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

器官纤维化，如纤维化间质性肺疾病(ILD)，在发达国家导致相当大的发病率和40%的死亡率。目前的治疗选择有限，不能治愈、逆转或稳定疾病。Galectin-3蛋白在多种相关细胞类型的细胞表面的功能相互作用与肺和其他器官的纤维化有关。Galectin-3有可能形成一个扩展的大分子复合体，聚集在一系列促纤维化途径上，通过调节串扰，形成纤维性突触或检查点。我们称其为Gal-3-纤维体。我们最近鉴定了Galectin-3和CD98：整合素复合体在肺组织和细胞中的紧密共存(&lt；40 nm)，并且它们在纤维化的ILD上皮细胞中的表达增加[1]。我们展示了后者如何调节对刺激的炎症反应，模拟(AE-)ILD的急性加重。物理聚集可能增强AE-ILD和慢性纤维化进展之间的分子串扰(图1)。该项目建议在细胞和肺组织中详细研究这一点。同时，它将探索脱糖和小分子Galectin-3：碳水化合物结合抑制物对与炎症和纤维化相关的明确和新的输出的影响。

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.