Arsenic-induced lung inflammation and fibrosis in a rat model: Contribution of the HMGB1/RAGE, PI3K/AKT, and TGF-β1/SMAD pathways.

Abstract An increasing number of studies have shown that arsenic exposure increases the risk of lung cancer as well as a variety of non-malignant respiratory diseases, including bronchitis and tracheobronchitis. HMGB1 is widely expressed in a variety of tissues and cells and is involved in the pathological processes of many lung diseases through binding to the corresponding receptors and activating the downstream signaling pathways. However, the exact role of HMGB1/RAGE in arsenic-induced lung injury remains unknown. The aim of this study was to investigate whether HMGB1/RAGE and its activated downstream pathways are involved in the process of arsenic exposure-induced lung injury in rats. In this study, an animal model of oral exposure to arsenic was induced using 2.5, 5 and 10 mg/kg NaAsO2. The results showed that capillary permeability (LDH, TP, ACP, and AKP) was increased in the arsenic exposure groups, resulting in cell damage; this was accompanied by acute inflammation marked by significant neutrophil infiltration. Meanwhile, obvious histopathological damage, including thickening of the lung epithelium, increased infiltration of inflammatory cells, rupture of the alveolar wall, swelling of the mitochondria, and chromatin agglutination was observed by H&E staining and transmission electron microscopy. Furthermore, the results confirmed that the expressions of HMGB1 and RAGE in lung tissue were enhanced, and protein expression of PI3K, p-AKT, IL-1β, IL-18, and MMP-9 was increased in lung homogenates from the arsenic-exposed groups compared to the control group. Finally, Masson's staining results revealed arsenic-induced fibrosis and collagen deposition. Moreover, a significant increase in key fibrosis factors, including TGF-β1, p-SMAD2, p-SMAD3, and SMAD4 was observed in the lung homogenates in arsenic-exposed groups. In conclusion, the current study demonstrates that sub-chronic arsenic exposure triggers the inflammatory response and collagen fiber deposition in rat lung tissue. The potential mechanism may be closely related to activation of the pro-inflammatory-related HMGB1/RAGE pathway and initiation of the PI3K/AKT and TGF-β1/SMAD pathways.