A longitudinal evaluation of localised chronic Pseudomonas aeruginosa infection in cystic fibrosis rat models.

Abstract

Recurrent bacterial infections with Pseudomonas aeruginosa result in chronic airway inflammation, lung damage and eventual respiratory failure, and are the major cause of morbidity and mortality in people with cystic fibrosis (CF). Animal models are essential for understanding disease progression and assessing potential treatments in the presence of infection. Previously reported P. aeruginosa lung infection rodent models for CF research have weaknesses that include being acute rather than chronic infections, high levels of associated mortality, use laboratory strains of P. aeruginosa, or do not utilise CF rodents. The aim of this study was to create a localised single-lung P. aeruginosa infection in wildtype and two CF rat models, by using a miniature bronchoscope to deliver bacteria embedded in agar beads generated from a clinical CF bacterial isolate. Cohorts of animals were assessed at days 7, 14, 21 and 63. The number of colony forming units were measured, along with bronchoalveolar lavage, flexiVent mechanics, X-ray Velocimetry (XV) ventilation analysis, and histopathology. The resulting infection was well tolerated by all animals of all genotypes with no mortality associated with the procedure or infection. The right-lung exhibited localised acute bronchopneumonia and lymphocytic vasculitis early, progressing to chronic interstitial pneumonia with fibrosis and emphysema. Bacteria persisted for 9 weeks (63 days) in all genotypes, with lung mechanics changes observed by day 63 of the infection. The precise delivery of bacterial laden beads using a miniature bronchoscope generated a controlled and reproducible infection that persisted for up to nine weeks, with minimal impact on animal health.