Early pulmonary disease manifestations in cystic fibrosis mice

Abstract

Background Altered pulmonary function is present early in the course of cystic fibrosis (CF), independent of documented infections or onset of pulmonary symptoms. New initiatives in clinical care are focusing on detection and characterization of pre-clinical disease. Thus, animal models are needed which recapitulate the pulmonary phenotype characteristic of early stage CF. Methods We investigated young CF mice to determine if they exhibit pulmonary pathophysiology consistent with the early CF lung phenotype. Lung histology and pulmonary mechanics were examined in 12–16 week old congenic C57bl/6 F508del and R117H CF mice using a forced oscillation technique (flexiVent). Results There were no significant differences in the resistance of the large airways. However, in both CF mouse models, prominent differences in the mechanical properties of the peripheral lung compartment were identified including decreased static lung compliance, increased elastance and increased tissue damping. CF mice also had distal airspace enlargement with significantly increased mean linear intercept distances. Conclusions An impaired ability to stretch and expand the peripheral lung compartment, as well as increased distances between gas exchange surfaces, were present in young CF mice carrying two independent Cftr mutations. This altered pulmonary histopathophysiology in the peripheral lung compartment, which develops in the absence of infection, is similar to the early lung phenotype of CF patients.

Roadmap for an early gene therapy for cystic fibrosis airway disease

“…Pulmonary function tests inform on vital capacity, resistance, and compliance of the respiratory system. Forced expiratory volumes (FEV) can be obtained in animals, but is not yet routinely used . The human equivalent of this, FEV in 1 second (FEV 1 ), is the primary end‐point in most clinical trials.…”

Weighted gene co-expression network analysis in identification of metastasis-related genes of lung squamous cell carcinoma based on the Cancer Genome Atlas database

“…CF affects not only the physiological function of lungs, but also the pancreas, liver and intestines (22,28). In our study, CFTR was the hub protein in the PPI network, had the highest connectivity with 182 genes (Figure 2).…”

“…Several articles demonstrate that abnormal CFTR expression is related to the tumorigenesis and development of NSCLC. Low CFTR expression is significantly associated with advanced stage, lymph node metastasis and poor prognosis in NSCLC patients (22). The in vivo and in vitro experiments present knockdown of CFTR promotes epithelial-mesenchymal transition, invasion and migration of NSCLC cells; conversely, overexpression of CFTR suppresses cancer progression of NSCLC (22).…”

“…Low CFTR expression is significantly associated with advanced stage, lymph node metastasis and poor prognosis in NSCLC patients (22). The in vivo and in vitro experiments present knockdown of CFTR promotes epithelial-mesenchymal transition, invasion and migration of NSCLC cells; conversely, overexpression of CFTR suppresses cancer progression of NSCLC (22). Methylation of the CFTR gene is significantly greater in lung SCC than in lung adenocarcinomas and CFTR gene methylation is associated with significantly poorer survival in young patients, but not in elderly patients (30).…”

Cystic Fibrosis Mice Develop Spontaneous Chronic Bordetella Airway Infections

“…Our previous work describes an increased respiratory rate and alterations in pulmonary mechanics in uninfected CF mice, indicating the presence of a pulmonary phenotype that is not solely a consequence of infection [7,8]. However, in the course of those studies, spontaneous Bordetella respiratory tract infections in our CF mouse models were discovered by routine surveillance.…”