curcumin and Idiopathic-Pulmonary-Fibrosis

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.. 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.

Topics: Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Collagen; Curcumin; Extracellular Matrix; Idiopathic Pulmonary Fibrosis; Lung; Macrophages, Alveolar; Male; Rats; Rats, Wistar; Transforming Growth Factor beta

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease. Currently, therapeutic options are limited for this fatal disease. Curcumin, with its pleiotropic effects, has been studied for its potential therapeutic utilities in various diseases, including pulmonary fibrosis. However, the detailed mechanisms have not been studied comprehensively. We conducted a next-generation sequencing and bioinformatics study to investigate changes in the profiles of mRNA and microRNA after curcumin treatment in IPF fibroblasts. We identified 23 downregulated and 8 upregulated protein-coding genes in curcumin-treated IPF fibroblasts. Using STRING and IPA, we identified that suppression of cell cycle progression was the main cellular function associated with these differentially expressed genes. We also identified 13 downregulated and 57 upregulated microRNAs in curcumin-treated IPF fibroblasts. Further analysis identified a potential microRNA-mediated gene expression alteration in curcumin-treated IPF fibroblasts, namely, downregulated hsa-miR-6724-5p and upregulated

Topics: Cell Proliferation; Cell Survival; Computational Biology; Curcumin; Fibroblasts; Gene Expression Profiling; Gene Expression Regulation; High-Throughput Nucleotide Sequencing; Idiopathic Pulmonary Fibrosis; Lung; MicroRNAs; Models, Biological; Open Reading Frames; Protein Interaction Maps; RNA, Messenger

Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease of unknown etiology with only two federally approved drug options. Given the complex molecular pathogenesis of IPF involving multiple cell types and multiple pathways, we explore the effects of a potential antifibrotic and antioxidant drug combination. Curcumin is a polyphenolic compound derived from turmeric with significant biological activity including a potential antifibrotic capacity. N-acetylcysteine (NAC) is a precursor to the antioxidant glutathione. To advance our understanding of these molecules, and to identify a clinical application, we present a small number of focused experiments that interrogates the effect of curcumin and NAC on pathways relevant to IPF in both fibroblasts and epithelial cells.. Primary epithelial cell and fibroblasts isolated from patients with IPF were challenged with a combination treatment of NAC and curcumin. Evaluation of the antifibrotic potential and effect on oxidative stress was performed through QPCR gene expression analysis and functional assays including scratch tests, viability assays, and measurement of induced reactive oxygen species.. We demonstrate that curcumin alone does have antifibrotic potential, but that effect is accompanied by proapoptotic increases in oxidative stress. Coupled with this, we find that NAC alone can reduce oxidative stress, but that epithelial cell viability is decreased through this treatment. However, co-administration of these two molecules decreases oxidative stress and maintains high cell viability in both cell types. In addition, this co-treatment maintains an antifibrotic potential.. These findings suggest a novel application for these molecules in IPF and encourage further exploration of this potential therapeutic approach.

Topics: Acetylcysteine; Antioxidants; Cell Survival; Cells, Cultured; Curcumin; Epithelial Cells; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Oxidative Stress; Polymerase Chain Reaction; Reactive Oxygen Species

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with high mortality and poor prognosis. Curcumin shows anti-inflammatory effect by suppressing pro-inflammatory cytokines and inhibiting NF-κB mediated inflammation. Here, we developed inhalable curcumin-loaded poly(lactic-co-glycolic)acid (PLGA) large porous microparticles (LPMPs) for the treatment of IPF. Curcumin LPMPs were rough and loose particles with many pores on the surfaces and channels in the inner spaces. The mean geometric diameter of them was larger than 10 µm while the aerodynamic diameter was only 3.12 µm due to their porous structures. They showed a fine particle fraction (FPF) <4.46 μm of 13.41%, 71% cumulative release after 9 h, and more importantly, they avoided uptake by alveolar macrophages. Therefore, most of released curcumin had opportunities to enter lung tissues. Rat pulmonary fibrosis models were established via once intratracheal administration of bleomycin. Curcumin powders and curcumin LPMPs were administered on Days 2, 7, 14, and 21. Curcumin LPMPs remarkably attenuated lung injuries, decreased hydroxyproline contents, reduced the synthesis of collagen I, and inhibited the expressions of TNF-α, TGF-β1, NF-κB p65 and MMP9. Moreover, curcumin LPMPs showed higher antifibrotic activity than curcumin powders. Curcumin LPMPs are a promising inhalable medication for the treatment of IPF.

Topics: Administration, Inhalation; Animals; Collagen Type I; Curcumin; Drug Carriers; Hydroxyproline; Idiopathic Pulmonary Fibrosis; Lung; Macrophages, Alveolar; Male; Matrix Metalloproteinase 9; Microspheres; Polylactic Acid-Polyglycolic Acid Copolymer; Porosity; Rats, Sprague-Dawley; Transcription Factor RelA; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on IPF and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from IPF patients. To further examine the potential usefulness of curcumin in IPF, we examined its ability to reduce fibrosis in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and IPF fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-β (TGF-β) signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive IPF therapy.

Topics: Administration, Oral; Animals; Bleomycin; Cell Differentiation; Cell Proliferation; Cells, Cultured; Collagen; Curcumin; Extracellular Signal-Regulated MAP Kinases; Fibroblasts; Humans; Idiopathic Pulmonary Fibrosis; Injections, Intraperitoneal; Lung Injury; Mice; Mice, Inbred C57BL; Phosphorylation; Signal Transduction; Smad Proteins; Transforming Growth Factor beta