Abstract
Ozone (O3) plays an extremely important role in airway inflammation by generating reactive oxygen species (ROS) including hydrogen peroxide, then promoting redox actions and causing oxidative stress. Evidences indicate that TRPC6 (canonical transient receptor potential channel 6) is a redox-regulated Ca2+ permeable nonselective cation channel, but its role in the setting of oxidative stress-related airway inflammation remains unknown. Here, we found that both TRPC6−/− mice and mice pretreated with SAR7334, a potent TRPC6 inhibitor, were protected from O3-induced airway inflammatory responses. In vitro, both knockdown of TRPC6 expression with shRNA and TRPC6 blockage markedly attenuated the release of cytokines IL-6 and IL-8 induced by O3 or H2O2 in 16HBE cells (human bronchial epithelial cell line). Treatment with O3 or H2O2 enhanced TRPC6 protein expression in vivo and vitro. We also observed that TRPC6-dependent increase of intracellular Ca2+ concentration ([Ca2+]i) was triggered by H2O2, which consisted of the release from intracellular calcium store and the influx of extracellular Ca2+ and could be further strengthened by 6-h O3 exposure in both 16HBE cells and HBEpiCs (primary human bronchial epithelial cells). Moreover, we confirmed that the activation of MAPK signals (ERK1/2, p38, JNK) was required for the inflammatory response induced by O3 or H2O2 while only the phosphorylation of ERK pathway was diminished in the TRPC6-knockdown situation. These results demonstrate that oxidative stress regulates TRPC6-mediated Ca2+ cascade, which leads to the activation of ERK pathway and inflammation and could become a potential target to treat oxidative stress-associated airway inflammatory diseases.
Highlights
IntroductionChen et al Cell Death and Disease (2020)11:170 airway inflammatory responses
Abnormal airway inflammation resulting from exposure to various oxidizing ambient pollutants is one of the most common and significant pathogenesis for numerous respiratory diseases, including asthma, chronic obstructiveCa2+, an essential secondary messenger relevant to a variety of cellular processes, plays a key role in mediatingOfficial journal of the Cell Death Differentiation AssociationChen et al Cell Death and Disease (2020)11:170 airway inflammatory responses
The major findings of our study demonstrated for the first time that TRPC6 acted as an oxidative stress sensor in bronchial epithelium and mediated oxidants-induced inflammatory responses via activating ERK
Summary
Chen et al Cell Death and Disease (2020)11:170 airway inflammatory responses. Rises in [Ca2+]i in pulmonary cells are essential for the activation of inflammatory signal transduction proteins and transcriptions factors[1,2,3]. ROS has been found to be responsible for the activity of various calcium channels[7]. Compared with WT mice, TRPM2−/− mice exhibits enhanced gastric inflammation after infecting with Helicobacter pylori, which is owing to intracellular calcium overloading and augmented oxidative stress[9]. These findings suggest that the abnormality of [Ca2+]i suffered from ROS in pulmonary cells may be involved in airway inflammation
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