It has recently been shown that the radical nitric oxide (NO) is a previously unrecognized key player in many pathophysiological conditions of relevance to surgery, shock, and many other clinically important phenomena. Many (if not most) of these conditions involve cell and tissue injury from reactive oxidative species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radical. Numerous studies in diverse disciplines have shown that NO can result in either dramatic protection or enhancement of injury. The overall purpose of the work described in this proposal is to utilize one well-developed and well-defined system, the isolated rat hepatocyte, to uncover the factors which determine whether NO will be protective or damaging in oxidative injury. The major hypothesis in this work is that the outcome (protective vs. damaging) of NO/ROS interactions in cells is determined by (1) which of the many possible chemical/biochemical NO/ROS interactions in the cell predominate under specific conditions and (2) the biological defensive responses mounted by cells when pre-exposed to small nontoxic amounts of these reactive species. The two Specific Aims based on this hypothesis are: 1) Identify which specific chemical/biochemical interactions within cells determine the protective vs. damaging effects of NO on oxidative injury. By utilizing effectors of specific biochemical steps in oxidative injury, identification will be accomplished of those steps which are modulated by NO and thus result in its protective and also damaging actions in isolated hepatocytes. 2) Identify the protective responses induced by pre-exposure to small amounts of NO/ROS which cause resistance to the damaging effects of a subsequent oxidative injury. Pre-exposure of isolated hepatocytes to a small amount of NO or ROS induces resistance to a second otherwise toxic treatment, which involves upregulation of new protein(s) synthesis. By determining the phenotypic and genotypic changes in cells induced by this pre-exposure, the specific protective mechanisms which are upregulated in this defensive response will be identif d.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK046935-09
Application #
6735296
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Doo, Edward
Project Start
1993-08-01
Project End
2004-02-29
Budget Start
2002-07-01
Budget End
2003-02-28
Support Year
9
Fiscal Year
2002
Total Cost
$121,669
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Lancaster Jr, Jack R (2006) Nitroxidative, nitrosative, and nitrative stress: kinetic predictions of reactive nitrogen species chemistry under biological conditions. Chem Res Toxicol 19:1160-74
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Schopfer, Francisco J; Baker, Paul R S; Giles, Gregory et al. (2005) Fatty acid transduction of nitric oxide signaling. Nitrolinoleic acid is a hydrophobically stabilized nitric oxide donor. J Biol Chem 280:19289-97
Lancaster Jr, Jack R (2003) Sickle cell disease: loss of the blood's WD40? Trends Pharmacol Sci 24:389-91
Brookes, Paul S; Kraus, David W; Shiva, Sruti et al. (2003) Control of mitochondrial respiration by NO*, effects of low oxygen and respiratory state. J Biol Chem 278:31603-9
Joshi, Mahesh S; Ferguson Jr, T Bruce; Han, Tae H et al. (2002) Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions. Proc Natl Acad Sci U S A 99:10341-6
Lancaster Jr, Jack R (2002) Reaping of nitric oxide by sickle cell disease. Proc Natl Acad Sci U S A 99:552-3
Liu, Xiaoping; Samouilov, Alexandre; Lancaster Jr, Jack R et al. (2002) Nitric oxide uptake by erythrocytes is primarily limited by extracellular diffusion not membrane resistance. J Biol Chem 277:26194-9
Thomas, D D; Liu, X; Kantrow, S P et al. (2001) The biological lifetime of nitric oxide: implications for the perivascular dynamics of NO and O2. Proc Natl Acad Sci U S A 98:355-60
Joshi, M S; Lancaster Jr, J R; Liu, X et al. (2001) In situ measurement of nitric oxide production in cardiac isografts and rejecting allografts by an electrochemical method. Nitric Oxide 5:561-5

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