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Purpose Effective treatment of idiopathic pulmonary fibrosis (IPF) is still difficult. Macrophages (Mφ) are closely related to IPF. M1 phenotype Mφ exhibit proinflammatory properties, M2 phenotype Mφ promote fibrogenesis. We found that pirfenidone (PFD), a representative medication of IPF, suppresses lung fibrosis through M2 polarization. Furthermore, liposomal clodronate (LC) is reported to suppress lung fibrosis by depleting Mφ. This study aimed to investigate the effects of combined LC and PFD on lung fibrosis and M2 Mφ polarization and populations. Method Rats were randomly divided into five groups: sham, bleomycin (BLM), PFD, LC, and PFD+LC. Following intratracheal instillation of BLM, rats were orally administered PFD daily. Rats were administered LC intravenously at 7 days and sacrificed at 14 days. Fibrosis and Mφ polarization and populations were analyzed in lung. Results Fibrosis and M2 marker levels were increased in BLM group, whereas PFD, LC, and PFD+LC groups showed significantly suppressed fibrosis and M2 markers. However, there were no synergistic effects of PFD+LC. Conclusion PFD or LC regulated lung fibrosis and M2 markers, but the suppressive effect on lung fibrosis and M2 Mφ polarization and populations was not be enhanced by the combination of PFD and LC. [ABSTRACT FROM AUTHOR]

Purpose The etiology of idiopathic pulmonary fibrosis (IPF) is still largely unknown and effective treatment is difficult. Pirfenidone (PFD) is a representative medication used to treat IPF, although its anti-fibrotic mechanism is unclear. Researchers reported PFD (> 100 µg/ml) significantly suppressed fibroblast growth in vitro. However, clinically, the Cmax of PFD in the blood is approximately 10 µg/ml. From this discrepancy, we hypothesized that there might be an additional mechanism of PFD action besides the direct effect on fibroblasts. Macrophages (Mϕ) control fibrosis via the regulation of M1/M2 polarization. M1 Mϕ exhibit proinflammatory properties, whereas M2 Mϕ promote fibrogenesis and tissue remodeling. Therefore, the aim of this study was to investigate the effects of PFD on M1/M2 polarization. Method Rat alveolar Mϕ (NR8383) were stimulated in vitro with LPS (5 ng/ml) and IFN-γ (10 U/ml), or IL-10 (10 ng/ml) to induce M1 and M2 phenotypes, respectively. Expression of M1 markers, iNOS, SOCS3 and TNF-α, and M2 markers, mannose receptor and arginase-1, was assessed by western blotting after 24 hours in the absence or presence of PFD (10, 100 µg/ml). Additionally, 7-week-old male Wistar rats were randomly divided into sham, bleomycin (BLM), 10 and 100 mg/kg PFD groups. Following intratrachial instillation of BLM (3 mg/kg) or saline, rats were orally administered PFD daily. Rats were killed at 14 days post-BLM and the polarization of Mϕ in pulmonary tissues analyzed. Results Treatment with LPS+INF-γ or IL-10 significantly increased the level of M1 or M2 markers respectively. PFD significantly reduced M2 marker expression at both 10 and 100 µg/ml, whereas it showed no significant effect on M1 marker expression. Moreover, M2 marker expression was increased in the rats of the BLM-treated groups. Notably, the level of M2 markers decreased significantly in the 10 and 100 mg/kg PFD groups compared with that of the BLM groups. Conclusions These results suggest PFD suppresses lung fibrosis through regulation of M2 Mp at clinically relevant concentrations. [ABSTRACT FROM AUTHOR]

Objectives S-allyl cysteine (SAC) is the most abundant compound in aged garlic extracts (AGEs). AGE has been reported to ameliorate the oxidative damage implicated in a variety of diseases. However, the effects of SAC have not been established in liver cirrhosis. The aim of this study was to examine the survival and the effect of therapeutic administration of SAC in the established liver fibrosis by chronic carbon tetrachloride (CCl 4 ) administration in rats. Materials & Methods Male Wistar rats (4 weeks age) were used. Cirrhosis was induced by chronic CCl 4 (2 ml/kg, 25% in corn oil, twice a week) intraperitoneal administration. Four weeks after CCl 4 treatment, SAC or cysteine compounds (cysteine, N-acethyl cysteine) were given by mixed diets for 8 weeks (CCl 4 :total 12 weeks) or longer (survival rate). Results CCl 4 administration elevated plasma alanine aminotransferase, plasma lipid peroxidation, liver hydroxyproline, and liver transforming growth factor (TGF)-beta at 12 weeks. SAC markedly normalized these changes induced by CCl 4 than other cysteine compounds. Furthermore, SAC improved survival in a dose-dependent manner following consecutive CCl 4 administration. The inhibitory mechanisms may be associated with a decrease in the profibrogenic cytokine, TGF-beta as well as the antioxidative properties of SAC. Conclusion Therapeutic administration of SAC improved liver fibrosis developed by CCl 4 and survival rate. These findings suggest SAC is a beneficial candidate for therapeutic agents on the liver cirrhosis. [ABSTRACT FROM AUTHOR]