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Modelling lung repair in health and disease

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Understanding lung injury and repair

Acute and chronic lung injury is a major cause of morbidity and mortality worldwide. Understanding and modelling the mechanisms of lung tissue repair are needed to find ways to replace damaged alveolar epithelium.

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During physiological repair of the damaged alveolar epithelium, there is differentiation from alveolar type II into alveolar type I. On the contrary, in pathological repair mechanisms, lung cells undergo epithelial-mesenchymal transition (EMT), associated with scar formation after epithelial injury. This contributes to lung fibrosis in both acute and chronic alveolar diseases. Wnt11, a signalling protein, promotes alveolar type II-like differentiation while preventing EMT in human small airway epithelium. It may also have an important role in lung tissue regeneration. The EU-funded project 'Modelling lung repair in health and disease' (LUNG REPAIR MODEL) investigated the role of Wnt11 in the differentiation of lung cells. Scientists studied human alveolar epithelial cells and human lung stem cells. They used a tissue-engineered 3D lung microtissue model mimicking epithelial-mesenchymal interactions in human lung tissue. The project characterised Wnt11 effects in the lung and showed that Wnt11 interferes with TGF-beta1 signalling. TGF-beta1 is an important growth factor in the pathogenesis of several chronic respiratory diseases. Wnt11 antagonises several effects of TGF-beta1 on both alveolar epithelial cells and pulmonary fibroblasts by interfering with the SMAD pathway. Antagonising TGF-beta1 has a high therapeutic potential. Experiments with the 3D lung microtissue characterised the model system as viable for the in vitro studies of human cells. To understand the differentiation of alveolar type II into alveolar type I cells, the project used a microarray approach. The experiments revealed the changes in the expression of Wnt pathway-associated genes. Microarray and quantitative polymerase chain reaction data showed the important role of Wnt4 and Wnt7a ligands in transdifferentiation, and involvement of Fzd2 receptor in alveolar injury repair. Project results may have important therapeutic implications in the future.

Keywords

Lung injury, alveolar epithelium, tissue regeneration, lung repair, Wnt11, TGF-beta1

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