The natural product tannic acid has anti-fibrotic effects on cultured human lung fibroblasts and in an in vivo idiopathic pulmonary fibrosis (IPF) mouse model by reducing signals from TGF-beta receptors, a new study has found.
The study, “Anti-fibrotic effects of tannic acid through regulation of a sustained TGF-beta receptor signaling,” was published in the journal Respiratory Research.
IPF is a disease characterized by scarring and structural deformation of the lungs. The disease is thought to be caused by an abnormal wound-healing response, initially triggered by a response to injury. The healing process activates many pro-inflammatory and pro-fibrotic signaling proteins, of which transforming growth factor-β1 (TGF-β1) is most well-known.
The role of TGF-β1 in wound healing is to stimulate fibroblasts, the most common cells of connective tissue, to transform into myofibroblasts, a type of cell that facilitates the wound healing process.
However, the transformation to myofibroblasts is also associated with an increase in pro-fibrotic factors that can perpetuate the healing process. As such, myofibroblasts are invariably found in the lungs of patients with IPF, leading researchers to propose that disrupting this transformation into myofibroblasts may attenuate the fibrotic response in IPF.
Tannic acid is a natural polyphenol used for staining wood and textiles, and as a treatment for burns. It has also been found to provide a protective effect against liver fibrosis in mice and cardiac fibrosis in rats, suggesting that it may be a potential treatment for IPF in humans.
To evaluate the effectiveness of tannic acid, researchers cultured fibroblast cells from human lungs, and treated them with tannic acid at two doses — 1 and 3 micromolar — in the presence of TGF-β1.
They found that tannic acid inhibits the production of two proteins associated with myofibroblast transformation — collagen-1 and smooth muscle α-actin (SMA) — in a dose-dependent manner. Also, pre-treatment with tannic acid abolished TGF-β1-induced structural deformation in lung cells.
TGF-β1 works by activating TGF-β receptors. The stimulation of these receptors subsequently activates the signaling protein Smad2, by the addition of a phosphate (phosphorylation), leading to myofibroblast transformation. The researchers found that tannic acid significantly inhibited sustained Smad2 phosphorylation induced over a 48-hour period.
To support these results, the team tested tannic acid in mice in which lung fibrosis was induced by the chemical agent bleomycin. They found that the therapeutic application of tannic acid consistently resulted in a reduction of lung fibrosis, a decrease in collagen-1 levels, and the inhibition of Smad2 phosphorylation in the lungs.
Overall, these data “demonstrate for the first time the powerful anti-fibrotic effect of tannic acid in cultured human lung fibroblasts in vitro, and in the bleomycin model of pulmonary fibrosis in vivo,” the researchers wrote, through a mechanism involving TGF-β1-induced cell signaling, and subsequent inhibition of the myofibroblast formation.
According to the researchers, the next step will be to determine if tannic acid could be an effective treatment for IPF patients.
“It would be also important to investigate if the similar effects and mechanisms of regulation of myofibroblast phenotype by tannic acid that we describe in this study would translate to human lung fibroblasts cultured from IPF patients,” they said.