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From INSERM Unité 314*
and Laboratoire
d'Immunologie,
CHU Maison Blanche, Reims,
and Département de Chirurgie
Cardio-Vasculaire,
Hôpital Broussais,
Paris, France
Accumulating evidence suggests that the early pulmonary
inflammation pathogenesis in cystic fibrosis (CF) may be associated
with an abnormal increase in the production of pro-inflammatory
cytokines in the CF lung, even in the absence of infectious
stimuli. We have postulated that if baseline abnormalities in airway
epithelial cell production of cytokines occur in CF, they
should be manifested in the CF bronchial submucosal glands,
which are known to express high levels of CFTR (cystic fibrosis
transmembrane conductance regulator) protein, the gene product
mutated in CF disease. Immunohistochemical analyses showed that CF
bronchial submucosal glands in patients homozygous for the 
F508
deletion expressed elevated levels of the endogenous chemokine
interleukin (IL)-8 but not the pro-inflammatory cytokines IL-1ß and
IL-6, compared with non-CF bronchial glands. Moreover,
basal protein and mRNA expression of IL-8 were constitutively
up-regulated in cultured F508 homozygous CF human bronchial gland
cells, in an unstimulated state, compared with non-CF
bronchial gland cells. Furthermore, the exposure of CF and
non-CF bronchial gland cells to an elevated extracellular
Cl- concentration markedly increased the release of
IL-8, which can be corrected in CF gland cells by reducing the
extracellular Cl- concentration. We also found
that, in contrast to non-CF gland cells, dexamethasone
did not inhibit the release of IL-8 by cultured CF gland cells. The
selective up-regulation of bronchial submucosal gland IL-8 could
represent a primary event that initiates early airway submucosal
inflammation in CF patients. These findings are relevant to the
pathogenesis of CF and suggest a novel pathophysiological concept for
the early and sustained airway inflammation in CF
patients.
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