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

Horizontal Medical Research Organization (HMRO), and Departments of Respiratory Medicine and Surgery, Graduate School of Medicine, Kyoto University, Kyoto; and Department of Internal Medicine, Hyogo Prefectural Tsukaguchi Hospital, Hyogo, Japan

Correspondence and requests for reprints should be addressed to Chiharu Tabata, M.D., HMRO, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, Japan 606–8501. E-mail: ctabata{at}kuhp.kyoto-u.ac.jp

Rationale: 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.

Objectives: 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.

Measurements: We performed histologic examinations and quantitative measurements of IL-6, transforming growth factor (TGF)-₁, and collagen type I1 (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-₁, and collagen from IMR90 cells, and (2) IL-6–dependent proliferation and TGF-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.

Key Words: cytokines • interstitial lung disease • lung fibroblasts

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Pulmonary fibrosis caused by radiation therapy for lung cancer and of unknown etiology is characterized by progressive worsening in pulmonary function, leading to a high incidence of death. To date, there has been little progress toward effective preventive and therapeutic strategies. What This Study Adds to the Field The data provide a rationale to explore clinical use of all-trans-retinoic acid for the prevention of radiation-induced lung fibrosis and other pulmonary fibrosis.

 

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