Investigation into the Roles of Epithelial-Mesenchymal Transition (EMT) in Idiopathic Pulmonary Fibrosis (IPF)

Abstract

Idiopathic pulmonary fibrosis (IPF) is a type of chronic, interstitial lung disease, characterised by aberrant extracellular matrix (ECM) deposition. It is an ageing-associated disease, with a poor prognosis and limited treatments are available. Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose cell polarity and cell junctions, gaining a mesenchymal phenotype. The role of EMT, in the generation of fibroblasts in IPF, is controversial, with studies now suggesting that EMT contributes indirectly.
Here, we utilised bioinformatic analysis to evaluate IPF microarray datasets. We showed that the epidermal growth factor receptor-mitogen-activated protein kinase (EGFR-MAPK) pathway and EMT could both be involved in the pathogenesis of IPF. These findings were validated with proteomic analysis of RAS-activated alveolar type II epithelial (ATIIER:KRASV 12) cells, where EMT was identified as a top process. In vitro studies of ATIIER:KRASV 12 cells were used to dissect the mechanisms underlying these processes. We found that RAS-activated EMT was induced via the EGFR-RAS-ERK-ZEB1 axis, but it was insufficient to induce the expression of ECM components in IPF. Autophagy was shown to be reduced in IPF. As autophagy and EMT have a complicated relationship, we explored this in IPF. Using ATII cells, we showed that autophagy inhibition induced EMT via the p62/NF-κB/Snail2 axis. In a similar manner to RAS-induced EMT, autophagy inhibition-induced EMT was insufficient to produce ECM components, however it did mediate secreted factors which were able to augment fibrosis via Snail2.
Together, these findings demonstrate the importance of the EGFR-RAS signalling pathway and autophagy in the pathogenesis of IPF. EMT was induced in ATII cells, but was not sufficient to augment fibrosis directly. We demonstrate that secreted factors, induced by EMT, promote fibrosis. This thesis advances the understanding of the mechanisms underlying the activation of EMT in the fibrotic lung, but also, how this can indirectly result in fibrosis by paracrine signalling mechanisms.

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ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

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