Abstract
Purpose :
Metabolites of long-chain polyunsaturated fatty acids generated by the cytochrome P450 (CYP) pathway have potent anti-angiogenic effects in neovascular eye disease. Specifically, epoxyeicosatetraenoic acids (EEQs) alleviate choroidal neovascularization (CNV) by suppressing inflammation. However, EEQs are rapidly broken down by the soluble epoxide hydrolase (sEH), and sEH products are pro-inflammatory. We therefore generated an analog of 17,18-EEQ, known as C21, which lacks an expoxidation site and therefore cannot be broken down by sEH. In the present study, we assessed anti-angiogenic and anti-inflammatory effects of C21 in laser-induced CNV, and identified novel systemic immunomodulatory effects.
Methods :
CNV was induced by laser photocoagulation in C57BL/6J mice, and C21 was administered intraperitoneally (i.p., 50 mg/kg/day) immediately after photocoagulation and daily thereafter. At day 7, CNV lesion size, lesion edema, vascular leakage, and immune cell recruitment were measured. Serum concentrations of C21 were measured to determine serum half-life of C21 in mice receiving i.p. injection. To determine if the protective effects of C21 were systemic or local, peritoneal cells of donor mice receiving vehicle or C21 were transferred to untreated recipient mice, and CNV disease severity was assessed in recipient mice.
Results :
C21 administration significantly decreased CNV disease severity, decreasing neovascular lesion size, lesion edema, and lesion vascular leakage. Further, C21 decreased immune cell recruitment to CNV lesions. Pharmacokinetic studies demonstrated a relatively short serum half-life of C21 in mice receiving i.p. injections, prompting us to investigate whether the effects of C21 were localized to the retina, or rather were systemic, modulating immune cell differentiation and/or activation. Interestingly, adoptive transfer of peritoneal cells from C21-treated donor mice to naïve recipient mice decreased CNV disease severity in recipient mice, suggesting C21 plays a systemic role in CNV resolution that may be due in part to immunomodulation.
Conclusions :
Together, these data demonstrate that EEQs modulate immune cell recruitment to CNV lesions, suppressing inflammation and subsequent neovascularization. C21, which is resistant to breakdown by sEH, may be a particularly effective therapeutic modality for neovascular AMD.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.