title: Grape seed proanthocyanidins prevent irradiation-induced differentiation of human lung fibroblasts by ameliorating mitochondrial dysfunction.
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.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
authors.forename: XiaoHong
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Fangqin
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China.
authors.forename: Qunfang
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, College of Pharmacy, Third Military Medical University, Chongqing, 400038, China. pharma821@163.com.
authors.forename: XiaoHong
authors.initials: X
authors.lastname: Chen
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D005720:Gamma Rays / Q000009:adverse effects; D006019:Glycolysis; D056604:Grape Seed Extract / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000166:cytology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D044945:Proanthocyanidins / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D056604:Grape Seed Extract; C511402:Grape Seed Proanthocyanidins; D047908:Intracellular Signaling Peptides and Proteins; D044945:Proanthocyanidins; D017382:Reactive Oxygen Species