Protective effect of USP22 against paraquat-induced lung injury via activation of SIRT1/NRF2 pathway

Abstract

Introduction: The nonselective herbicide Paraquat (PQ) is broadly used in agricultural production. However, PQ has severe toxicity in humans and results in over 90% of death due to lack of effective therapy strategies. Ubiquitin Specific Peptidase 22 (USP22) is a deubiquitinase and it exerts a vital role in regulating ROS production. This study aimed to study the effect of USP22 on PQ-induced lung injury and investigate the precise mechanism. Methods: The lung injury model was induced by treating with PQ. Hematoxylin and eosin (HE) staining and lung wet/dry ratio were conducted to assess lung tissue injury. Myeloperoxidase (MPO) activity was detected to evaluate neutrophil infiltration in the lung tissues. Superoxidase dismutase (SOD) activity and Malondialdehyde (MDA) content were measured to determine oxidative damage. Cell viability and cell apoptosis were detected using MTT assay and Flow cytometry. Results: PQ caused lung tissue damage and increased lung wet/dry ratio. PQ increased the MPO activity and MDA content, and decreased SOD activity. USP22 was down-regulated in PQ-treated mice. Besides, overexpression of USP22 alleviated PQ-induced cell apoptosis and oxidative damage in vitro. Furthermore, overexpression of USP22 increased the expression of Sirtuin 1 (SIRT1)/nuclear factor E2-related factor 2 (NRF2). Down-regulation of SIRT1 reversed the beneficial influence of overexpressed USP22 on PQ-induced cell apoptosis and oxidative damage. Moreover, overexpression of USP22 attenuated PQ induced lung injury in vivo. Conclusions: Overexpression of USP22 alleviated PQ-induced lung injury through activating SIRT1/NRF2 pathway. USP22 may be a valuable target for the treatment of PQ-induced lung injury.