Paracrine signalling during ZEB1-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in lung fibrosis
2019
The contribution of
epithelial–mesenchymal transition(EMT) to
human lungfibrogenesis is controversial. Here we provide evidence that ZEB1-mediated EMT in human alveolar epithelial type II (ATII) cells contributes to the development of
lung fibrosisby
paracrine signallingto underlying fibroblasts. Activation of EGFR–RAS–ERK signalling in ATII cells induced EMT via ZEB1. ATII cells had extremely low
extracellular matrixgene expression even after induction of EMT, however conditioned media from ATII cells undergoing RAS-induced EMT augmented TGFβ-induced profibrogenic responses in lung fibroblasts. This epithelial–mesenchymal crosstalk was controlled by ZEB1 via the expression of
tissue plasminogen activator(tPA). In human fibrotic lung tissue, nuclear ZEB1 expression was detected in alveolar epithelium adjacent to sites of
extracellular matrix(ECM) deposition, suggesting that ZEB1-mediated
paracrine signallinghas the potential to contribute to early fibrotic changes in the lung interstitium. Targeting this novel ZEB1 regulatory axis may be a viable strategy for the treatment of
pulmonary fibrosis.
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