All-trans-retinoic acid attenuates radiation-induced intestinal fibrosis in mice.
BACKGROUND
Intestinal fibrosis leading to severe bowel dysmobility or obstruction is a troublesome adverse effect of abdominal or pelvic radiation therapy. We have recently reported that all-trans-retinoic acid (ATRA) prevents radiation- or bleomycin-induced lung fibrosis. Here, we examined the impact of ATRA on the mouse model of radiation-induced intestinal fibrosis.


METHODS
We evaluated the histology of late radiation fibrosis in surgical samples. We then performed histological examinations and quantitative measurements of mRNA of interleukin-6 and transforming growth factor-beta(1) in intestinal tissues of irradiated mice with or without intraperitoneal administration of ATRA and investigated the effect of ATRA on the transdifferentiation and the production of collagen of irradiated human intestinal fibroblasts.


RESULTS
Human samples of late radiation enteritis showed thickened submucosa and serosa, consistent with mouse model. Administration of ATRA attenuated irradiation-induced intestinal fibrosis and reduced mRNA of interleukin-6 and transforming growth factor-beta(1). In vitro studies disclosed that ATRA suppressed the transdifferentiation of irradiated intestinal fibroblasts and diminished the production of collagen from the cells.


CONCLUSIONS
Our findings indicate that ATRA ameliorates irradiation-induced intestinal fibrosis. ATRA could be a novel approach in the treatment of fibrosis associated with chronic radiation enteritis.
Okoshi
Kae
K
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kubo
Hajime
H
Nagayama
Satoshi
S
Tabata
Chiharu
C
Kadokawa
Yoshio
Y
Hisamori
Shigeo
S
Yonenaga
Yoshikuni
Y
Fujimoto
Akihisa
A
Mori
Akira
A
Onodera
Hisashi
H
Watanabe
Go
G
Sakai
Yoshiharu
Y
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004751:Enteritis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011878:Radiotherapy / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D015850:Interleukin-6; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D014212:Tretinoin