AUTHOR=Tu Wei , Xiao Xiaojun , Lu Jiahua , Liu Xiaoyu , Wang Eryi , Yuan Ruyi , Wan Rongjun , Shen Yingchun , Xu Damo , Yang Pingchang , Gong Miao , Gao Peisong , Huang Shau-Ku 

TITLE=Vanadium exposure exacerbates allergic airway inflammation and remodeling through triggering reactive oxidative stress

JOURNAL=Frontiers in Immunology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1099509

DOI=10.3389/fimmu.2022.1099509

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>Metal components of environmental PM2.5 are associated with the exacerbation of allergic diseases like asthma. In our recent hospital-based population study, exposure to vanadium is shown to pose a significant risk for current asthma, but the causal relationship and its underlying molecular mechanisms remain unclear.</p></sec><sec><title>Objective</title><p>We sought to determine whether vanadium co-exposure can aggravate house dust mite (HDM)-induced allergic airway inflammation and remodeling, as well as investigate its related mechanisms.</p></sec><sec><title>Methods</title><p>Asthma mouse model was generated by using either vanadium pentoxide (V<sub>2</sub>O<sub>5</sub>) or HDM alone or in combination, in which the airway inflammation and remodeling was investigated. The effect of V<sub>2</sub>O<sub>5</sub> co-exposure on HDM-induced epithelial-derived cytokine release and oxidative stress (ROS) generation was also examined by <italic>in vitro</italic> analyses. The role of ROS in V<sub>2</sub>O<sub>5</sub> co-exposure-induced cytokine release and airway inflammation and remodeling was examined by using inhibitors or antioxidant.</p></sec><sec><title>Results</title><p>Compared to HDM alone, V<sub>2</sub>O<sub>5</sub> co-exposure exacerbated HDM-induced airway inflammation with increased infiltration of inflammatory cells and elevated levels of Th1/Th2/Th17 and epithelial-derived (IL-25, TSLP) cytokines in the bronchoalveolar lavage fluids (BALFs). Intriguingly, V<sub>2</sub>O<sub>5</sub> co-exposure also potentiated HDM-induced airway remodeling. Increased cytokine release was further supported by <italic>in vitro</italic> analysis in human bronchial epithelial cells (HBECs). Mechanistically, ROS, particularly mitochondrial-derived ROS, was significantly enhanced in HBECs after V<sub>2</sub>O<sub>5</sub> co-exposure as compared to HDM challenge alone. Inhibition of ROS with its inhibitor N-acetyl-L-cysteine (NAC) and mitochondrial-targeted antioxidant MitoTEMPO blocked the increased epithelial release caused by V<sub>2</sub>O<sub>5</sub> co-exposure. Furthermore, vitamin D<sub>3</sub> as an antioxidant was found to inhibit V<sub>2</sub>O<sub>5</sub> co-exposure-induced increased airway epithelial cytokine release and airway remodeling.</p></sec><sec><title>Conclusions</title><p>Our findings suggest that vanadium co-exposure exacerbates epithelial ROS generation that contribute to increased allergic airway inflammation and remodeling.</p></sec>