Acute Pseudomonas challenge in cystic fibrosis mice causes prolonged nuclear factor-kappa B activation, cytokine secretion, and persistent lung inflammation.
BACKGROUND
Cystic fibrosis (CF) is characterized by an excessive and prolonged inflammatory response to Pseudomonas aeruginosa in the lung. There are high levels of cytokines and chemokines and an exaggerated PMN influx causing significant morbidity and mortality.


OBJECTIVE
To compare the kinetics of the inflammatory response with the kinetics of clearance of acute bacterial challenge in the lungs of CF and wild-type (WT) mice.


METHODS
We challenged CF knockout (KO) and WT mice intratracheally with P aeruginosa in suspension and evaluated bacteria counts, nuclear factor-kappaB (NF-kappaB), and inhibitor of NF-kappaB alpha protein (I-kappaBalpha) in lung tissue, cytokines, and PMN in bronchoalveolar lavage (BAL).


RESULTS
Both groups of mice cleared the infection with the same kinetics. CF-KO mice had more PMN in BAL than WT mice. CF-KO mice had high concentrations of proinflammatory cytokines in BAL on days 2 and 4, whereas cytokines in BAL from WT mice were only slightly elevated. CF-KO mice failed to regenerate I-kappaBalpha once it was degraded, and consequently had prolonged and excessive activation of NF-kappaB for the entire 6-day duration of the study. In contrast, WT mice showed only slight NF-kappaB activation, which plateaued at day 4.


CONCLUSIONS
These data suggest that NF-kappaB is dysregulated in CF lung infection and could be a good target for therapy. Prolonged responses to initial acute infections may contribute to the eventual establishment of chronic persistent inflammation.


CONCLUSIONS
Dysregulation of the I-kappaB/NF-kappaB pathway in cystic fibrosis leads to prolonged cytokine secretion and persistent inflammation in response to acute challenges and may be important in the development of chronic lung inflammation and infection.
Saadane
Aicha
A
Department of Pediatrics, Rainbow Babies and Childrens' Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Soltys
Jindrich
J
Berger
Melvin
M