New research from the University of North Carolina (UNC) School of Medicine suggests new targets for cystic fibrosis (CF) therapy and further supports the case for inflammation as an acquired response unrelated to the CFTR genetic mutation.

To conduct the research, scientists harvested alveolar macrophages from human CF lungs and healthy lungs that showed that CF alveolar macrophages display an increased basal inflammatory response when compared to healthy macrophages, according to a UNC School of Medicine news release.

The researchers observed that when stimulated with factors present in CF airways, both sets of macrophages responded; however, the inflammatory response of CF macrophages was larger. The inflammatory response was coupled to activation of XBP-1 in both sets of cells, but the activation was greater in CF macrophages. The research team then over-expressed the activated XBP-1 protein in normal macrophages and reproduced the hyper-inflammatory phenotype found in CF macrophages.

In contrast, decreasing the XBP-1 levels blunted the inflammatory response. The UNC School of Medicine news release notes that these findings led the researchers to surmise that the XBP-1 pathway was implicated in the hyper-inflammatory response of CF alveolar macrophages. As inhibition of CFTR function did not elicit a CF-like response in the macrophages harvested from healthy lungs, the research indicated that this particular immune response was not directly due to the CFTR mutation but was, instead, acquired, according to UNC.

Overall, the research team showed that CF alveolar macrophages are key contributors to the inflammation of CF airways and that the overabundance of the protein XBP-1 in these cells mediates their inflammatory effect.

Carla Ribeiro, PhD, associate professor of medicine, says, “By studying alveolar macrophages, which provide our airways with a crucial defense against pathogens, we are able to more fully understand the larger picture of CF symptoms and continue progress towards targeted treatment for patients.”

Ribeiro adds, “Our work has shown that the alveolar macrophage plays a key role in the pathogenesis of CF airway inflammation,” Ribeiro said. “And that activation of XBP-1 mediates the secretion of inflammatory factors by alveolar macrophages. This is all helping to make a stronger case for why this pathway may be an important target for therapy.” Ribeiro says the work may have implications in airway diseases beyond CF, including asthma and COPD.

Source: UNC School of Medicine