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Novel mechanisms in interstitial lung disease

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AC MacKinnon, SL Farnworth, M Gibbons, SJ Forbes, T Sethi. University of Edinburgh, Edinburgh, UK

Galectin-3 is a beta-galactoside binding animal lectin of approximately 30 kDa, which is highly expressed in fibrotic tissue of diverse aetiologies. Mice deficient in galectin-3 develop reduced fibrosis in several models of organ fibrosis in vivo. Galectin-3 is secreted by macrophages and is a potent mitogen for fibroblasts in vitro. In the chronic inflammatory milieu macrophages interact with other cell types including cells of mesenchymal origin (fibroblasts), which transdifferentiate into matrix-secreting myofibroblasts, with resultant scar formation and disruption of tissue architecture. Our previous work has demonstrated that fibroblasts deficient in galectin-3 fail to differentiate into myofibroblasts in vitro and in vivo. In addition, myofibroblasts may arise from epithelial cells by a process of epithelial to mesenchymal transition (EMT). EMT of alveolar epithelial cells (AEC) has been widely observed in patients with interstitial pulmonary fibrosis (IPF). AEC convert into myofibroblasts following exposure to the profibrotic cytokine transforming growth factor beta (TGF-β) raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF. Primary epithelial cells from galectin-3 null mice show reduced differentiation into myofibroblasts in response to TGF-β in vitro, suggesting that galectin-3 may play a role in EMT in these cells. In the human lung epithelial cell line A549, inhibition of galectin-3 function with Bis-(3-deoxy-3-(3-methoxybenzamido)-β-d-galactopyranosyl)-sulfane a specific inhibitor of extracellular galectin-3 carbohydrate binding and siRNA-mediated depletion of galectin-3 and its membrane receptor CD98 inhibited TGF-β-mediated downstream signalling showing reduced activation of SMAD2/3. Inhibition of galectin-3/CD98 function reduced TGF-β-mediated expression of the myofibroblast marker alpha-smooth muscle actin and increased expression of the epithelial marker E-cadherin suggesting that galectin-3/CD98 regulates TGF-β-induced signalling and the development of EMT in alveolar epithelial cells. Therefore galectin-3 via its interaction with CD98 …

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