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

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Abstract

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-β1 (TGF-β1) 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-β1.

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-β1.

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Acknowledgements

The authors would like to thank Dr. V. Arumugam for his help in statistical analysis and Mr V. Elango for his help in animal experiments.

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Authors and Affiliations

  1. Department of Biotechnology, Central Leather Research Institute, Chennai, India

    Punithavathi Durairaj & Mary Babu

  2. Department of Biochemistry, Central Leather Research Institute, Chennai, India

    Venkatesan Narayanan

  3. Cavinkare Pharmaceuticals, Chennai, India

    Mary Babu

  4. Biology Department, Concordia University, Montreal, Canada

    Santosh Venkatesan

  5. Montreal, Canada

    Venkatesan Narayanan

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  1. Punithavathi Durairaj
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  2. Santosh Venkatesan
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  3. Venkatesan Narayanan
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Contributions

Conceived and designed the current manuscript study: PD, VN, MB. Developed study protocols: PD, VN, MB. Data collection: PD, VN, MB. Analyzed and interpreted data: PD, VN, SV, MB. Prepared and edited the manuscript: PD, VN, SV, MB. All authors read and approved the final manuscript.

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Correspondence to Venkatesan Narayanan.

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All animals were treated with humane conditions and institutional guidelines for the care and use of animals were followed.

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Durairaj, P., Venkatesan, S., Narayanan, V. et al. Curcumin inhibition of bleomycin-induced changes in lung collagen synthesis, deposition and assembly. Mol Biol Rep 48, 7775–7785 (2021). https://doi.org/10.1007/s11033-021-06790-3

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