Ionizing radiation induces iNOS-mediated epithelial dysfunction in the absence of an inflammatory response

Ionizing radiation induces intestinal epithelial hyporesponsiveness to secr etagogues through an unknown mechanism. We investigated the role of the ind ucible isoform of nitric oxide (NO) synthase (iNOS)-derived NO in radiation -induced hyporesponsiveness. C57BL/6 mice were sham treated or exposed to 1 0-Gy gamma-radiation and were studied 3 days later. Tissues were mounted in Ussing-type diffusion chambers to assess chloride secretion in response to electrical field stimulation (EFS) and forskolin (10 mu M). Transport stud ies were also repeated in iNOS-deficient mice. White blood cell counts were significantly lower in irradiated mice, and there was no inflammatory resp onse as shown by myeloperoxidase activity and histological assessment. iNOS mRNA levels and nitrate/nitrite concentrations were significantly elevated in irradiated colons. iNOS immunoreactivity localized to the epithelium. C olons from irradiated wild-type, but not iNOS-deficient, mice exhibited a s ignificant reduction in the responsiveness of the tissue to EFS and forskol in. The hyporesponsiveness was reversed by L-N-6-(1-iminoethyl)lysine, 1400 W, and dexamethasone treatments. iNOS-derived NO mediates colonic hyporespo nsiveness 3 days after irradiation in the mouse in the absence of an inflam matory response.