Redox-mediated gene therapies for environmental injury: approaches and concepts

Cellular redox state has been increasingly recognized as a critical component of stress-induced cellular responses and disease. Inherent in these responses are reactive oxygen species (ROS), which inflict direct cellular damage in addition to acting as intracellular second messengers modulating signal transduction pathways. These intracellular highways of communication are critical in determining cell fates and whole-organ responses following environmental injury. Although gene therapy for inherited and acquired disorders has exploded in the last decade, the application of gene therapeutic approaches for transient pathologic conditions resulting from environmental stress is just beginning to be recognized. This review will summarize the theoretical and practical applications of gene therapy for the treatment of environmental injury by modulating redox-activated cellular responses. Several approaches can be utilized to achieve this goal. These include the application of gene targeting to modulate the cellular redox state directly by expressing recombinant genes capable of degrading ROS at pathophysiologic important subcellular sites. The use of mitochondrial superoxide dismutase (MnSOD), which degrades superoxides arising from ischemia/reperfusion injury, is one example of this approach. MnSOD serves as a "garbage disposal" for potentially toxic ROS prior to cellular injury and the activation of signal transduction cascades important in whole-organ pathology and inflammation. In contrast, some ROS have been suggested to have beneficial effects on cellular responses following environmental injury. Hence, expressing the nitrogen oxygen synthetase gene (NOS) to enhance the levels of nitric oxide (NO.) and augment the beneficial effects of this compound has also been suggested as a useful redox-modulating gene therapy approach. Lastly, indirect intervention in signal transduction pathways following environmental stress by expressing dominant inhibitory proteins of redox-activated signal transduction cascades has also been useful in modulating cellular responses to redox stress. Two such examples have utilized dominant inhibitory forms of the retinoblastoma gene product (Rb) and IkappaBalpha which prevent activation of cyclin-dependent protein kinases and NF-kappaB, respectively. Ultimately, the most efficacious therapeutic approach or combination of approaches that alter the redox responsiveness of cells and organs to environmental injury will be determined through a comprehensive understanding of the relevant pathophysiologic processes.