ABSTRACT
[This corrects the article DOI: 10.1016/j.heliyon.2022.e09773.].
ABSTRACT
Idiopathic pulmonary fibrosis (IPF), a disorder observed mostly in older human beings, is characterised by chronic and progressive lung scarring leading to an irreversible decline in lung function. This health condition has a dismal prognosis and the currently available drugs only delay but fail to reverse the progression of lung damage. Consequently, it becomes imperative to discover improved therapeutic compounds and their cellular targets to cure IPF. In this regard, a number of recent studies have targeted the epigenetic regulation by histone deacetylases (HDACs) to develop and categorise antifibrotic drugs for lungs. Therefore, this review focuses on how aberrant expression or activity of Classes I, II and III HDACs alter TGF-ß signalling to promote events such as epithelial-mesenchymal transition, differentiation of activated fibroblasts into myofibroblasts, and excess deposition of the extracellular matrix to propel lung fibrosis. Further, this study describes how certain chemical compounds or dietary changes modulate dysregulated HDACs to attenuate five faulty TGF-ß-dependent profibrotic processes, both in animal models and cell lines replicating IPF, thereby identifying promising means to treat this lung disorder.
ABSTRACT
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.
Subject(s)
DNA-Binding Proteins/metabolism , Idiopathic Pulmonary Fibrosis/physiopathology , Respiratory Mucosa/physiology , Transcription Factors/metabolism , Animals , DNA-Binding Proteins/genetics , Disease Models, Animal , Female , Fetus/metabolism , Gene Expression Regulation, Developmental/physiology , Humans , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/metabolism , Male , Mesoderm/metabolism , Mesoderm/physiology , Mice , Mice, Mutant Strains , Middle Aged , Pregnancy , Pulmonary Alveoli/cytology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/physiology , Respiratory Mucosa/cytology , Respiratory Mucosa/metabolism , Species Specificity , Transcription Factors/geneticsABSTRACT
Intracellular membrane trafficking regulates a wide variety of developmental processes, including cell and tissue morphogenesis. Here we report developmental expression of Drosophila Rab11, a small GTP-binding protein, required for both endocytic recycling and exocytosis. Rab11 is expressed in the epithelial cell types of diverse lineages at all developmental stages, beginning from the cellular blastoderm in early embryos to adult primordia and adult tissues, like the columnar epithelia lining male ejaculatory bulb. A robust expression of Rab11 is seen both in the amnioserosa and in the lateral epidermis during embryonic dorsal closure, a morphogenetic event that involves spreading and fusion of the contra-lateral sides of epidermis. Rab11 mutant embryos fail to display the characteristic morphological changes in these two epithelial tissues during dorsal closure, providing a strong basis to dissect the role of Rab11 in coordinated epithelial sheet movements. genesis 47:32-39, 2009. (c) 2008 Wiley-Liss, Inc.
