Abstract
Radiation-induced lung fibrosis (RILF) is a long-term adverse effect of curative radiotherapy. The accumulation of myofibroblasts in fibroblastic foci is a pivotal feature of RILF. In the study, we found the inhibitory effect of grape seed proanthocyanidins (GSPs) on irradiation-induced differentiation of human fetal lung fibroblasts (HFL1). To explore the mechanism by which GSPs inhibit fibroblast differentiation, we measured the reactive oxygen species (ROS) levels, mitochondrial function, mitochondrial dynamics, glycolysis and the signaling molecules involved in fibroblast transdifferentiation. GSPs significantly reduced the production of cellular and mitochondrial ROS after radiation. The increases in mitochondrial respiration, proton leak, mitochondrial ATP production, lactate release and glucose consumption that occurred in response to irradiation were ameliorated by GSPs. Furthermore, GSPs increased the activity of complex I and improved the mitochondrial dynamics, which were disturbed by irradiation. In addition, the elevation of phosphorylation of p38MAPK and Akt, and Nox4 expression induced by irradiation were attenuated by GSPs. Blocking Nox4 attenuated irradiation-mediated fibroblast differentiation. Taken together, these results indicate that GSPs have the ability to inhibit irradiation-induced fibroblast-to-myofibroblast differentiation by ameliorating mitochondrial dynamics and mitochondrial complex I activity, regulating mitochondrial ROS production, ATP production, lactate release, glucose consumption and thereby inhibiting p38MAPK-Akt-Nox4 pathway.
Highlights
Radiation-induced lung fibrosis (RILF) is a long-term adverse effect of curative radiotherapy
To the best of our knowledge, this study is the first report regarding the inhibitory effects of grape seed proanthocyanidins (GSPs) on irradiation-induced cell differentiation in the human lung fibroblast cell line HFL1 in vitro
We clarify that irradiation leads to increases in cellular and mitochondrial reactive oxygen species (ROS) levels, up-regulation of mitochondria respiration and ATP production, increased proton leak, increased glycometabolism, decreased mitochondrial membrane potential, disturbance of mitochondrial fission and fusion homeostasis, impaired mitochondria complex I activity, activated p38MAPK-Akt-Nox[4] pathway and lung fibroblast cell differentiation
Summary
Radiation-induced lung fibrosis (RILF) is a long-term adverse effect of curative radiotherapy. Grape seed extract can reduce silica-induced and bleomycin-induced pulmonary fibrosis in rats[17], and GSPs protect mice from RILI by inhibiting the TGF-β1/ Smad3/Snail signaling pathway, scavenging hydroxyl radicals (OH) and modulating the levels of RILI-associated cytokine (interferon-γ, IL-4 and IL-13) derived from Th1/Th2 cells[18]. Taken together, these results show that GSPs have strong anti-oxidation, anti-fibrosis and anti-cancer effects against lung disease. Whether GSPs ameliorate irradiation-induced pulmonary fibrosis by affecting the main source of ROS derived from the mitochondrial electron transport chain (ETC) has not yet been reported
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