Normalization of Muc5b ameliorates airway mucus plugging during persistent Pseudomonas aeruginosa infection in the CFTR-/- rat

In cystic fibrosis, the airway gel-forming mucin MUC5B accumulates in the airways, preventing clearance of pathogens like Pseudomonas aeruginosa (PA). The cystic fibrosis transmembrane conductance regulator (CFTR)-/- (KO) rat model exhibits a similar accumulation of Muc5b. Our lab has shown that increased Muc5b precipitates the development of chronic PA infection. We hypothesized that reducing Muc5b in the KO rat airway would prevent occlusive mucus plugs and development of persistent PA infection. Six-month-old KO rats received Muc5b or scramble siRNA via intratracheal instillation. Rats were then inoculated with 106 colony-forming units of mucoid P. aeruginosa isolate PAM57-15 and euthanized at 3- or 14-days post infection (dpi) to assess acute and persistent infection. At 14 dpi, Muc5b siRNA-treated KO rats had increased weight, decreased neutrophilic inflammation, and reduced mucus plugging in the small airways compared with scramble-treated KO and WT rats. These results indicate that pharmacological intervention of Muc5b reduces mucus plugging during persistent PA infection.