Curcumin inhibition of bleomycin-induced changes in lung collagen synthesis, deposition and assembly.

BACKGROUND: Idiopathic pulmonary fibrosis is characterized by progressive lung tissue remodeling and disproportionate deposition of collagenous proteins with limited therapeutic interventions. The purpose of this study was to determine whether curcumin inhibits bleomycin (BLM)-induced increases in synthesis, degradation and cross-linking of lung collagen in rats. METHODS AND RESULTS: Following a single intratracheal instillation of BLM to rats (0.75 U/100 g, sacrificed 3, 5, 7, 14 and 28 days post-BLM), lung collagen synthesis (determined by incorporation of 3H-proline) and deposition (determined by lung hydroxyproline content) progressively increased at days 7, 14 and 28 post-BLM injection. Lung lavage fluid hydroxyproline and collagenase levels (a measure of collagen turnover) were increased in BLM rats compared with control groups. In addition, BLM instillation resulted in increased concentrations of collagenase and collagenolytic cathepsin in the lungs. Furthermore, increased cross-linking (as determined by aldehyde content of acid soluble collagen), and decreased susceptibility of fibrotic lung insoluble collagen to denaturing agents occurred in BLM-injured lungs. Significant increases in alveolar macrophage (AM) release of transforming growth factor-ß1 (TGF-ß1) were noted at various time points (days 3, 5, 7, 14 and 28 post-BLM) during the development and progression of lung fibrosis in rats. Curcumin treatment to BLM rats (300 mg/kg 10 days before and daily thereafter throughout the experimental time period) was associated with marked reductions in lung collagen synthesis and deposition, BALF and lung collagenase activity, BALF hydroxyproline content and lung collagenolytic levels. Additionally, reduced levels of collagen cross-linking and enhanced susceptibility of insoluble lung collagen to denaturing agents were observed in curcumin-treated BLM rats. Finally, curcumin inhibited BLM-induced increases in AM production of TGF-ß1. CONCLUSIONS: Our data demonstrate for the first time that curcumin prevents fibrotic deposits by modulating collagen turnover, assembly and deposition in BLM-instilled rat lungs, and that curcumin treatment protects against BLM activation of macrophages by suppressing the release of TGF-ß1.

Protective effects of curcumin on bleomycin-induced changes in lung glycoproteins.

The present study investigated the therapeutic effect of curcumin on bleomycin (BLM)-induced alterations in glycoprotein components in the fibrotic lungs. Analysis of the bronchoalveolar lavage fluid (BALF) demonstrated increased fibronectin content at 3, 5, 7, and 14 days after BLM administration. Similarly, lung tissue fibronectin content revealed a progressive increase at various times (days 3, 5, 7, 14, and 28) during the development of lung fibrosis. In addition, alveolar macrophage release of fibronectin was also elevated in BLM-treated rats. Analysis of carbohydrate moieties of glycoproteins revealed an increase in total hexose, fucose, sialic acid and hexosamine levels at 7, 14, and 28 days after BLM treatment. Furthermore, the activities of lung glycosidases such as N-acetyl-ß-D-glucosaminidase, ß-glucosidase, ß-galactosidase, and ß-fucosidase in the fibrotic rats were elevated. Importantly, curcumin significantly inhibited the BLM-induced increases in BALF and lung fibronectin levels. Treatment of BLM rats with curcumin dramatically suppressed alveolar macrophage release of fibronectin. Curcumin also inhibited the increases in complex carbohydrates and glycosidases in the fibrotic lungs. These findings suggest that BLM-induced lung fibrosis is associated with accumulation of glycoproteins, and curcumin has the ability to suppress the enhanced deposition of glycoproteins in the fibrotic lung.