EXCESSIVE INFLAMMATORY RESPONSE OF CYSTIC-FIBROSIS MICE TO BRONCHOPULMONARY INFECTION WITH PSEUDOMONAS-AERUGINOSA

In cystic fibrosis (CF), defective function of the cystic fibrosis tra nsmembrane conductance regulator (CFTR) in airway epithelial cells and submucosal glands results in chronic pulmonary infection with Pseudom onas aeruginosa. The pulmonary infection incites an intense host infla mmatory response, causing progressive suppurative pulmonary disease, M ouse models of CF, however, fail to develop pulmonary disease spontane ously, We examined the effects of bronchopulmonary infection on mice h omozygous for the S489X mutation of the CFTR gene using an animal mode l of chronic Pseudomonas endobronchial infection, Slurries of sterile agarose beads or beads containing a clinical isolate of mucoid P. aeru ginosa were instilled in the right lung of normal or CF mice, The mort ality of CF mice inoculated with Pseudomonas-laden beads was significa ntly higher than that of normal animals: 82% of infected CF mice, but only 23% of normal mice, died within 10 d of infection (P = 0.023), Th e concentration of inflammatory mediators, including TNF-alpha, murine macrophage inflammatory protein-2, and KC/N51, in bronchoalveolar lav age fluid in CF mice 3 d after infection and before any mortality, was markedly elevated compared with normal mice, This inflammatory respon se also correlated with weight loss observed in both CF and normal lit termates after inoculation, Thus, this model may permit, examination o f the relationship of bacterial infections, inflammation, and the cell ular and genetic defects in CF.