Changes in energy metabolism and macrophage polarization: Potential mechanisms of arsenic-induced lung injury

Abstract Exposure to arsenic is epidemiologically associated with increased lung disease. In detailing the mechanism by which arsenic exposure leads to disease, studies have emphasized that metabolic reprogramming and immune dysfunction are related to arsenic-induced lung injury. However, the association between the mechanisms listed above is not well understood. Thus, the current study aimed to investigate the interaction of energy metabolism and macrophage polarization, by which arsenic exposure adversely induced lung injury in both in vitro and human studies. First, we confirmed a shift to glycolytic metabolism resulting from mitochondrial dysfunction. This shift was accompanied by an increase in the levels of phosphorylated PDHE1α (S293) and PDK1 and a concomitant marked increase in several key markers of the HIF-1α signaling pathway (HIF-1α, p-PKM2, GLUT1 and HK-2). In addition, utilizing an in vitro model in which lung epithelial cells are cultured with macrophages, we determined that arsenic treatment polarizes macrophages towards the M2 phenotype through lactate. In the human study, the serum lactate and TGF-β levels were higher in arsenic-exposed subjects than that in reference subjects (t= 4.50, 6.24, both p