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

Horizontal Medical Research Organization, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Japan.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 01/2007; 174(12):1352-60. DOI: 10.1164/rccm.200606-862OC
Source: PubMed


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.

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    • "The inflammation process leads to the release of cytokines including interleukin-6 (IL-6), which operates through specific hepatic receptors to prevent the synthesis of albumin.[34] On the other hand, IL-6, through a positive autocrine feedback loop, stimulates the proliferation of lung fibroblasts.[3637] "
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    • "However, 20% of these patients develop radiation-induced pulmonary injury (RILI). The effectiveness of radiotherapy for thoracic malignancies is limited by the occurrence of RILI[2], which has no effective treatment or prophylaxis yet[3]. RILI is usually divided into two stages, namely, early radiation pneumonitis and late fibrosis. "
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    • "Moreover, it has been recently shown that RA, when administered to adult animals, triggers some genes normally active during lung development, thus ameliorating both functions and structure of damaged lung [21]–[23]. Finally, retinoids are molecular inducers of cell differentiation in many organs and may influence the expression of intermediate filaments such as keratins in different cell types [24]–[26], including MSCs and embryonic stem cells [27], [28]; in addition, RA can reduce the fibrosis occurring after lung injury by down-regulating cytokine secretion and directly inhibiting the proliferation of fibroblasts [29], [30]. "
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