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Soluble Epoxide Hydrolase as a Target for Modulation of the Inflammatory Response

  • Author(s): Fife, Kimberly L.
  • Advisor(s): Kroetz, Deanna L
  • et al.
Abstract

Epoxyeicosatrienoic acids (EETs) are derived from cytochrome P450 (CYP)-catalyzed epoxygenation of arachidonic acid and have emerged as important mediators of numerous biological effects. The major elimination pathway for EETs is through metabolism to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (Ephx2; sEH). EETs are proposed to have significant effects in the control of vascular tone and gene regulation. The current studies were designed to characterize the anti-inflammatory properties of EETs in in vitro models of inflammation and to test whether chronic inhibition or genetic disruption of sEH attenuates a lipopolysaccharide (LPS)-induced inflammatory response in vivo. EETs or overexpression of CYP2J2 did not attenuate tumor necrosis factor-α-induced expression of vascular cellular adhesion molecule-1 in human umbilical vein endothelial cells. Continuous dosing of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA), a polyethylene glycol-conjugated AUDA (AUDA-PEG), or 1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)urea (AEPU) to mice for six days significantly increased plasma EET/DHET ratios, but did not attenuate LPS-induced expression of NF-ĸB-mediated inflammatory genes in the liver or kidney, nor decrease neutrophil infiltration to the liver. Similarly, there was no attenuation of LPS-induced inflammatory gene expression in Ephx2-/- mice. In contrast, CYP eicosanoids had a modest anti-inflammatory effect on LPS- and interleukin 1β-induced inducible nitric oxide synthase expression in primary hepatocytes, in which LPS-induced expression of NF-ĸB-mediated inflammatory genes was also attenuated by chemical and genetic disruption of sEH activity. Together, these studies suggest that EETs have a modest anti-inflammatory effect in hepatocytes, but not endothelial cells, and that EETs do not affect an LPS-induced inflammatory response in vivo. These findings do not confirm previous reports of an anti-inflammatory effect of EETs. Despite these generally negative findings, several observations suggested that EETs may still play an important role in the inflammatory response. First, inflammatory stimuli temporally down-regulated sEH expression and caused interesting changes in hepatic and renal CYP epoxygenase expression. LPS also induced a significant shift in plasma EET/DHET levels. In summary, these studies suggest that EETs have only a modest anti-inflammatory effect, but the CYP epoxygenase-catalyzed eicosanoid pathway may still play an important role in the inflammatory response.

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