Transcriptional Activation of Mucin by Pseudomonas aeruginosa Lipopolysaccharide in the Pathogenesis of Cystic Fibrosis Lung Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 3; pp. 967 - 972
• Main Authors: Li, Jian-Dong, Dohrman, Austin F., Gallup, Marianne, Miyata, Susumu, Gum, James R., Kim, Young S., Nadel, Jay A., Prince, Alice, Basbaum, Carol B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 04-02-1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Benzylidene Compounds - pharmacology; Biological Sciences; Bronchi - metabolism; Cell Line; Cell lines; Cultured cells; Cystic fibrosis; Cystic Fibrosis - metabolism; Cystic Fibrosis - microbiology; Cystic Fibrosis Transmembrane Conductance Regulator - physiology; Enzyme Inhibitors - pharmacology; Epithelial cells; Epithelium; Humans; Infections; Lipids; Lipopolysaccharides - pharmacology; Lungs; Medical research; Messenger RNA; Molecular Sequence Data; Mucin-2; Mucins; Mucins - genetics; Mucus; Nitriles - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Pseudomonas aeruginosa; Pseudomonas aeruginosa - chemistry; Pseudomonas aeruginosa - metabolism; Respiratory diseases; RNA, Messenger - analysis; Transcriptional Activation - drug effects; Tyrphostins; Up regulation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.3.967

An unresolved question in cystic fibrosis (CF) research is how mutations of the CF transmembrane conductance regulator, a CI ion channel, cause airway mucus obstruction leading to fatal lung disease. Recent evidence has linked the CF transmembrane conductance regulator mutation to 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 lipopolysaccharide profoundly upregulates transcription of the mucin gene MUC 2 in epithelial cells via inducible enhancer elements and that this effect is blocked by the tyrosine kinase inhibitors genistein and tyrphostin AG 126. These findings improve our understanding of CF pathogenesis and suggest that the attenuation of mucin production by lipopolysaccharide antagonists and tyrosine kinase inhibitors could reduce morbidity and mortality in this disease.