Direct contribution of epithelium to organ fibrosis: epithelial-mesenchymal transition

Fibrosis of epithelial parenchymal organs and end-stage organ failure represent the final common pathway of many chronic diseases and are a major determinant of morbidity and mortality worldwide. Fibrosis is a complex response initiated to protect the host from an injurious event; nevertheless, it leads to serious organ damage when it becomes independent from the initiating stimulus. It involves massive deposition of matrix by ail expanded pool of fibrogenic cells, disruption of the normal tissue architecture, and parenchymal destruction. Fibroblasts, the effector cells of matrix production, when engaged in fibrogenesis, display the highly activated phenotype characteristic of myofibroblasts. These cells arc present in a large number in sites with ongoing inflammation, reparative reaction, and fibrosis, but their origin has not yet been definitely elucidated. Although proliferation of preexisting stromal fibroblasts and, probably, recruitment of bone marrow-derived fibrogenic tells may account for a portion of them, emerging evidence seems to indicate that an important number of matrix-producing fibroblasts/myofibroblasts arises through a mechanism of epithelial-mesenchymal transition. Through this process, epithelial cells would lose intercellular cohesion and would translocate from the epithelial compartment into the interstitium where, gaining a full mesenchymal phenotype, they could participate in the synthesis of the fibrotic matrix. Epithelial mesenchymal transition is induced by the integrated actions of many stimuli including transforming growth factor-beta and matrix-generated signals that are also known to be implicated in inflammation, repair responses, and fibrosis. The consequences of epithelial-mesenchymal transition in chronic fibrosing diseases could be two-fold as follows: oil one hand, by supplementing new mesenchymal cells, it might feed the expanding pool of interstitial fibroblasts/myofibroblasts responsible for the matrix accumulation; oil the other hand, it could cause loss of epithelial cells, thus, contributing to the parenchyma destruction seen in advanced fibrosis. Markers of epithelium undergoing epithelial-mesenchymal transition include loss of E-cadherin and cytokeratin; de novo expression of fibroblast-specific protein 1/S100A4, vimentin, and alpha-smooth muscle actin; basement membrane component loss; and production of interstitial-type matrix molecules such as fibronectin and type I/III collagen. Evidence of epithelial-mesenchymal transition has been reported in the kidney, lung, liver, eye, and serosal membranes suggesting that epithelial-mesenchymal transition could be involved in the pathogenesis of fibrotic disorders in these organs. Thus, because of its fibrogenic potential, the detection of epithelial-mesenchymal transition in biopsy specimens could be useful diagnostically and represent a new biomarker of progression in chronic fibrosing diseases. (c) 2009 Elsevier Inc. All rights reserved.