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Digestive diseases and sciences

Palmitoylethanolamide regulates development of intestinal radiation injury in a mast cell-dependent manner.


PMID 24848354

Abstract

Mast cells and neuroimmune interactions regulate the severity of intestinal radiation mucositis, a dose-limiting toxicity during radiation therapy of abdominal malignancies. Because endocannabinoids (eCB) regulate intestinal inflammation, we investigated the effect of the cannabimimetic, palmitoylethanolamide (PEA), in a mast competent (+/+) and mast cell-deficient (Ws/Ws) rat model. Rats underwent localized, fractionated intestinal irradiation, and received daily injections with vehicle or PEA from 1xa0day before until 2xa0weeks after radiation. Intestinal injury was assessed noninvasively by luminol bioluminescence, and, at 2xa0weeks, by histology, morphometry, and immunohistochemical analysis, gene expression analysis, and pathway analysis. Compared with +/+ rats, Ws/Ws rats sustained more intestinal structural injury (pxa0=xa00.01), mucosal damage (pxa0=xa00.02), neutrophil infiltration (pxa0=xa00.0003), and collagen deposition (pxa0=xa00.004). PEA reduced structural radiation injury (pxa0=xa00.02), intestinal wall thickness (pxa0=xa00.03), collagen deposition (pxa0=xa00.03), and intestinal inflammation (pxa0=xa00.02) in Ws/Ws rats, but not in +/+ rats. PEA inhibited mast cell-derived cellular immune response and anti-inflammatory IL-6 and IL-10 signaling and activated the prothrombin pathway in +/+ rats. In contrast, while PEA suppressed nonmast cell-derived immune responses, it increased anti-inflammatory IL-10 and IL-6 signaling and decreased activation of the prothrombin pathway in Ws/Ws rats. These data demonstrate that the absence of mast cells exacerbate radiation enteropathy by mechanisms that likely involve the coagulation system, anti-inflammatory cytokine signaling, and the innate immune system; and that these mechanisms are regulated by PEA in a mast cell-dependent manner. The eCB system should be explored as target for mitigating intestinal radiation injury.