Up-regulation of endothelin type a receptor in human and rat radiation proctitis: preclinical therapeutic approach with endothelin receptor blockade.
OBJECTIVE
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(A)), and ET type B receptor (ET(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
Routine histological studies of sections of healthy and radiation-injured human rectum tissue were done; the sections were also immunostained for ET(A) and ET(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(A)/ET(B) expression and ET(A)/ET(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(A) and ET(B) in healthy human rectums was similar to that in rat rectums. However, strong ET(A) immunostaining was seen in the presence of human radiation proctitis, and increased ET(A) mRNA levels were seen in the rat following colorectal irradiation. Immunostaining for ET(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(A), radiation exposure deregulates the endothelin system through an "ET(A) profile" in the human and rodent rectum. However, therapeutic interventions involving mixed or specific ET(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.
Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-roses, France.
Nicolas
N
Jullien
Karl
K
Blirando
Fabien
F
Milliat
Jean-Christophe
JC
Sabourin
Marc
M
Benderitter
Agnès
A
François
D000818:Animals; D000077868:Atrasentan; D000077300:Bosentan; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D006801:Humans; D008297:Male; D011349:Proctitis / Q000378:metabolism* / Q000517:prevention & control; D011759:Pyrrolidines / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011832:Radiation Injuries / Q000378:metabolism* / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D017466:Receptors, Endothelin; D012007:Rectum / Q000098:blood supply / Q000528:radiation effects; D013449:Sulfonamides / Q000627:therapeutic use; D015854:Up-Regulation
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011759:Pyrrolidines; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan; D000077868:Atrasentan