No abstract

These results demonstrate that apigenin and apigenin-rich diets exert effective anti-inflammatory activity in vivo by reducing LPS-induced expression of miR-155, thereby restoring immune balance.

No abstract

Multiciliated cell loss is a hallmark of airway epithelial remodeling in chronic inflammatory airway diseases including cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease. It disrupts mucociliary clearance, which fuels disease progression. Effective clearance requires an optimal proportion of multiciliated and secretory cells. This is controlled by Notch signaling such that between two adjacent cells the one that activates Notch becomes a secretory cell and the one that avoids Notch activation becomes a multiciliated cell. Consequently, blocking Notch by a small molecule inhibitor of the gamma-secretase enzyme that cleaves the Notch receptor for signal activation directs differentiation towards the multiciliated lineage. Thus, gamma-secretase inhibitor (GSI) treatment may alleviate multiciliated cell loss in lung disease. Here we demonstrate therapeutic restoration of multiciliated cells by the GSI LY450139 (semagacestat). LY450139 increased multiciliated cell numbers in a dose-dependent manner in healthy primary human nasal epithelial cells (HNECs) during differentiation and in mature cultures, but not when applied during early epithelialization of progenitors. LY450139 did not impact stem cell proliferation. Basal and apical administration were equally effective. In healthy adult mice, LY450139 increased multiciliated cell numbers without detectible toxicity. LY450139 also increased multiciliated cells and decreased excess mucus secretory cells in CF HNECs and IL-13 remodeled healthy HNECs. LY450139 normalized multiciliated cell numbers in CF HNECs without interfering with the activity of CFTR modulator compounds. In sum, we demonstrate that GSI administration is a promising therapeutic to restore multiciliated cells and potentially improve epithelial function in a wide range of chronic lung diseases.

Basal airway epithelial cells are a multipotent stem cell population which gives rise to several airway cell types. Basal cells are known to be critical to airway epithelium homeostasis and repair, and altered basal cell phenotypes have been reported in cystic fibrosis and idiopathic pulmonary fibrosis. However, very little is known about how basal cells respond to stimuli in the cystic fibrosis airway environment. Cystic fibrosis patients experience chronic infection with Pseudomonas aeruginosa and contain both high quantities of lipopolysaccharide (LPS) as well as the filamentous bacteriophage Pf produced by biofilm-state P. aeruginosa in the airway. In this study, we sought to investigate the transcriptional responses of human basal cells from both healthy controls and patients with cystic fibrosis to LPS and Pf phage. Basal cells from wildtype and cystic fibrosis donors were cultured in vitro and exposed to LPS and/or Pf phage, followed by single-cell sequencing on the 10x platform. We report that basal cells show strong antiviral responses and neutrophil chemokine production in response to Pf phage. We validate these findings in additional donors by qRT-PCR and show that Pf phage is internalized by basal cells. We also show that Pf decreases basal cell migration and proliferation. We demonstrate that Pf phage, a bacteria-infecting virus which does not replicate in mammalian cells, is taken up by basal cells and activates immune responses. Further studies are needed to determine the impact of this antiviral response to bacterial clearance.