| The excessive production of reactive oxygenated species (ROS) such as in infection not only directly causes vascular endothelial cell damage but are known to stimulate the overproduction of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which play important roles in the pathogenesis of septic shock. One of the reactive oxygenated species, nitrous oxide precipitates systemic hypotension leading to circulatory collapse. The reactive oxygenated species therefore provide for a therapeutic target in the treatment of septic shock. The natural antagonist antioxidants to reactive oxygenated species toxicity include 1. superoxide dismutase and 2. catalase. Both are highly efficient in their catalytic conversions of 1. 4O2- + 4H+→H2O2 + O2 and 2. 2H2O2→2H2O + O2 respectively. Catalase and superoxide dismutase can be readily overwhelmed by excessive production of ROS. Therapeutic use of these antioxidants has been limited by their suboptimal intracellular delivery and short biological half-lives. By microencapsulating these antioxidants in an albumin matrix this project sought to increase the stability and enhance endothelial intracellular uptake of the antioxidants to antagonize the effects of excessive ROS production and thus septic shock.;We report enhanced intracellular uptake of microencapsulated catalase and dose-dependent inhibition of pro-inflammatory cytokines in vitro. We further report catalase inhibition of nitric oxide in vitro and cytokines in ex vivo and in vivo endotoxic shock models. Finally, we report the development of a novel technique for content analysis of microencapsulated antisense NF-κB oligonucleotides using ATR-FTIR. |
