CVRI Scientists

Jay A. Nadel, M.D.
Professor of Medicine and Physiology

Research Interests:
Signaling mechanisms in airway epithelium

Summary:
Inhaled bacteria and viruses, as well as irritants such as cigarette smoke, occupational hazardous materials and allergens, are deposited in the airways and result in inflammatory changes. The airway epithelium attempts to defend the organism by mounting defenses, and the airway epithelial surface becomes the 'battlefront' of interaction between the 'invaders' and the epithelial 'defenses.' How does the surface epithelium mount defensive responses? We have shown that in airway epithelium activation of epidermal growth factor receptor (EGFR) leads to the production of mucins, interleukin-8 (a potent neutrophil chemoattractant), and COX2 and cyclooxygenase products. Thus, neutrophils are recruited to the airway lumen, where they can ingest and kill invading bacteria. Subsequently, the secreted mucins trap the bacteria-laden neutrophils and assist in their clearance via cough and mucociliary clearance. How are diverse epithelial cell outcomes governed? EGFR activation is known to be involved in epithelial cell migration, multiplication and differentiation. We have shown that EGFR activation increases mucin production markedly in dense, but not sparse, cultures. Further, we found that the cell surface adhesion molecule, E-cadherin, promotes EGFR- mediated mucin production in a cell density- and cell cycle-dependent fashion via a protein tyrosine phosphatase-dependent EGFR dephosphorylation. Thus, cell surface signaling is responsible for EGFR-dependent cell differentiation. Because the first contact of environmental stimuli (e.g. bacterial products) with the airways occurs at the epithelial luminal surface, we examined potential epithelial molecules capable of intercepting invaders. Airway epithelial cells express EGFR proligands attached to the epithelial luminal surface. We found that activation of metalloprotease TACE causes shedding of EGFR ligand. The released ligand binds to and activates EGFR. This provides a powerful autocrine signaling pathway. TACE is activated by reactive oxygen species (ROS). We discovered that Duox1, a dual oxidase present on the surface of airway epithelial cells, plays a critical role in EGFR activation by releasing ROS, activating TACE, releasing EGFR proligand, causing EGFR activation.