Background: Cystic fibrosis (CF) airways are characterized by both bacterial and immune protease activation, which contributes to subse- quent airway remodeling, ultimately leading to bronchiectasis. Pseudo- monas aeruginosa (P. aeruginosa) is a major pathogen in CF and releases virulence factors, including metalloproteases (MPs), whose synthesis is inhibited by the macrolide azithromycin (AZM). Methods: Metalloprotease activity was measured by zymography assay of bacterial culture supernatant (BCS) from P. aeruginosa clinical strains whose pro-inflammatory activity was evaluated in an in vivo murine model of lung inflammation. Results: 87% of MP-releasing P. aeruginosa strains derived from patients classified as “intermittently infected” (n=45) responded to AZM by decreasing MPs activity. This happened in only 50% of the carriers of a “chronic infection” (n=24). Growth in the presence of AZM or incubation of BCS with the protease inhibitor GM6001 (galardin, ilomastat) strongly inhibits the pro-inflammatory response in mice. Knocking out AprA decreases pro- inflammatory activity of bacterial BCS while addition of purified AprA synergizes with P. aeruginosa LPS by increasing leukocyte recruitment. Bacterial MPs are detectable in sputa from P. aeruginosa-colonized CF patients and lung function of chronically colonized patients whose P. aeruginosa strains did not respond to AZM in terms of reduction of MP activity had a median value of FEV1% 17% lower than those carrying AZM-responsive P. aeruginosa strains (P=0.04). Conclusion: MPs play a critical role in the clinical manifestations of P. aeruginosa infection and their strain-specific modulation by AZM con- tributes to explain the variable response of CF patients to this treatment. Supported by: The Italian Cystic Fibrosis Research Foundation (FFC #17/2006, FFC #15/2008, FFC #07/2012), Lega Italiana Fibrosi Cistica- Associazione Veneta Lotta contro la Fibrosi Cistica Onlus and American Cystic Fibrosis Foundation (CFF).
|Titolo:||Poster Session Abstracts|
|Data di pubblicazione:||2016|
|Appare nelle tipologie:||04.03 Poster|