Background
Mast cells and neuroimmune interactions regulate the severity of intestinal radiation mucositis, a dose-limiting toxicity during radiation therapy of abdominal malignancies.
Aims
Because endocannabinoids regulate intestinal inflammation, we investigated the effect of the cannabimimetic, palmitoylethanolamide (PEA), in a mast competent (+/+) and mast cell deficient (Ws/Ws) rat model.
Methods
Rats underwent localized, fractionated intestinal irradiation and received daily injections with vehicle or PEA from 1 day before until 2 weeks after radiation. Intestinal injury was assessed non-invasively by luminol bioluminescence, and, at 2 weeks, by histology, morphometry, and immunohistochemical analysis, gene expression analysis, and pathway analysis.
Results
Compared to +/+ rats, Ws/Ws rats sustained more intestinal structural injury (p=0.01), mucosal damage (p=0.02), neutrophil infiltration (p=0.0003), and collagen deposition (p=0.004). PEA reduced structural radiation injury (p=0.02), intestinal wall thickness (p=0.03), collagen deposition (p=0.03), and intestinal inflammation (p=0.02) 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 non-mast 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.
Conclusions
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 endocannabinoid system should be explored as target for mitigating intestinal radiation injury.