Bacterial sepsis remains a leading cause of mortality and critical illness worldwide. To date, no specific treatment has been approved for sepsis despite intense research. Insufficient understanding of the inflammatory response that occurs during septic shock has led to numerous clinical trials intended to blunt the immune process, none of which have been successful. Recently, alternative strategies that boosts host defenses have gained attention.
Our lab recently showed that lack of a critical antioxidant enzyme, glutathione peroxidase-1 (GPx1) leads to a greater likelyhood of survival of bacterial challenge, strongly suggestive of a role for oxidative stress and hydrogen peroxide in particular, in the enhanced bacterial killing by the host. Indeed, our data showed a significant role for reactive oxygen species (ROS)- mediated activation of the major cytokine producing platform, the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, in this process.
Expanding on our initial findings our new research proposal has three main goals:
- To assess the effects of the pharmacological inhibition of glutathione peroxidase 1 in a preclinical model of septic shock.
- To unravel the mechanistic roles of various reactive oxygen species and their dedicated antioxidant enzymes.
- To discriminate between the effects of GPx1 inhibition/gene knockout in immune cells and in parenchymal cells, especially lung epithelial cells during pneumonia.
These studies are expected to show the importance of targeting the antioxidant response during sepsis as a novel strategy to lessen the clinical burden of septic shock in patients for whom the burden of mortality and morbidity is still very high despite intensive anti-inflammatory drug regimens.