Vascular oxidative stress and inflammation are intertwined mutually propagating mechanisms of tissue injury in many human maladies including cardiovascular, neurological and pulmonary acute dangerous critical care conditions. Much evidence implicate reactive oxygen species produced by endothelial cells in these conditions in response to cytokines and other pathological agents. Antioxidants have no natural affinity to endothelium and do not quench ROS in endothelial intracellular compartments. We achieve this goal by immunotargeting antioxidants such as antioxidant enzymes (SOD and catalase) into specific sub-types of endothelial endosomes. Results of our previous and pilot studies show that this approach affords remarkable protection in animal models of acute pulmonary inflammation. Further, new findings of collaborative dual targeting open avenues for concomitant delivery of synergizing SOD and catalase. In this project that capitalizes on the wealth of our experience in targeted antioxidants and on unique collaborative opportunities offered by PENN Lung Transplant Center, we will make the decisive steps towards translation of our approach to medical practice via pursuing the following Specific Aims.
In Aim 1 we will maximize precision and effect of targeted antioxidants by addressing them to caveolar vs clathrin endosomes.
In Aim 2 we will address the mechanism and utility of dual collaborative targeting of SOD and catalase.
In Aim 3 we will appraise protective and adverse effects of lead formulations in animals, devise translational targeted antioxidants based on clinically acceptable elements and test their targeting antioxidants in human lungs. All components of the study including unique reagents, models and methods are in place in our collaborative team. Implementation of this project will shed light on poorly understood aspects of mechanisms of vascular oxidative stress and inflammation and provide new specific and potent treatment for human pathologies involving these conditions.
Our goal is to develop effective treatment for vascular inflammation and oxidative stress that represent a common pathological mechanism in many disease conditions including ischemia, stroke, sepsis and acute lung injury. The pulmonary vascular endothelium is a key target for therapeutic interventions in the latter setting. We have designed targeted antioxidants that provide specific and effective treatment of the inflamed endothelium. In this grant we will further excel these targeted antioxidants by achieving selective sub-cellular delivery, test and optimize these modalities in animal models of acute pulmonary vascular inflammation, and bring them to translation into the clinical domain.
