Role of Nrf2 and Autophagy in Acute Lung Injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.

Keywords: Acute lung injury; Nrf2; autophagy; oxidative stress.

Conflict of interest statement

CONFLICT OF INTEREST

The authors have no conflict of interest to disclose.

Figures

Fig. 1. Nrf2 and autophagy are activated during ALI/ARDS

During ALI, production of reactive oxygen species activates Nrf2 and autophagy.Nrf2 pathway. The transcription factor Nrf2 binds to Keap1-Cul3-Rbx1 E3 ubiquitin ligase complex to be ubiquitinated and degraded. During ALI/ARDS, ROS modify cysteine 151 in Keap1 (C151), affecting its interaction with Nrf2. As a result, Nrf2 is no longer ubiquitinated and is stabilized. Newly synthesized Nrf2 accumulates in the cytosol, translocates to the nucleus, dimerizes with small Maf proteins, and binds to the antioxidant response element (ARE) in the regulatory regions of its target genes to promote their transcription (Canonical Nrf2 activation). Nrf2 can also be regulated by autophagy during ALI/ARDS. The autophagy substrate protein p62 binds to Keap1, sequestering it into the autophagosome and allowing for Nrf2 accumulation (Non-canonical Nrf2 activation). Autophagy pathway. ALI/ARDS induce autophagy, a bulk degradation pathway that occurs in three main stages: i) initiation, ii) elongation, and iii) fusion. Initiation involves the formation of the phagophore, which then elongates to encapsulate damaged proteins and organelles in a double membrane bound autophagosome. The autophagosome then fuses with the lysosome, and the damaged cargo is degraded by lysosomal hydrolases.