High Levels of DMBT1 Protein in Lungs May Mark CF Progression

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by Patricia Inacio PhD |

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Elevated levels of DMBT1 in the lungs, a protein previously linked with inflammatory processes, may be a biomarker of progression in cystic fibrosis (CF) patients, a study suggests.

High DMBT1 levels impaired the movement of cilia, the finger-like projections that help to clear mucus from the airways, its scientists noted, adding that their findings support DMBT1 as a potential treatment target for CF.

The study, “DMBT1 is upregulated in cystic fibrosis, affects ciliary motility, and is reduced by acetylcysteine,” was published in the journal Molecular and Cellular Pediatrics.

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Inflammation and poorer lung function are common in CF, a disease marked by the production of unusually thick mucus and salty sweat due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

DMBT1 is a protein found in several lung cells, including alveolar type II cells that play key roles in lung function, including the regeneration of the epithelium — which lines the respiratory tract — following injury.

In healthy lungs, DMBT1 is found at low to moderate levels that rise during inflammation and with bacterial and viral infections. Besides its role in inflammation, DMBT1 promotes blood vessel formation and epithelial cell maturation, highlighting its role in tissue repair.

To further understand DMBT1, researchers in Germany examined post-mortem lung tissue from a 20-year-old man with CF and tissues from of 13 CF patients who underwent a lung transplant.

Compared to samples from people without lung disease, those from CF patients had markedly higher levels of the DMBT1 protein. Their alveoli (tiny air sacs) were filled with mucus and immune cells — specifically macrophages — were positive for DMBT1.

“Results obtained from human and mouse lung tissue showed that DMBT1 expression was upregulated in CF which goes in line with the known functions of DMBT1 during inflammation,” the researchers wrote, adding that “upregulation of DMBT1 in CF is observed in the respiratory and gastrointestinal tract, both organs with … multiple contacts to different bacteria, viruses, and pathogens.”

Researchers then measured levels of the messenger RNA (mRNA) molecule for DMBT1 in a mouse model of CF-like disease. Of note, mRNA is the molecule generated from DNA that is used as the template for protein production.

Levels of the DMBT1 mRNA were found to be six times higher in the lungs of CF mice compared to normal (wild-type) mice. Several of DMBT1’s binding partners were also increased in the CF mice.

A549 cells, a human lung epithelial cell line with features of alveolar type II cells, were then engineered to express DMBT1 at higher levels (DMBT1-positive cells) and lower levels (DMBT1-negative cells). This was done to assess acetylcysteine (ACC), a modified amino acid previously shown to lower the levels other inflammatory markers in the airways. (Amino acids are the building blocks of proteins.)

Adding ACC to the lab dish culture of DMBT1-positive and -negative cells resulted in a significant reduction in DMBT1 levels in their culture. This drop was sustained at least for 24 hours after removing ACC from the cell culture, an effect that was more pronounced in DMBT1-positive cells.

“ACC might be a therapeutic option to dampen elevated respiratory DMBT1 levels in CF patients,” the study noted, adding that an inhalation therapy bringing the treatment “directly into the airways” would be most effective.

An analysis of cells expressing a lab-made human DMBT1 also showed that DMBT1 significantly altered the movement of cilia, affecting mucus clearance in the airways.

High “DMBT1 levels in patients with CF may impede the ciliary function and thus mucus removal,” the researchers wrote.

These findings suggest that DMBT1 “may be used as a potential biomarker to diagnose and monitor CF lung disease,” they added.

“Treatment of human lung epithelial cells with ACC leads to reduced DMBT1 concentrations, thus providing a new molecular mechanism of ACC function in CF,” they concluded.