CF Lung Inflammation in Mice Treated with a DNA-Modifying Therapy

Suppressing a specific type of immune cell called Th17 may aid cystic fibrosis (CF) patients with Pseudomonas aeruginosa infection, one of the most common infections in CF, as suggested by findings of a recent study in mice.

The study, “Antiinflammatory effects of bromodomain and extraterminal domain inhibition in cystic fibrosis lung inflammation,” was developed by researchers at the Children’s Hospital of Pittsburgh and published in the journal JCI Insight.

Patients with CF often suffer from chronic respiratory infections, most commonly due to P. aeruginosa bacteria, inflaming airways and increasing morbidity.

Although clearing airways of the bacteria is a major focus of CF care, this work is largely impaired by antimicrobial resistance and the formation of bacteria-derived barriers that affect drug uptake. Other treatment strategies need to be considered.

Th17 cells are a type of CD4 T-cells and the major producers of the interleukin 17 (IL-17), a protein that controls immune responses. While Th17-mediated inflammation is essential to fight pathogens such as K. pneumoniae and C. albicans, the researchers previously found that IL-17 is involved in the exacerbation of P. aeruginosa infection in mice models.

They hypothesized that Th17 inflammatory responses could be targeted to attenuate chronic lung inflammation in CF patients.

In the new study, Jay Kolls and colleagues at the University of Pittsburgh used a class of drugs, called bromodomain and extraterminal domain (BET) inhibitors, that modify the DNA architecture and change gene expression.

Using immune cells isolated from the lungs of CF patients, the researchers found that BET inhibitors suppressed the response of Th17 cells, as well as the release of inflammatory factors by these cells.

In addition, when a P. aeruginosa lung infection mouse model was used, BET inhibition decreased lung inflammation, suggesting that BET inhibition may be a potential novel candidate for CF treatment.

Researchers warn, however, that BET inhibitors can increase the risk of opportunistic infections, and also influence a variety of physiological processes, which may lead to severe side effects. Choosing highly specific inhibitors is crucial to taking these drugs into clinical trials.