Ionizing radiation induces iNOS-mediated epithelial dysfunction in the absence of an inflammatory response.
Ionizing radiation induces intestinal epithelial hyporesponsiveness to secretagogues through an unknown mechanism. We investigated the role of the inducible isoform of nitric oxide (NO) synthase (iNOS)-derived NO in radiation-induced hyporesponsiveness. C57BL/6 mice were sham treated or exposed to 10-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 microM). Transport studies were also repeated in iNOS-deficient mice. White blood cell counts were significantly lower in irradiated mice, and there was no inflammatory response 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. Colons from irradiated wild-type, but not iNOS-deficient, mice exhibited a significant reduction in the responsiveness of the tissue to EFS and forskolin. The hyporesponsiveness was reversed by L-N(6)-(1-iminoethyl)lysine, 1400W, and dexamethasone treatments. iNOS-derived NO mediates colonic hyporesponsiveness 3 days after irradiation in the mouse in the absence of an inflammatory response.
Freeman
S L
SL
Gastrointestinal Research Group and Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
MacNaughton
W K
WK
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000201:enzymology* / Q000502:physiology / Q000528:radiation effects*; D004558:Electric Stimulation; D004751:Enteritis / Q000209:etiology; D005720:Gamma Rays; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000502:physiology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D002712:Chlorides; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D005576:Colforsin; D009569:Nitric Oxide; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse