maintains alveolar epithelial cell integrity by directly regulating components of adherens and tight junctions and thus hypothesized an important role of GRHL2 in pathogenesis of IPF. Comparison of GRHL2 distribution at different stages of human lung development showed its abundance in developing lung epithelium and in adult lung epithelium. However, GRHL2 is detected in normal human lung mesenchyme only at early fetal stage (week 9). Similar mesenchymal reexpression of GRHL2 was also observed in IPF. Immunofluorescence analysis in serial sections from three IPF patients revealed at least two subsets of alveolar epithelial cells (AEC), based on differential GRHL2 expression and the converse fluorescence intensities for epithelial vs. mesenchymal markers. Grhl2 was not detected in mesenchyme in intraperitoneal bleomycin-induced injury as well as in spontaneously occurring fibrosis in double-mutant HPS1 and HPS2 mice, whereas in contrast in a radiation-induced fibrosis model, with forced Forkhead box M1 (Foxm1) expression, an overlap of Grhl2 with a mesenchymal marker was observed in fibrotic regions. Grhl2's role in alveolar epithelial cell plasticity was confirmed by altered Grhl2 gene expression analysis in IPF and further validated by in vitro manipulation of its expression in alveolar epithelial cell lines. Our findings reveal important pathophysiological differences between human IPF and specific mouse models of fibrosis and support a crucial role of GRHL2 in epithelial activation in lung fibrosis and perhaps also in epithelial plasticity.