Palmitoylethanolamide regulates development of intestinal radiation injury in a mast cell-dependent manner.
BACKGROUND
Mast cells and neuroimmune interactions regulate the severity of intestinal radiation mucositis, a dose-limiting toxicity during radiation therapy of abdominal malignancies.


OBJECTIVE
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.


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 noninvasively by luminol bioluminescence, and, at 2 weeks, by histology, morphometry, and immunohistochemical analysis, gene expression analysis, and pathway analysis.


RESULTS
Compared with +/+ 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 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.


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 eCB system should be explored as target for mitigating intestinal radiation injury.
Division of Radiation Health, University of Arkansas for Medical Sciences (UAMS), 4301 West Markham, Slot 522-10, Little Rock, AR, 72205, USA, WangJunru@uams.edu.
Junru
J
Wang
Junying
J
Zheng
Ashwini
A
Kulkarni
Wen
W
Wang
Sarita
S
Garg
Paul L
PL
Prather
Martin
M
Hauer-Jensen
D000577:Amides; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D063388:Endocannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004983:Ethanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation; D007413:Intestinal Mucosa / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000528:radiation effects*; D052016:Mucositis / Q000209:etiology / Q000517:prevention & control*; D010169:Palmitic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D000577:Amides; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D004983:Ethanolamines; D010169:Palmitic Acids; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D016212:Transforming Growth Factor beta; C005958:palmidrol