Up-Regulation of Endothelin Type A Receptor in Human and Rat Radiation Proctitis: Preclinical Therapeutic Approach With Endothelin Receptor Blockade
- Laboratoire de Radiopathologie, SRBE/DRPH, Institut de Radioprotection et de Surete Nucleaire, Fontenay-aux-roses (France)
- Departement de Pathologie, Hopital Universitaire de Rouen (France)
Purpose: Rectum radiation damage and fibrosis are often associated with radiation therapy of pelvic tumors. The endothelin (ET) system has been implicated in several fibrotic diseases but never studied in the context of gastrointestinal radiation damage. This study assessed modifications in ET type 1 (ET-1), ET type A receptor (ET{sub A}), and ET type B receptor (ET{sub B}) localization and/or expression in irradiated human rectal tissue and in a rat model of delayed colorectal injury. We also evaluated the therapeutic potential of long-term ET receptor blockade. Methods and Materials: Routine histological studies of sections of healthy and radiation-injured human rectum tissue were done; the sections were also immunostained for ET{sub A} and ET{sub B} receptors. The rat model involved the delivery of 27 Gy in a single dose to the colons and rectums of the animals. The ET-1/ET{sub A}/ET{sub B} expression and ET{sub A}/ET{sub B} localization were studied at 10 weeks postexposure. The abilities of bosentan and atrasentan to protect against delayed rectal injury were also investigated. Results: The immunolocalization of ET{sub A} and ET{sub B} in healthy human rectums was similar to that in rat rectums. However, strong ET{sub A} immunostaining was seen in the presence of human radiation proctitis, and increased ET{sub A} mRNA levels were seen in the rat following colorectal irradiation. Immunostaining for ET{sub A} was also strongly positive in rats in areas of radiation-induced mucosal ulceration, atypia, and fibroproliferation. However, neither bosentan nor atrasentan prevented radiation damage to the rectum when given long term. The only effect seen for atrasentan was an increased number of sclerotic vessel sections in injured tissues. Conclusions: As the result of the overexpression of ET{sub A}, radiation exposure deregulates the endothelin system through an 'ET{sub A} profile' in the human and rodent rectum. However, therapeutic interventions involving mixed or specific ET{sub A} receptor blockade do not prevent radiation damage. Further studies are necessary to identify the precise roles of ET in the gastrointestinal response to radiation exposure.
- OSTI ID:
- 21276834
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 74, Issue 2; Other Information: DOI: 10.1016/j.ijrobp.2008.12.086; PII: S0360-3016(09)00240-5; Copyright (c) 2009 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
Similar Records
Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK
Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling