Inflammatory and fibrotic pathways in lung fibrosis: cross-talk and targeting within a gal-3-fibrosome

Organ fibrosis, e.g. in fibrotic interstitial lung disease (ILD), causes substantial morbidity and >40% of mortality in the developed world. Treatment options are currently limited and don't cure, reverse, or stabilise disease. Functional interactions of the protein galectin-3 at the cell surface in a wide range of relevant cell types are implicated in fibrosis in the lung and other organs. Galectin-3 has potential to nucleate an extended macromolecular complex clustering a range of pro-fibrotic pathways, with modulatory cross-talk, to give a fibrotic synapse or checkpoint. We term this the gal-3-fibrosome. We have recently characterised close co-localisation (<40 nm) between galectin-3 and the CD98:integrin complex in lung tissue and cells and that their expression was increased in fibrotic ILD epithelia [1]. We demonstrated how the latter mediate inflammatory responses to stimuli modelling acute exacerbations of (AE-)ILD. Physical clustering may potentiate molecular cross-talk between AE-ILD and chronic fibrosis progression (Fig. 1). The project proposes to study this in detail in cells and in lung tissue. In parallel it will probe the effects of deglycosylation and small molecule galectin-3:carbohydrate-binding inhibitors on defined and novel outputs relevant to inflammation and fibrosis.