Interleukin-8 (IL-8) is a proinflammatory peptide secreted by activated endothelial cells. Vascular injury frequently results from excessive IL-8 secretion during spesis, trauma, or ischemia-reperfusion injury. Nitric oxide (NO), which has many important physiological roles, can serve an anti-inflammatory role under conditions of intense endothelial activation but may be proinflammatory under other conditions and promote IL-8 secretion. Research performed by the applicant suggests that NO may have different regulatory actions on IL-8 gene expression depending on the activation state of the endothelium.
The aims of the proposal are (1) to characterize the role of NO in stimulus-specific regulation of IL-8 expression in activated in vitro endothelium; (2) to define promoter regions of the IL-8 gene necessary for IL-8 induction in resting endothelium; (3) to identify transcription factors involved in mediating NO's effects on endothelial IL-8 expression; and (4) to use site-directed mutagenesis to confirm identity and activity of transcription factors conferring NO-responsiveness in promoter constructs. A number of different molecular techniques will be used to accomplish these aims. There is still an incomplete understanding of NO's regulation of inflammation, yet human trials of NO therapy for inflammatory injury of the lung are under way. A great deal remains to be learned about NO's role in the inflammatory process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061359-03
Application #
6330172
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Garfinkel, Susan J
Project Start
1998-12-01
Project End
2002-11-30
Budget Start
2000-12-12
Budget End
2001-11-30
Support Year
3
Fiscal Year
2001
Total Cost
$201,424
Indirect Cost
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Alzoghaibi, Mohammad A; Walsh, Scott W; Willey, Amy et al. (2004) Linoleic acid induces interleukin-8 production by Crohn's human intestinal smooth muscle cells via arachidonic acid metabolites. Am J Physiol Gastrointest Liver Physiol 286:G528-37
Natarajan, Ramesh; Fisher, Bernard J; Fowler 3rd, Alpha A (2003) Regulation of hypoxia inducible factor-1 by nitric oxide in contrast to hypoxia in microvascular endothelium. FEBS Lett 549:99-104
Natarajan, Ramesh; Fisher, Bernard J; Jones, Drew G et al. (2002) Reoxygenating microvascular endothelium exhibits temporal dissociation of NF-kappaB and AP-1 activation. Free Radic Biol Med 32:1033-45
Natarajan, Ramesh; Fisher, Bernard J; Jones, Drew G et al. (2002) Atypical mechanism of NF-kappaB activation during reoxygenation stress in microvascular endothelium: a role for tyrosine kinases. Free Radic Biol Med 33:962
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Natarajan, R; Ghosh, S; Fisher, B J et al. (2001) Redox imbalance in Crohn's disease intestinal smooth muscle cells causes NF-kappaB-mediated spontaneous interleukin-8 secretion. J Interferon Cytokine Res 21:349-59
Fowler 3rd, A A; Fisher, B J; Sweeney, L B et al. (1999) Nitric oxide regulates interleukin-8 gene expression in activated endothelium by inhibiting NF-kappaB binding to DNA: effects on endothelial function. Biochem Cell Biol 77:201-8