Resolvins suppress tumor growth and enhance cancer therapy

National Cancer Institute grants RO1 01CA170549-02 (to D. Panigrahy and C.N. Serhan), ROCA148633-01A4 (to D. Panigrahy), and GM095467 (to C.N. Serhan); the Stop and Shop Pediatric Brain Tumor Fund (to M.W. Kieran); the CJ Buckley Pediatric Brain Tumor Fund (to M.W. Kieran); Alex Lemonade Stand (to M.W. Kieran); Molly’s Magic Wand for Pediatric Brain Tumors (to M.W. Kieran); the Markoff Foundation Art-In-Giving Foundation (to M.W. Kieran); the Kamen Foundation (to M.W. Kieran); Jared Branfman Sunflowers for Life (to M.W.K.); and The Wellcome Trust program 086867/Z/08 (to M. Perretti)

Epoxyeicosanoids promote organ and tissue regeneration

Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis