Interplay between RAGE, CD44, and focal adhesion molecules in epithelial-mesenchymal transition of alveolar epithelial cells

被引:45
作者
Buckley, Stephen T.
Medina, Carlos
Kasper, Michael [2 ]
Ehrhardt, Carsten [1 ]
机构
[1] Trinity Coll Dublin, Sch Pharm & Pharmaceut Sci, Panoz Inst, Dublin 2, Ireland
[2] Tech Univ Dresden, Inst Anat, Dresden, Germany
关键词
fibrosis; ezrin/radixin/moesin; transdifferentiation; cytoskeleton; GLYCATION END-PRODUCTS; LUNG INJURY; PULMONARY-FIBROSIS; RECEPTOR; MARKER; MATRIX-METALLOPROTEINASE-9; CYTOSKELETON; MECHANISMS; EXPRESSION; PROTEINS;
D O I
10.1152/ajplung.00230.2010
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Buckley ST, Medina C, Kasper M, Ehrhardt C. Interplay between RAGE, CD44, and focal adhesion molecules in epithelial-mesenchymal transition of alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 300: L548-L559, 2011. First published January 28, 2010; doi:10.1152/ajplung.00230.2010.-Fibrosis of the lung is characterized by the accumulation of myofibroblasts, a key mediator in the fibrogenic reaction. Cumulative evidence indicates that epithelial-mesenchymal transition (EMT), a process whereby epithelial cells become mesenchyme-like, is an important contributing source for the myofibroblast population. Underlying this phenotypical change is a dramatic alteration in cellular structure. The receptor for advanced glycation end-products (RAGE) has been suggested to maintain lung homeostasis by mediating cell adhesion, while the family of ezrin/radixin/moesin (ERM) proteins, on the other hand, serve as an important cross-linker between the plasma membrane and cytoskeleton. In the present investigation, we tested the hypothesis that RAGE and ERM interact and play a key role in regulating EMT-associated structural changes in alveolar epithelial cells. Exposure of A549 cells to inflammatory cytokines resulted in phosphorylation and redistribution of ERM to the cell periphery and localization with EMT-related actin stress fibers. Simultaneously, blockade of Rho kinase (ROCK) signaling attenuated these cytokine-induced structural changes. Additionally, RAGE expression was diminished after cytokine stimulation, with release of its soluble isoform via a matrix metalloproteinase (MMP)-9-dependent mechanism. Immunofluorescence microscopy and coimmunoprecipitation revealed association between ERM and RAGE under basal conditions, which was disrupted when challenged with inflammatory cytokines, as ERM in its activated state complexed with membrane-linked CD44. Dual-fluorescence immunohistochemistry of patient idiopathic pulmonary fibrosis (IPF) tissues highlighted marked diminution of RAGE in fibrotic samples, together with enhanced levels of CD44 and double-positive cells for CD44 and phospho (p) ERM. These data suggest that dysregulation of the ERM-RAGE complex might be an important step in rearrangement of the actin cytoskeleton during proinflammatory cytokine-induced EMT of human alveolar epithelial cells.
引用
收藏
页码:L548 / L559
页数:12
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