PARENT SESSION

Experimental and Clinical Therapeutics

(PP190) Regulation of the acute intestinal radiation response by calcitonin gene-related peptide (CGRP) and substance P (SP).

Wang, Junru^*,1, Qiu, Xiaohua¹, Kulkarni, Ashwini¹, Hauer-Jensen, Martin¹, ¹ Arkansas Cancer Research Center, Little Rock, AR

ABSTRACT- Background: Intestinal mast cells (MC) and sensory nerves (SN) are closely associated, both anatomically and functionally, and crosstalk between MC and SN is critical for mucosal homeostasis and an appropriate response to injury. Moreover, absence of MC or ablation of SN is associated with enhanced acute intestinal radiation toxicity, suggesting that neuroimmune interactions regulate the intestinal radiation response. The present study assessed the role of CGRP and SP, the two major neuropeptides released by SN, in acute intestinal radiation injury. Methods: Male Sprague-Dawley rats underwent localized X irradiation of a 4-cm loop of small bowel. Groups of rats were treated with 1) vehicle, 2) CGRP, 3) CGRP antagonist (CGRP [8-37]), 4) SP, or 5) SP antagonist (the NK-1 receptor antagonist, SR140333). All compounds were delivered subcutaneously, beginning immediately after irradiation and continuing until termination of the experiment at 2 weeks. Intestinal CGRP and SP steady-state mRNA levels were measured by real time PCR. Intestinal radiation injury was assessed using established methodology with quantitative histology, morphometry, and immunohistochemistry. Results: Steady-state CGRP and SP levels in intestinal tissue increased after irradiation. Exogenous SP administration did not affect the level of intestinal radiation injury. However, SR140333 attenuated acute structural radiation injury (RIS, intestinal wall thickness, and mucosal surface area), as well as post-radiation intestinal mucositis, smooth muscle cell proliferation, and collagen III deposition. In contrast, CGRP ameliorated and the CGRP antagonist exacerbated post-radiation structural bowel injury (RIS and serosal thickening), intestinal inflammation, and collagen III deposition. Conclusions: These data suggest that the major neuropeptides released by enteric nerves in response to injury, CGRP and SP, have opposing effects during the development of acute intestinal radiation injury. The effects of CGRP appear to be largely protective, while those of SP may be detrimental. NK-1 receptor antagonists may be useful as protective agents against intestinal radiation toxicity.

Key words: Intestine, Enteric nervous system, Substance P, Calcitonin gene-related peptide