Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa.
In cystic fibrosis (CF), defective function of the cystic fibrosis transmembrane conductance regulator (CFTR) in airway epithelial cells and submucosal glands results in chronic pulmonary infection with Pseudomonas aeruginosa. The pulmonary infection incites an intense host inflammatory response, causing progressive suppurative pulmonary disease. Mouse models of CF, however, fail to develop pulmonary disease spontaneously. We examined the effects of bronchopulmonary infection on mice homozygous for the S489X mutation of the CFTR gene using an animal model of chronic Pseudomonas endobronchial infection. Slurries of sterile agarose beads or beads containing a clinical isolate of mucoid P. aeruginosa were instilled in the right lung of normal or CF mice. The mortality of CF mice inoculated with Pseudomonas-laden beads was significantly 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). The concentration of inflammatory mediators, including TNF-alpha, murine macrophage inflammatory protein-2, and KC/N51, in bronchoalveolar lavage fluid in CF mice 3 d after infection and before any mortality, was markedly elevated compared with normal mice. This inflammatory response also correlated with weight loss observed in both CF and normal littermates after inoculation. Thus, this model may permit examination of the relationship of bacterial infections, inflammation, and the cellular and genetic defects in CF.
Heeckeren
A
A
Department of Pediatrics at Rainbow Babies and Childrens Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-6006, USA.
Walenga
R
R
Konstan
M W
MW
Bonfield
T
T
Davis
P B
PB
Ferkol
T
T
D000818:Animals; D018893:Bronchoalveolar Lavage; D003550:Cystic Fibrosis / Q000150:complications* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018410:Pneumonia, Bacterial / Q000150:complications / Q000382:microbiology / Q000473:pathology*; D011552:Pseudomonas Infections / Q000150:complications / Q000473:pathology*
D018836:Inflammation Mediators