Inflammation is a fundamental process which plays an integral role in the pathogenesis of numerous disease states in humans. Nuclear factor kappa B (NF-?B) is a central mediator of the inflammatory response via transcriptional activation of cytokine, chemokine and cellular adhesion molecule expression. Consequently, identification of novel strategies aimed at inhibition of this pathological process offers substantial therapeutic potential. Arachidonic acid is oxidatively metabolized by cytochrome P450 (CYP) epoxygenases from the CYP2J and CYP2C subfamilies to epoxyeicosatrienoic acids (EETs) in hepatic and extra-hepatic tissue. The EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to less active dihydroxyeicosatrienoic acids (DHETs). Arachidonic acid is also metabolized to 20-hydroxyeicosatetraenoic acid (20-HETE) by CYP ?- hydroxylases from the CYP4A and CYP4F subfamilies. Recent evidence has demonstrated that CYP-derived EETs and 20-HETE possess anti- and pro-inflammatory effects, respectively. However, the contribution of CYP-mediated eicosanoid metabolism to the regulation of inflammation in vivo has not been rigorously characterized. We hypothesize that the functional balance between CYP epoxygenase- and CYP ?- hydroxylase-mediated arachidonic acid metabolism is integral to the regulation of NF-?B-mediated inflammatory responses in vivo, and modulation of this balance in favor of the CYP epoxygenase pathway offers substantial therapeutic potential. The primary objectives of this proposal are to: (1) define the impact of the inflammatory response on hepatic and extra-hepatic CYP-mediated eicosanoid metabolism, (2) define the functional role of CYP epoxygenase-mediated EET biosynthesis and sEH-mediated EET hydrolysis in the regulation of inflammation, and (3) characterize the relative impact of CYP epoxygenase and CYP ?- hydroxylase pathway modulation on inflammatory responses in vivo. This project will utilize novel transgenic and knock-out mice and pharmacological tools to manipulate CYP-mediated eicosanoid metabolism in vivo, while characterizing NF-?B-mediated inflammatory responses using established molecular biology and analytical techniques. Collectively, this series of novel experiments will define the mechanistic contribution of CYP epoxygenase-derived EETs and CYP ?-hydroxylase-derived 20-HETE to the regulation of hepatic and extra-hepatic inflammatory responses in vivo, and facilitate the development of new anti-inflammatory strategies with potential therapeutic application to numerous disease states in humans.

Public Health Relevance

Inflammation is a fundamental process which plays an integral role in the pathogenesis of numerous diseases in humans. Completion of this research project will define the contribution of cytochrome P450-mediated eicosanoid metabolism to the regulation of inflammation in vivo, characterize the underlying mechanisms, and facilitate the development of novel therapeutic strategies aimed at inhibition of inflammation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088199-04
Application #
8271446
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$335,452
Indirect Cost
$101,635
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Schuck, Robert N; Zha, Weibin; Edin, Matthew L et al. (2014) The cytochrome P450 epoxygenase pathway regulates the hepatic inflammatory response in fatty liver disease. PLoS One 9:e110162
Oni-Orisan, Akinyemi; Alsaleh, Nasser; Lee, Craig R et al. (2014) Epoxyeicosatrienoic acids and cardioprotection: the road to translation. J Mol Cell Cardiol 74:199-208
Zha, Weibin; Edin, Matthew L; Vendrov, Kimberly C et al. (2014) Functional characterization of cytochrome P450-derived epoxyeicosatrienoic acids in adipogenesis and obesity. J Lipid Res 55:2124-36
Cheng, Jennifer; Edin, Matthew L; Hoopes, Samantha L et al. (2014) Vascular characterization of mice with endothelial expression of cytochrome P450 4F2. FASEB J 28:2915-31
Zhang, Wenri; Davis, Catherine M; Edin, Matthew L et al. (2013) Role of endothelial soluble epoxide hydrolase in cerebrovascular function and ischemic injury. PLoS One 8:e61244
Panigrahy, Dipak; Kalish, Brian T; Huang, Sui et al. (2013) Epoxyeicosanoids promote organ and tissue regeneration. Proc Natl Acad Sci U S A 110:13528-33
Theken, Katherine N; Deng, Yangmei; Schuck, Robert N et al. (2012) Enalapril reverses high-fat diet-induced alterations in cytochrome P450-mediated eicosanoid metabolism. Am J Physiol Endocrinol Metab 302:E500-9
Panigrahy, Dipak; Edin, Matthew L; Lee, Craig R et al. (2012) Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice. J Clin Invest 122:178-91
Deng, Yangmei; Edin, Matthew L; Theken, Katherine N et al. (2011) Endothelial CYP epoxygenase overexpression and soluble epoxide hydrolase disruption attenuate acute vascular inflammatory responses in mice. FASEB J 25:703-13
Edin, Matthew L; Wang, Zhongjing; Bradbury, J Alyce et al. (2011) Endothelial expression of human cytochrome P450 epoxygenase CYP2C8 increases susceptibility to ischemia-reperfusion injury in isolated mouse heart. FASEB J 25:3436-47

Showing the most recent 10 out of 13 publications