The overall hypothesis of this proposal is that the cytokine, tumor necrosis factor alpha (TNFalpha) plays an important role in the pathophysiology of airway diseases, such as asthma. We propose that TNFalpha interacts with airway epithelial cells provoking enhanced intercellular adhesion molecule-1 (ICAM-1) surface and gene expression which is mediated by reactive oxygen intermediates (ROI). This proposal will investigate the complex signal transduction cascade associated with TNFalpha - induced ICAM-1 gene and surface expression. The HYPOTHESIS to be addressed in this proposal is: TNFalpha binds to a specific cell-surface receptor on airway epithelial cells activating a Pertuss-toxin (PT) sensitive G protein linked to a phosphatidylcholine-specific phospholipase C (PC-PLC). Activation of PC- PLC results in production of diacylglycerol (DAG) which activates protein kinase C (PKC). Activation of PKC activates, in turn, the oxidant sensitive nuclear transcription factors activator protein-1 (AP-1) and nuclear factor kappa B (NFkappaB). This can occur directly and/or via PKC enhancement of intracellular ROI. Thus, interactions of PKC, transcription factors NFkappaB and AP-1, and the redox state of the cells results in enhanced ICAM-1 gene and surface expression. To address this hypothesis, normal human bronchial epithelial (NBHE) cells and the immortalized human bronchial epithelial cell line (BEAS-2B) will be utilized. These studies will elucidate mechanistic aspects of interactions between the pleuripotent cytokine TNFalpha: and airway epithelial cell ICAM-1 expression. Ultimately, this information will be helpful in developing new therapies for potentially life threatening pulmonary diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL009512-03
Application #
2713935
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1996-10-12
Project End
Budget Start
1998-06-01
Budget End
1999-05-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
North Carolina State University Raleigh
Department
Anatomy/Cell Biology
Type
Schools of Veterinary Medicine
DUNS #
City
Raleigh
State
NC
Country
United States
Zip Code
27695