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Published ahead of print on October 5, 2006, doi:10.1164/rccm.200606-862OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 12, December 2006, 1352-1360

A more recent version of this article appeared on December 15, 2006
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Submitted on June 27, 2006
Accepted on October 4, 2006

All-trans-retinoic Acid Prevents Radiation- or Bleomycin-induced Pulmonary Fibrosis

Chiharu Tabata1*, Yoshio Kadokawa2, Rie Tabata3, Meiko Takahashi4, Kae Okoshi2, Yoshiharu Sakai5, Michiaki Mishima6, and Hajime Kubo4

1 HMRO, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 2 HMRO, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 3 Department of Internal Medicine, Hyogo Prefectural Tsukaguchi Hospital, Hyogo, Japan, 4 HMRO, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 5 Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan, 6 Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

* To whom correspondence should be addressed. E-mail: ctabata{at}kuhp.kyoto-u.ac.jp.

Rationale: Although radiotherapy is effective for 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. Objectives: Previously we reported that All-trans-retinoic acid (ATRA) reduced both irradiation-induced 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. Measurements: We performed histological examinations and quantitative measurements of IL-6, TGF-{beta}1 and collagen type I{alpha}1 (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 weeks 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, 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 pathological conditions involving pulmonary fibrosis.
Key words: interstitial lung disease, lung fibroblasts, cytokines




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