Bi-directional regulation of TGF-β/Smad pathway by arsenic: A systemic review and meta-analysis of in vivo and in vitro studies

Abstract

BackgroundArsenic exposure can cause fibrosis of organs including the liver, heart and lung. It was reported that TGF-β/Smad pathway played a crucial role in the process of fibrosis. However, the mechanism of arsenic-induced fibrosis through TGF-β/Smad signaling pathway has remained controversial. ObjectiveA systematic review and meta-analysis was performed to clarify the relationship between arsenic and TGF-β/Smad pathway, providing a theoretical basis of fibrosis process caused by arsenic. MethodsA meta-analysis was used to reveal a correlation between arsenic and fibrosis markers of TGF-β/Smad pathway, including 47 articles of both in vivo and in vitro studies. (Standardized Mean Difference) SMD was employed to compare and analyze the combined effects. When I2 > was 50%, random effect model was selected and subgroup analysis was used to explore the source of heterogeneity. ResultsArsenic exposure up-regulated the expression of TGF-β1, p-Smad2/3, α-SMA, Collagen1/3 and FN. The dose-response relationship showed that low dose (≤5 μmol/L) arsenic exposure up-regulated the expression of TGF-β1, whereas high doses had a tendency to down-regulate that of TGF-β1. Subgroup analysis showed that low or short-term arsenic exposure induced the expression of TGF-β1 and fibrosis markers. ConclusionThe results indicated that arsenic activates the TGF-β/Smad pathway and induced fibrosis. The mechanism is related to the up-regulation of NADPH oxidase and ROS accumulation. However, high-dose arsenic exposure may inhibit this pathway.