Alveolar Epithelial Inter-alpha-trypsin Inhibitor Heavy Chain 4 Deficiency Associated With Senescence-regulated Apoptosis by Particulate Air Pollution

Abstract

Background: Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) is considered a type II acute-phase protein; however, the role of ITIH4 in the lungs after exposure to fine particulate matter (PM2.5) remains unclear. The objective of this study was to investigate the role of ITIH4 in the lungs in response to PM2.5 exposure.Results: ITIH4 expression in bronchoalveolar lavage fluid (BAL) of 47 healthy subjects and of SD rats exposed to PM2.5 was determined, and the underlying anti-apoptotic and matrix-stabilizing pathways in A549 cells by diesel exhaust particles (DEPs) were also investigated. First, we observed that an interquartile range (IQR) increase in PM2.5 accounted for a decrease of 2.673 ng/mL in ITIH4, an increase of 1.104 pg/mL in 8-isoprostane, and an increase of 6.918 pg/mL in interleukin (IL)-6 in human BAL. Increases in 8-isoprostane and IL-6 in the lungs and decreases in ITIH4 in the BAL, lungs, and serum were observed after PM2.5 exposure. ITIH4 was correlated with lung lysates and BAL samples (r=0.377, p<0.01), whereas ITIH4 was correlated with IL-6 in BAL (r=-0.420, p<0.01). ITIH4 expression was significantly reduced in alveolar epithelial cells by PM2.5. ITIH4 expression decreased after DEP exposure in a dose-dependent manner. A decrease in sirtuin 1 (Sirt1) and increases in phosphorylated extracellular signal-regulated kinase (p-ERK) and caspase-3 were observed after DEP exposure. Conclusions: In conclusion, PM2.5 decreased ITIH4 in the lungs, which was associated with alveolar epithelial cell senescence and apoptosis. ITIH4 could be a vital protein in regulating alveolar destruction, and its deficiency occurs due to PM2.5.