Downregulation of the Notch Pathway in Human Airway Epithelium in Association with Smoking and COPD.
Division of Pulmonary and Critical Care Medicine, Weill Medical College of Cornell University, New York, New York, United States.
RATIONALE: The airway epithelium of smokers is subject to a variety of mechanisms of injury, with consequent modulation of epithelial regeneration and disordered differentiation. Several signaling pathways, including the Notch pathway, control epithelial differentiation in lung morphogenesis, but little is known about the role of these pathways in adults. OBJECTIVE: We tested the hypotheses that Notch-related genes are expressed in the normal nonsmoker adult human small airway epithelium, and that Notch-related gene expression is downregulated in healthy smokers and smokers with COPD. METHODS: We used microarray technology to evaluate expression of 55 Notch-related genes in the small airway epithelium of nonsmokers. We used TaqMan quantitative PCR to confirm expression of key genes and immunohistochemistry to assess for expression of Notch-related proteins in the airway epithelium. Changes in expression of Notch genes in healthy smokers and smokers with COPD compared to nonsmokers were evaluated by PCR. RESULTS: Microarray analysis demonstrated that 45 of 55 Notch-related genes are expressed in the adult small airway epithelium. TaqMan PCR confirmed expression of key genes with highest expression of the ligand DLL1, the receptor NOTCH2, and the downstream effector HES1. Immunohistochemistry demonstrated expression of Jag1, Notch2, Hes1 and Hes5 in airway epithelium. Several Notch ligands, receptors and downstream effector genes were downregulated in smokers, with more genes downregulated in smokers with COPD than healthy smokers. CONCLUSIONS: These observations are consistent with the hypothesis that the Notch pathway likely plays a role in the adult human airway epithelium, with downregulation of Notch pathway gene expression in association with smoking and COPD.
PMID: 19106307 [PubMed - as supplied by publisher]