Among many intracellular players that contribute to the pathogenesis of sepsis, oxidative stress is well recognized as a major promoter of the condition. However, clinical trials of antioxidant therapy have yielded inconsistent efficacy at maximum tolerated doses.
One limitation of the currently available antioxidants is that they are globally acting agents, and lower antioxidant efficacy is speculated as possible reason for the failures. For the same reason, these antioxidants are often administered prophylactically as preventive agents rather than therapeutic regimens.
To date, the massive oxidative injury induced by sepsis remains untreatable and is a major obstacle in the field.
Because mitochondria are the main organelles generating reactive oxygen species, concentrating antioxidant activities specifically in mitochondria may enhance both efficacy and safety. We, and others, hypothesize that the newly developed mitochondria-targeted antioxidants (MTAs) may offer an opportunity for the development of a promising therapy for sepsis.
In a pneumonia-related sepsis model, our laboratory recently showed that mitochondria-targeted vitamin E protected cardiac mitochondrial structure and function, attenuated myocardial inflammation, and improved heart performance.
We are currently evaluating the therapeutic value of MTAs as a post-injury intervention using sepsis animal models. These studies will lay a solid preclinical groundwork for translation of new drugs into clinical applications.