Mucociliary clearance in cystic fibrosis knockout mice infected with Pseudomonas aeruginosa

Abstract

In this study, we examined whether mucociliary clearance differed between cystic fibrosis (CF) knockout mice and wildtype controls. Additionally, we investigated whether infection with Pseudomonas aeruginosa, a common pathogen in the CF lung, affected this important host defence mechanism.Ciliary beat frequency (fcb) and particle transport (PT) were recorded using an in vitro lung explant preparation. Measurements were made from uninfected cystic fibrosis transmembrane conductance regulator (CFTR) knockout (-/-) mice and littermate controls (+/+) and compared to measurements from infected animals.While there were no differences detectable in fcb between CFTR -/-mice and their +/+ controls either in the presence or absence of P. aeruginosa, PT rates were different between these groups; interestingly, PT rates appeared dependent on both CFTR and infection status, with uninfected CFTR +/+ animals demonstrating higher rates of PT than their -/-littermates, while CFTR +/+ P. aeruginosa-infected mice demonstrated lower PT than knockout mice.These data demonstrate differences in mucociliary clearance between cystic fibrosis transmembrane conductance regulator knockout mice and controls, and further that Pseudomonas aeruginosa infection affects mucociliary clearance in the peripheral airways of mice. Additionally, the observed differences in particle transport suggest that cystic fibrosis transmembrane conductance regulator knockout mice demonstrate different mucociliary responses to infection.

Mucociliary transport determined by in vivo microdialysis in the airways of normal and CF mice

“…This finding was not surprising, since we have been unable to detect an altered bioelectric phenotype in the trachea of the cftr tm1UNC CF mouse (14). However, in an in vitro study in which the University of North Carolina CF mouse was bred on a C57BL/6 background, the investigators reported a significant decrease in the rate of MCT (particle transport) in CF mice (5). In another study of CF mice (cftr m1HGU ), the investigators reported a significant decrease in the rate of MCT (39), although the rates of MCT in both normal and CF preparations were very low (see Table 1).…”

“…There are published studies on measurement of lower airway MCT in the mouse by particle transport (3,5,19,39) and isotopic clearance (8). Values from these studies vary widely, and there is no method available for in vivo measurement of MCT in the nasal cavity of the mouse.…”

Animal models of cystic fibrosis

“…Although this may be largely true, a variety of interesting observations have subsequently been made in the apparent absence of infection. These include excessive inflammation observed by histology in Cftr tm1Hgu mice [41], abnormal MCC in the Cftr tm1Hgu and Cftr tm1Unc mice [41,42], an increase in goblet cells, with decreased volume of airway surface liquid in the nasal epithelium of Cftr tm1Unc mice [43], a more distal extension of submucosal glands in Cftr tm1Hgu and Cftr tm1G551D mice [44], hypersensitivity of bone marrow-derived macrophages from Cftr tm1G551D mice to bacterial lipopolysaccharide (LPS) [45], and abnormalities in intracellular nitric oxide syntethase (iNOS) expression in Cftr tm1Unc and Cftr tm1Kth mice [46,47].…”

Comparative Biology of Cystic Fibrosis Animal Models

“…Furthermore, most of these CF mouse models retain defects in cAMP-inducible chloride permeability in the nasal epithelium as seen in humans. Though not extensively studied in each model, reports have suggested decreased mucociliary clearance (22–24), reduced fertility (25, 26), mild pancreatic dysfunction (27–29), and liver abnormalities (28). However, these models thus far lack the development of significant spontaneous lung disease as observed in humans with CF.…”