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Activation of NF-kB by cigarette smoke

Institution: University of California, Davis
Investigator(s): Richart Harper, M.D.
Award Cycle: 1999 (Cycle 8) Grant #: 8KT-0092 Award: $224,217
Subject Area: Pulmonary Disease
Award Type: New Investigator Awards
Abstracts

Initial Award Abstract
There are many ways in which the body responds to toxins such as cigarette smoke. One way is through the formation and storage of protective chemicals that prevent injury before it occurs. Antioxidants such as Vitamin E and Vitamin C, and the chemicals they help to synthesize, are good examples of this mechanism. Another manner in which the body responds to toxins is by elimination. There are many systems in the body that are able to trap and the remove harmful elements. Another mechanism to respond to injury is through the production of protective proteins, or genes. This gene production is dependent on signals that allow the cell to recognize the presence of the toxin and to communicate the appropriate response that is needed. Finally, when injury does occur the body has many well balanced systems to ensure that repair takes place. All of these are important in protecting against injury and activating repair.

Of specific interest is the individual variability to tobacco smoke. With respect to smoking related lung diseases such as emphysema and lung cancer, there is clear evidence that cigarette smoke is one of the major risk factors for the development of both. Yet, only a minority of all cigarette smokers will develop either lung disease. There currently is not a clear explanation of why some individuals are partially protected against the pulmonary effects of cigarette smoke, while others are acutely sensitive to its effects. There may be individual differences in the protective and reparative mechanisms that were outlined above.

This particular research project will attempt to identify potential differences in individuals that will explain the variability that is observed. Specifically, we will focus on the signaling pathways that recognize the presence of cigarette smoke and are able to direct the cell to respond appropriately We plan to examine a protein, NF KB, whose role is to increase the production of specific genes. Some of these genes are responsible for responding to inflammation and cellular injury. Our hypothesis is that NF KB is important in the response of lungs to cigarette smoke. We plan to carefully examine the molecular events that occur after cells are exposed to cigarette smoke using NF KB as our focal point. We will initially use lung cells in isolation. Once we are able to describe the events that occur in isolated cells, we will determine if similar events can be observed in whole lungs. We will compare smoke exposed and non smoke exposed cells and tissues. With this work, we hope to identify important differences between non smokers and smokers hat may lead to future preventative measures or new therapeutic options.
Publications

Mechanisms of signal transduction in tobacco smoke induced by gene expression in airway epithelium
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yoneda K, Harper RW, Chmiel K, Wu R ABS
Yr: 2001 Vol: 163 Nbr: 3 Abs: A544 Pg:

Regulation of thioredoxin gene expression by vitamin A in human airway epithelial cells.
Periodical: American Journal of Respiratory Cell and Molecular Biology Index Medicus:
Authors: Chang WH, Reddy SPM, Di YPP, Yoneda K, Harper R, and Wu R ART
Yr: 2001 Vol: 26 Nbr: Abs: Pg: 627-635

Molecular cloning and characterization of a human novel gene that is retinoic acid-inducible and encodes a secretory protein specific in upper respiratory tracts, SPURT.
Periodical: Journal of Biological Chemistry Index Medicus:
Authors: Di P, Harper R, Zhao Y, Pahlavan N, and Wu R, ART
Yr: 2002 Vol: Nbr: Abs: Pg:

Selective activation of the AP-1, but not the NF-kappaB, transcription factor by tobacco smoke in the regulation of gene expression in human airway epithelium.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Harper RW, Xu CH, Yoneda K, Chmiel K, Chang MM-J, Zhao YH, and Wu R ABS
Yr: 2000 Vol: 161 Nbr: 3 Abs: Pg: A536

Upregulation of JNK-1 MAPK pathway by tobacco smoke.
Periodical: American Journal of Respiratory and Critical Care Medicine Index Medicus:
Authors: Yoneda K, Harper RW, Chmiel K, Xu CH, Chang M M-J, Zhao YH, and Wu R ABS
Yr: 2001 Vol: 163 Nbr: 5 Abs: Pg: A341

Identification of a novel MAGE D2 antisense RNA transcript in human tissues.
Periodical: Biochemistry and Biophysics Research Communications Index Medicus:
Authors: Harper RW, Xu C, Di Y-P, Chen Y, Privalsky M, Wu R ART
Yr: 0 Vol: Nbr: Abs: Pg: