PDE4 Inhibitor Apremilast Rebalances Inflammatory Responses to Pseudomonas aeruginosa Infection in CF Rats

Abstract

CFTR modulator therapies have transformed CF care, yet chronic airway inflammation persists in many people with cystic fibrosis (pwCF) even after long-term highly effective modulator therapy (HEMT). Because of the adverse side effects or the incompatibility with CFTR modulators, the use of traditional anti-inflammatory therapies is very limited in CF. Hence, new therapeutic strategies that rebalance inflammation without worsening infection with immunosuppression are needed. We evaluated the selective phosphodiesterase 4 (PDE4) inhibitor apremilast (Apr) for its ability to modulate dysregulated inflammation in humanized CF (G551D) rats acutely challenged with Pseudomonas aeruginosa. Apr is an approved anti-inflammatory therapeutic strategy for several chronic inflammatory conditions, but it has not been well studied in CF. In the humanized CF (G551D) rats, a short prophylactic Apr regimen significantly preserved lung function and reduced lung injury, accompanied by broad modulation of inflammatory responses, notably within Th1 and Th17 axes. Importantly, Apr did not cause a significant increase in bacterial burden. Just as importantly, Apr did not reduce CFTR mRNA or protein in vivo, and it increased G551D-CFTR phosphorylation critical for channel gating in vitro, supporting mechanistic compatibility with HEMT. These findings suggest Apr as a potential adjunct to CFTR modulators to rebalance airway inflammation while preserving host defense.