SELECTIVE UP-REGULATION OF CHEMOKINE IL-8 EXPRESSION IN CYSTIC-FIBROSIS BRONCHIAL GLAND-CELLS IN-VIVO AND IN-VITRO

Accumulating evidence suggests that the early pulmonary inflammation p athogenesis in cystic fibrosis (CF) may be associated with an abnormal increase in the production of pro-inflammatory cytokines in the CF lu ng, even in the absence of infectious stimuli. We have postulated that if baseline abnormalities in airway epithelial cell production of cyt okines occur in CF, they should be manifested in the CF bronchial subm ucosal glands, which are known to express high levels of CFTR (cystic fibrosis transmembrane conductance regulator) protein, the gene produc t mutated in CF disease. Immunohistochemical analyses showed that CF b ronchial submucosal glands in patients homozygous for the Delta F508 d eletion expressed elevated levels of the endogenous chemokine interleu kin (IL)-8 but not the pro-inflammatory cytokines IL-1 beta and IL-6, compared with non-CF bronchial glands, Moreover, basal protein and mRN A expression of IL-8 were constitutively up-regulated in cultured Delt a F508 homozygous CF human bronchial gland cells, in an unstimulated s tate, compared with non-CF bronchial gland cells. Furthermore, the exp osure of CF and non-CF bronchial gland cells to an elevated extracellu lar Cl- concentration markedly increased the release of IL-8, which ca n be corrected in CF gland cells by reducing the extracellular Cl- con centration. We also found that, in contrast to non-CF gland cells, dex amethasone did not inhibit the release of IL-8 by cultured CF gland ce lls. The selective up-regulation of bronchial submucosal gland IL-8 co uld represent a primary event that initiates early airway submucosal i nflammation in CF patients. These findings are relevant to the pathoge nesis of CF and suggest a novel pathophysiological concept for the ear ly and sustained airway inflammation in CF patients.