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

• Published in: American journal of respiratory and critical care medicine Vol. 174; no. 12; pp. 1352 - 1360
• Main Authors: Tabata, Chiharu, Kadokawa, Yoshio, Tabata, Rie, Takahashi, Meiko, Okoshi, Kae, Sakai, Yoshiharu, Mishima, Michiaki, Kubo, Hajime
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15-12-2006; American Lung Association; American Thoracic Society
• Subjects: Acids; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Antineoplastic agents; Biological and medical sciences; Bleomycin - adverse effects; Cancer therapies; Cell growth; Cells, Cultured; Chemotherapy; Collagen; Collagen - biosynthesis; Collagen Type I - analysis; Cytokines; Female; Fibroblasts; Fluorescent Antibody Technique; Gamma rays; Growth factors; Humans; Intensive care medicine; Interleukin-6 - analysis; Kinases; Laboratory animals; Leukemia; Lung - chemistry; Lung - drug effects; Lung - radiation effects; Lung cancer; Lung diseases; Medical research; Medical sciences; Mice; Mice, Inbred C57BL; Mortality; Pharmacology. Drug treatments; Pneumology; Polymerase chain reaction; Proteins; Pulmonary arteries; Pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - pathology; Pulmonary Fibrosis - prevention & control; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Radiation therapy; Transforming Growth Factor beta1 - analysis; Tretinoin - therapeutic use; Tumor necrosis factor-TNF; Japan; Antineoplastic agent; Lung disease; Intensive care; Peptides; Respiratory disease; Retinoid; Cytokine; Antibiotic; Bleomycin; Pulmonary fibrosis; Glycopeptide; interstitial lung disease; lung fibroblasts; Interstitial pneumonitis; cytokines; Fibroblast; Resuscitation; Tretinoin
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200606-862OC

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.
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.
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.
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.
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.