TRANSCRIPTIONAL ACTIVATION OF MUCIN BY PSEUDOMONAS-AERUGINOSA LIPOPOLYSACCHARIDE IN THE PATHOGENESIS OF CYSTIC-FIBROSIS LUNG-DISEASE

An unresolved question in cystic fibrosis (CF) research is how mutatio ns of the CF transmembrane conductance regulator, a Cl ion channel, ca use airway mucus obstruction leading to fatal lung disease, Recent evi dence has linked the CF transmembrane conductance regulator mutation t o the onset and persistence of Pseudomonas aeruginosa infection in the airways, and here we provide evidence directly linking P. aeruginosa infection to mucus overproduction. We show that P. aeruginosa lipopoly saccharide profoundly upregulates transcription of the mucin gene MUC 2 in epithelial cells via inducible enhancer elements and that this ef fect is blocked by the tyrosine kinase inhibitors genistein and tyrpho stin AG 126. These findings improve our understanding of CF pathogenes is and suggest that the attenuation of mucin production by lipopolysac charide antagonists and tyrosine kinase inhibitors could reduce morbid ity and mortality in this disease.