All-trans-retinoic acid prevents radiation- or bleomycin-induced pulmonary fibrosis.
BACKGROUND
Although radiotherapy is effective in treating lung cancers, resultant pulmonary injury is the main obstacle. Pulmonary fibrosis is characterized by progressive worsening in pulmonary function leading to high incidence of death. Currently, however, there has been little progress in effective preventive and therapeutic strategies.


OBJECTIVE
Previously, we reported that all-trans-retinoic acid (ATRA) reduced both irradiation-induced interleukin (IL)-6 production in lung fibroblasts and IL-6-dependent cell growth, and also directly inhibited the proliferation of lung fibroblasts after irradiation. In this study, we examined the preventive effect of ATRA on the progression of lung fibrosis both in irradiated and bleomycin-treated mice.


METHODS
We performed histologic examinations and quantitative measurements of IL-6, transforming growth factor (TGF)-beta(1), and collagen type Ialpha1 (COL1A1) in irradiated and bleomycin- treated mouse lung tissues with or without the administration of ATRA.


RESULTS
Lethal irradiation effect was reduced by intraperitoneal administration of ATRA, and the overall survival rate at 16 wk was 30.0% without ATRA (n = 11), whereas it was 81.8% (n = 10) in the treatment group (p = 0.04). In vitro studies disclosed that the administration of ATRA reduced (1) irradiation-induced production of IL-6, TGF-beta(1), and collagen from IMR90 cells, and (2) IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of ATRA on lung fibrosis. Furthermore, ATRA ameliorated bleomycin-induced fibrosis in mouse lung tissues.


CONCLUSIONS
These data may provide a rationale to explore clinical use of ATRA for the prevention of radiation-induced lung fibrosis and other pathologic conditions involving pulmonary fibrosis.
Tabata
Chiharu
C
Horizontal Medical Research Organization, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan. ctabata@kuhp.kyoto-u.ac.jp
Kadokawa
Yoshio
Y
Tabata
Rie
R
Takahashi
Meiko
M
Okoshi
Kae
K
Sakai
Yoshiharu
Y
Mishima
Michiaki
M
Kubo
Hajime
H
D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D024042:Collagen Type I / Q000032:analysis; D000090602:Collagen Type I, alpha 1 Chain; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D053773:Transforming Growth Factor beta1 / Q000032:analysis; D014212:Tretinoin / Q000627:therapeutic use*
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D015850:Interleukin-6; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D014212:Tretinoin; D003094:Collagen