Aberrant tissue repair and persistent
inflammation following
oxidant-mediated
acute lung injury (ALI) can lead to the development and progression of various
pulmonary diseases, but the mechanisms underlying these processes remain unclear.
Hyperoxia is widely used in the treatment of
pulmonary diseases, but the effects of this
oxidant exposure in patients undergoing recovery from ALI are not clearly understood. Nrf2 has emerged as a crucial
transcription factor that regulates
oxidant stress through the induction of several detoxifying
enzymes and other
proteins. Using an experimental model of
hyperoxia-induced ALI, we have examined the role of
oxidant stress in resolving
lung injury and
inflammation. We found that when exposed to sublethal (72 h)
hyperoxia, Nrf2-deficient, but not wild-type mice, succumbed to death during recovery. When both genotypes were exposed to a shorter period of
hyperoxia-induced ALI (48 h), the lungs of Nrf2-deficient mice during recovery exhibited persistent cellular injury, impaired alveolar and endothelial cell regeneration, and persistent cellular infiltration by macrophages and lymphocytes.
Glutathione (GSH) supplementation in Nrf2-deficient mice immediately after
hyperoxia remarkably restored their ability to recover from
hyperoxia-induced damage in a manner similar to that of wild-type mice. Thus, the results of the present study indicate that the Nrf2-regulated transcriptional response and, particularly GSH synthesis, is critical for lung tissue repair and the resolution of
inflammation in vivo and suggests that a dysfunctional Nrf2-GSH pathway may compromise these processes in vivo.