Topi privi di CFTR infettati con Pseudomonas aeruginosa (Pa) sono stati trattati con RvD1 per misurare il numero di batteri vivi nei polmoni, il numero di globuli bianchi e il grado di lesione ai polmoni. Cellule epiteliali e macrofagi (un tipo di cellule di difesa) di volontari con FC sono stati trattati con RvD1 per stabilirne l’efficacia sulla risposta infiammatoria e antibatterica. I risultati indicano che nei modelli murini RvD1 riduce il numero di batteri, il grado di infiammazione e il danno polmonare. Inoltre, in cellule epiteliali primarie derivanti da volontari con FC, RvD1 stimola i macrofagi a eliminare i batteri e riduce le quantità di proteine (citochine e chemochine) implicate nell’infiammazione e nella risposta antibatterica. In sintesi, RvD1 stimola la risoluzione dell’infezione da Pa e dell’infiammazione sia su modelli animali sia su modelli cellulari FC. Le evidenze ottenute forniscono le conoscenze necessarie per l’eventuale sviluppo preclinico di RvD1 quale nuovo farmaco antinfiammatorio per la FC.
RvD1 significantly dampened bacterial burden in Cftr-/- mice chronically infected with a clinical strain of Pa. RvD1 also markedly dampened total leukocytes and PMN (polymorphonucleates) infiltration and ameliorated histological scores of lung pathology. In addition, RvD1 increased the percentage of phagocytosis of Pa by CF mouse and human CF macrophages along with a significant reduction in interleukin-8, -6, and -17. In primary CF airway epithelial cells (CFAEC) and macrophages (MΦ.) RvD1 regulated genes involved in inflammation and anti-microbial responses. These results indicate that RvD1 enhances the resolution of PA infection and inflammation in CF cellular and animal models, thus fostering further studies in preclinical models and clinical trials, as well as a spin-off for research applications in a relatively short time for exploring RvD1 as a novel therapeutic for CF.
– Pierdomenico AM, Patruno S, Codagnone M et al. “microRNA-181b is increased in cystic fibrosis cells and impairs lipoxin A4 receptor-dependent mechanisms of inflammation resolution and antimicrobial defense” SCI REP 2017 Oct 18;7(1):13519 11-mag-18
– Isopi E, Mattoscio D, Codagnone M et al “Resolution of chronic lung inflammation and infection in cystic fibrosis with resolvin D1” submitted
– Isopi E, Mattoscio D, Mari VC et al. “Harnessing resolution mediators as novel therapeutic for cystic fibrosis” North American Cystic Fibrosis Conference (NACF), October 18-20, 2018, Denver, CO, USA (Thematic poster view)
– Mattoscio D, Isopi E, Mari VC et al. “Resolvin D1 for targeting lung inflammation, infection, and damage in CF” North American Cystic Fibrosis Conference (NACF), October 18-20, 2018, Denver, CO, USA (Workshop presentation)
– Recchiuti A “Resolvins, lipoxins, and maresins in resolution of inflammation in cystic fibrosis “North American Cystic Fibrosis Conference (NACF), October 18-20, 2018, Denver, CO, USA (Invited Symposium lecture)
– Recchiuti A, Isopi E, Mattoscio D et al. “Harnessing resolution mediators as innovative therapeutics for cystic fibrosis” 2nd International Conference on Pharmacology, August 16-18, Rome, Italy
