Overactivation of a protein called mucin 1 (MUC1) triggers pro-fibrotic transformations in the lungs that could contribute to the development and progression of idiopathic pulmonary fibrosis (IPF), an early study using patient cells and mice has found.
The research furthers knowledge about the roles played by MUC1-induced pathways, which could be used to develop new treatments for IPF, researchers said.
The study “MUC1 intracellular bioactivation mediates lung fibrosis” was published in the journal Thorax.
An increasing number of studies have identified potential protein-based and cell-based prognostic markers of IPF. Elevated blood levels of several proteins — including the protein MUC1 — have been associated with poorer disease outcomes.
MUC1 falls into a group of proteins that make up the mucus of the airways and other organs. It also can work as a signaling factor at the cell’s membrane, sensing clues from the surrounding environment and communicating these clues to the cell.
When tissues are injured, a part of MUC1 protein is cut off and shed from cells. This part is found increased in the serum, the bronchoalveolar lavage fluid (BALF), and lung tissue of patients, and has been linked with worse IPF progression and disease severity.
Another piece of MUC1, known as cytoplasmic tail, or MUC1-CT, remains inside the cells, attached to the membrane. This is the part of the protein responsible for conveying different types of signals from the neighboring environment. In fact, several fibrosis-inducing signals can be transmitted this way.
However, how MUC1-CT potentially plays a role in the mechanisms underlying IPF remains unknown.
A team of investigators addressed that question in this study. Using lung tissue obtained from IPF patients and mouse models, they found that MUC1 is overactivated in the lungs of patients, perturbing the function of alveolar type II epithelial cells and fibroblasts — two cell types considered key for developing IPF.
Transforming growth factor-beta 1 (TGF-β1) — a main pro-fibrotic signaling molecule — seemed to be the trigger behind excess activation of MUC1-CT in the lungs.
GF-β1 sets out a gene activation program that drives the transformation of alveolar epithelial type II and fibroblasts to myofibroblasts, a type of cell involved in scarring, whose accumulation is a hallmark of IPF.
Such TGF-β1-triggered activation program also leads to cell senescence (an irreversible stoppage in cell growth), and the proliferation of fibroblasts — two processes believed to be central for triggering lung fibrosis.
Interestingly, the inhibition or silencing of MUC1-CT activity reduced the transition to myofibroblasts, cell senescence, and the proliferation of fibroblasts in vitro (in the lab) conditions, and also reduced lung fibrosis in animal models.
By a separate mechanism, another pro-fibrotic molecule, a sugar called galectin-3, also was found to activate MUC1-CT, suggesting that the activation of MUC1-CT can be done both by a TGF-β1-dependent and TGF-β1-independent pathways.
Overall, the results indicated that activation of MUC1-CT is likely to play a role in the development of IPF, and point to potential new targets to treat the disease, the researchers noted.
“MUC1 intracellular bioactivation is enhanced in IPF, and promotes fibrotic processes that could represent potential druggable targets for IPF,” the team concluded.
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