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Clifford Byungho Kim, Eiichi Hasegawa, Saori Inafuku, Deeba Husain, Joan W Miller, Kip M Connor; Cytochrome P450 lipid metabolites alter leukocyte kinetics in a mouse model of choroidal inflammation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2313. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Systemic leukocyte recruitment from blood vessels into tissues is a key process in many inflammatory ocular conditions, such as the development of choroidal neovascularization (CNV) in advanced age-related macular degeneration. Systemic leukocytes attach and roll along endothelial cells via adhesion molecules, such as intercellular cell-adhesion molecules (ICAM) or selectins. We previously found that omega fatty acid metabolites from the cytochrome P450 (CYP) pathway are integral to attenuating CNV severity. To explore mechanisms for this finding, this study examines how CYP-derived lipid metabolites affect leukocyte dynamics under inflammatory ocular conditions.
A 532 nm laser was used to induce CNV in C57BL/6 mice. Directly after laser treatment, mice were given daily intraperitoneal injections, for 3 to 7 days, of CYP-derived omega fatty acid metabolites: epoxydocosapentaenoic acid (EDP), epoxyeicosaquatraenoic acid (EEQ), or epoxyeicosatrienoic acid (EET). 3 days post-laser, an autoperfused microflow chamber assay was used to measure leukocyte rolling velocity in the blood, and fluorescence-activated cell sorting (FACS) of blood leukocytes was used to determine the expression of CD11b and CD18 (cell adhesion molecules). 7 days post-laser, real-time PCR of CNV lesions isolated via laser-capture dissection was conducted to determine expression of E-selectin and ICAM-1.
Mice administered EEQ or EDP had higher leukocyte rolling velocities, while mice administered EET had lower rolling velocities, compared to mice administered PBS (P<0.05, n=3 mice/group). From FACS analysis, CD11b and CD18 expression decreased in mice administered EDP and EEQ, respectively, while CD18 expression increased in mice administered EET, compared to mice administered PBS (P<0.05, n=10 mice/group). Finally, PCR analysis of isolated CNV lesions showed decreased expression of E-selectin and ICAM-1 in mice administered EEQ (P<0.05, n=6 mice/group), while mice administered EET showed increased ICAM-1 (P<0.001, n=6 mice/group), compared to mice administered PBS.
CYP-derived lipid metabolites EEQ and EDP decrease leukocyte adhesion ability, while EET increases leukocyte adhesion. The ability of these lipid metabolites to modulate adhesion molecule expression and leukocyte rolling velocity, and thus leukocyte recruitment, may influence disease severity in ocular inflammatory diseases.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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