Pirfenidone is a representative medication to treat interstitial pulmonary fibrosis. Researchers reported pirfenidone (>100 μg/ml) significantly suppressed fibroblast growth in vitro. However, clinically, the maximum concentration of pirfenidone in the blood is approximately 10 μg/ml. We hypothesized there might be an additional mechanism of pirfenidone to fibroblasts indirectly. Macrophages are known to control the activation of fibroblasts via the regulation of inflammatory M1 and suppressive M2 polarization. The aim of this study was to investigate the effects of pirfenidone on alveolar macrophage polarization. Rat alveolar macrophages (NR8383) were stimulated in vitro with lipopolysaccharide (LPS) + interferon (IFN)-γ, or interleukin (IL)-4 + IL-13. Expression of M1 and M2 markers and supernatant's levels of TGF-β1 were assessed after pirfenidone treatment (0-100 μg/ml). Treatment with LPS + INF-γ or IL-4 +IL-13 significantly increased the expression of M1 and M2 markers, respectively. In macrophage polarization assays, pirfenidone significantly reduced the expression of M2 markers at concentrations greater than 10 μg/ml but had no effect on the expression of M1 markers. At these concentrations, pirfenidone significantly reduced TGF-β1 levels in NR8383 culture supernatants. In rat lung fibroblasts treated with NR8383 culture supernatants, pirfenidone significantly suppressed proliferation, and the collagen mRNA and protein levels. In conclusion, our results demonstrated that pirfenidone suppressed polarization to M2 macrophages at clinically relevant concentrations and suppressed the rat lung fibroblasts fibrogenic activity.
CITATION STYLE
Toda, M., Mizuguchi, S., Minamiyama, Y., Yamamoto-Oka, H., Aota, T., Kubo, S., … Takemura, S. (2018). Pirfenidone suppresses polarization to M2 phenotype macrophages and the fibrogenic activity of rat lung fibroblasts. Journal of Clinical Biochemistry and Nutrition, 63(1), 58–65. https://doi.org/10.3164/jcbn.17-111
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