Evaluating the effects of ivacaftor exposure on small colony variant development and antibiotic tolerance.

Background: Ivacaftor exhibits anti-staphylococcal properties but does not clear from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence.

Methods: Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days.

Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats.

Background: Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.

Normalization of Muc5b ameliorates airway mucus plugging during persistent infection in the CFTR rat.

In cystic fibrosis, the airway gel-forming mucin MUC5B accumulates in the airways, preventing clearance of pathogens like (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.

Acute Infection with a Tobramycin-Induced Small Colony Variant of Staphylococcus aureus Causes Increased Inflammation in the Cystic Fibrosis Rat Lung.

Cystic fibrosis (CF) disease is characterized by lifelong infections with pathogens such as Staphylococcus aureus, leading to eventual respiratory failure. Small colony variants (SCVs) of S. aureus have been linked to worse clinical outcomes for people with CF.

Muc5b Contributes to Mucus Abnormality in Rat Models of Cystic Fibrosis.

Cystic fibrosis (CF) airway disease is characterized by excessive and accumulative mucus in the airways. Mucociliary clearance becomes defective as mucus secretions become hyperconcentrated and viscosity increases. The CFTR-knockout (KO) rat has been previously shown to progressively develop delayed mucociliary transport, secondary to increased viscoelasticity of airway secretions.

Static mucus impairs bacterial clearance and allows chronic infection with in the cystic fibrosis rat.

Cystic fibrosis (CF) airway disease is characterised by chronic infection. Successful eradication strategies have been hampered by a poor understanding of the mechanisms underlying conversion to chronicity. The CFTR-knockout (KO) rat harbors a progressive defect in mucociliary transport and viscosity.

Ivacaftor partially corrects airway inflammation in a humanized G551D rat.

Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when cystic fibrosis transmembrane conductance regulator (CFTR) activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy.

Ivacaftor Reverses Airway Mucus Abnormalities in a Rat Model Harboring a Humanized G551D-CFTR.

Animal models have been highly informative for understanding the characteristics, onset, and progression of cystic fibrosis (CF) lung disease. In particular, the CFTR rat has revealed insights into the airway mucus defect characteristic of CF but does not replicate a human-relevant CFTR (cystic fibrosis transmembrane conductance regulator) variant. We hypothesized that a rat expressing a humanized version of CFTR and harboring the ivacaftor-sensitive variant G551D could be used to test the impact of CFTR modulators on pathophysiologic development and correction.

Development of an airway mucus defect in the cystic fibrosis rat.

The mechanisms underlying the development and natural progression of the airway mucus defect in cystic fibrosis (CF) remain largely unclear. New animal models of CF, coupled with imaging using micro-optical coherence tomography, can lead to insights regarding these questions. The Cftr-/- (KO) rat allows for longitudinal examination of the development and progression of airway mucus abnormalities.